Appetite control

in Journal of Endocrinology
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  • Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK

Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity.

Abstract

Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity.

Introduction

In most adults, adiposity and body weight are remarkably constant despite huge variations in daily food intake and energy expended. A powerful and complex physiological system exists to balance energy intake and expenditure, composed of both afferent signals and efferent effectors. This system consists of multiple pathways which incorporate significant redundancy in order to maintain the drive to eat. In the circulation, there are both hormones which act acutely to initiate or terminate a meal and hormones which reflect body adiposity and energy balance. These signals are integrated by peripheral nerves and brain centres, such as the hypothalamus and brain stem. The integrated signals regulate central neuropeptides, which modulate feeding and energy expenditure. This energy homeostasis, in most cases, regulates body weight tightly. However, it has been argued that evolutionary pressure has resulted in a drive to eat without limit when food is readily available. The disparity between the environment in which these systems evolved and the current availability of food may contribute to over-eating and the increasing prevalence of obesity.

Current concepts

Hypothalamic neuropeptides

In order to maintain a stable body weight over a long period of time, we must continually balance food intake with energy expenditure. The hypothalamus was first implicated in this homeostatic process over 50 years ago. Lesioning and stimulation of the hypothalamic nuclei initially suggested roles for the ventromedial nucleus as a ‘satiety centre’ and the lateral hypothalamic nucleus (LHA) as a ‘hunger centre’ (Stellar 1994). However, rather than specific hypothalamic nuclei controlling energy homeostasis, it is now thought to be regulated by neuronal circuits, which signal using specific neuropeptides. The arcuate nucleus (ARC), in particular, is thought to play a pivotal role in the integration of signals regulating appetite.

The ARC is accessible to circulating signals of energy balance, via the underlying median eminence, as this region of the brain is not protected by the blood–brain barrier (Broadwell & Brightman 1976). Some peripheral gut hormones, such as peptide YY and glucagon-like peptide 1, are able to cross the blood–brain barrier via non-saturable mechanisms (Nonaka et al. 2003, Kastin et al. 2002). However, other signals, such as leptin and insulin, are transported from blood to brain by a saturable mechanism (Banks et al. 1996, Banks 2004). Thus, the blood–brain barrier has a dynamic regulatory role in the passage of some circulating energy signals.

There are two primary populations of neurons within the ARC which integrate signals of nutritional status, and influence energy homeostasis (Cone et al. 2001). One neuronal circuit inhibits food intake, via the expression of the neuropeptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) (Elias et al. 1998a, Kristensen et al. 1998). The other neuronal circuit stimulates food intake, via the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) (Broberger et al. 1998a, Hahn et al. 1998). See Figure 1.

NPY

NPY is one of the most abundant neurotransmitters in the brain (Allen et al. 1983). Hypothalamic levels of NPY reflect the body’s nutritional status, an essential feature of any long-term regulator of energy homeostasis. The levels of hypothalamic NPY mRNA and NPY release increase with fasting and decrease after refeeding (Sanacora et al. 1990, Kalra et al. 1991, Swart et al. 2002). The ARC is the major hypothalamic site of NPY expression (Morris 1989). ARC NPY neurons project to the ipsilateral paraventricular nucleus (PVN) (Bai et al. 1985), and repeated intracerebroventricular (icv) injection of NPY into the PVN causes hyperphagia and obesity (Stanley et al. 1986, Zarjevski et al. 1993). Central administration of NPY also reduces energy expenditure, resulting in reduced brown fat thermogenesis (Billington et al. 1991), suppression of sympathetic nerve activity (Egawa et al. 1991) and inhibition of the thyroid axis (Fekete et al. 2002). It also results in an increase in basal plasma insulin level (Moltz & McDonald 1985, Zarjevski et al. 1993) and morning cortisol level (Zarjevski et al. 1993), independent of increased food intake.

Although NPY seems to be an important orexigenic signal, NPY-null mice have normal body weight and adiposity (Thorsell & Heilig 2002), although they demonstrate a reduction in fast-induced feeding (Bannon et al. 2000). This absence of an obese phenotype may be due to the presence of compensatory mechanisms or alternative orexigenic pathways, such as those which signal via AgRP (Marsh et al. 1999). It is possible that there is evolutionary redundancy in orexigenic signalling in order to avert starvation. This redundancy may also contribute to the diffculty elucidating the receptor subtype that mediates NPY-induced feeding (Raposinho et al. 2004).

NPY is part of the pancreatic polypeptide (PP)-fold family of peptides, including peptide YY (PYY) and pancreatic polypeptide (PP). This family bind to seven-transmembrane-domain G-protein-coupled receptors, designated Y1–Y6 (Larhammar 1996). Y1–Y5 receptors have been demonstrated in rat brain, but Y6, identified in mice, is absent in rats and inactive in primates (Inui 1999). The Y1, Y2, Y4 and Y5 receptors, cloned in the hypothalamus, have all been postulated to mediate the orexigenic effects of NPY. The feeding effect of NPY may indeed be mediated by a combination of receptors rather than a single one.

Administration of antisense oligonucleotides to the Y5 receptor inhibits food intake (Schaffhauser et al. 1997), and Y5 receptor-deficient mice have an attenuated response to NPY (Marsh et al. 1998). However, Y5 receptor density in the hypothalamus appears to be reduced in response to fasting and upregulated in dietary-induced obesity (Widdowson et al. 1997). In addition, antagonists to the Y5 receptor have no major feeding effects in rats (Turnbull et al. 2002), and Y5 receptor-deficient mice develop late-onset obesity, rather than the expected reduction in body weight (Marsh et al. 1998). It has been postulated that the Y5 receptor may maintain the feeding response rather than initiate feeding in response to NPY, as Y5 receptor antisense oligonucleotide decreases food intake 10 h after NPY- or PP-induced feeding, but has no effect on the initial orexigenic response (Flynn et al. 1999).

NPY-induced and fast-induced feeding is prevented by antagonists to the Y1 receptor (Kanatani et al. 1996, Wieland et al. 1998), and is reduced in Y1 receptor- knockout mice (Kanatani et al. 2000). However, like Y5 receptors, ARC Y1 receptor numbers, distribution and mRNA, are reduced during fasting, an effect which is attenuated by administration of glucose (Cheng et al. 1998). Furthermore, NPY fragments with weak affinity to the Y1 receptor still elicit a similar dose-dependent increase in food intake to NPY, suggesting that the Y1 receptor may not be mediating its effect (O’Shea et al. 1997). Y1 receptor-deficient mice are obese, but are not hyperphagic, suggesting that the Y1 receptor may affect energy expenditure rather than feeding (Kushi et al. 1998).

The presynaptic Y2 and Y4 receptors have an auto-inhibitory effect on NPY neurons (King et al. 1999, 2000). As expected, Y2 receptor-knockout mice have increased food intake, weight and adiposity (Naveilhan et al. 1999). However, Y2 receptor conditional-knockout mice (perhaps with more normal development of the neuronal circuits) have a temporarily reduced body weight and food intake, which returns to normal after a few weeks (Sainsbury et al. 2002). There is also evidence for a role of Y4 receptors in the orexigenic NPY response. PP has a relative specificity for the Y4 receptor and central administration has been shown to elicit food intake in both mice (Asakawa et al. 1999) and rats (Campbell et al. 2003).

The melanocortin system

Melanocortins, including adrenocorticotrophin and melanocyte-stimulating hormones (MSHs), are peptide-cleavage products of the POMC molecule and exert their effects by binding to the melanocortin receptor family. Levels of POMC expression reflect the energy status of the organism. POMC mRNA levels are reduced markedly in fasted animals and increased by exogenous administration of leptin, or restored by refeeding after 6 h (Schwartz et al. 1997, Swart et al. 2002). Mutations within the POMC gene or abnormalities in the processing of the POMC gene product result in early-onset obesity, adrenal insufficiency and red hair pigmentation in humans (Krude et al. 1998). The loss of one copy of the POMC gene in mice is sufficient to render them susceptible to diet-induced obesity (Challis et al. 2004).

Melanocortin 3 (MC3R) and melanocortin 4 receptors (MC4R) are found in hypothalamic nuclei implicated in energy homeostasis, such as the ARC, ventromedial nucleus (VMH) and PVN (Mountjoy et al. 1994, Harrold et al. 1999). Lack of the MC4R leads to hyperphagia and obesity in rodents (Fan et al. 1997, Huszar et al. 1997) and these receptors are implicated in 1–6% of severe early-onset human obesity (Farooqi et al. 2000, Lubrano-Berthelier et al. 2003a, 2003b). Polymorphism of this receptor has also been implicated in polygenic late-onset obesity in humans (Argyropoulos et al. 2002).

Although the involvement of the MC4R in feeding is established, the function of the MC3R is still unclear. A selective MC3R agonist has been found to have no efect on food intake (Abbott et al. 2000), and although the MC4R is influenced by energy status, the MC3R is not (Harrold et al. 1999). However, there is some evidence that both the MC3R and MC4R are able to influence energy homeostasis. The MC3R/MC4R antagonist, AgRP, is able to increase food intake in MC4R-deficient mice (Butler 2004). Mice which lack the MC3R, although not overweight on a normal diet, have increased adiposity, and seem to switch from fat to carbohydrate metabolism (Butler et al. 2000). However, MC3-null mice are obese and develop increased adipose tissue when fed on high-fat chow. MC3R mutations have been found in human subjects with morbid obesity (Mencarelli et al. 2004).

The main endogenous ligand for the MC3R/MC4R is α-melanocyte-stimulating hormone (α-MSH), which is expressed by cells in the lateral part of the ARC (Watson & Akil 1979). i.c.v. administration of agonists to the hypothalamic MC4R suppresses food intake, and the administration of selective antagonists results in hyper-phagia (Benoit et al. 2000). In addition to its effects on feeding, α-MSH also stimulates the thyroid axis (Kim et al. 2000b) and increases energy expenditure, as measured by oxygen consumption (Pierroz et al. 2002), sympathetic nerve activity and the temperature of brown adipose tissue (Yasuda et al. 2004).

The agouti mouse is hyperphagic and obese, and expresses the agouti protein ectopically, which is normally restricted to the hair follicle. The agouti protein is a competitive antagonist of α-MSH and melanocortin receptors (Lu et al. 1994). The antagonist effect on the peripheral MC1R results in a yellow coat, and its effect on the hypothalamic MC4R results in obesity (Lu et al. 1994, Fan et al. 1997).

Although the agouti protein is not normally expressed in the brain, a partially homologous peptide, AgRP, is expressed in the medial part of the ARC (Shutter et al. 1997). AgRP mRNA increases during fasting (Swart et al. 2002) and the peptide is a potent selective antagonist at the MC3R and MC4R (Ollmann et al. 1997). AgRP (83–132), the C-terminal fragment, is able to block the reduction in food intake seen with the icv administration of α-MSH and increase nocturnal food intake (Rossi et al. 1998).

Transgenic mice with ubiquitous over-expression of AgRP are obese, but with no alteration of coat colour as AgRP is inactive at the MC1R (Ollmann et al. 1997). A polymorphism in the AgRP gene in humans is associated with lower body weight and fat mass (Marks et al. 2004). Consistent with its role in energy homeostasis, AgRP and AgRP(83–132) administered icv result in hyperphagia which can persist for a week (Hagan et al. 2000, Rossi et al. 1998). Although NPY mRNA levels are reduced 6 h after refeeding, AgRP levels remain elevated (Swart et al. 2002). This prolonged response results in a greater cumulative effect on food intake than NPY, and probably involves more diverse signalling pathways than the melanocortin pathway alone (Hagan et al. 2000, 2001, Zheng et al. 2002).

Consistent with the role of AgRP as an orexigenic peptide, the reduction of hypothalamic AgRP RNA by RNA interference results in lower body weight, although this may partly be an effect of increased energy expenditure (Makimura et al. 2002). Independent of its orexigenic effects, chronic icv administration of AgRP suppresses thyrotropin-releasing hormone, reduces oxygen consumption and decreases the ability of brown adipose tissue to expend energy (Small et al. 2001, 2003).

AgRP and NPY are potent orexigenic molecules which are 90% co-localized in ARC neurons (Hahn et al. 1998, Broberger et al. 1998a). NPY may inhibit the arcuate POMC neuron via ARC NPY Y1 receptors (Fuxe et al. 1997, Roseberry et al. 2004). Activation of ARC NPY/AgRP neurons therefore potently stimulates feeding via activation of PVN NPY receptors, inhibition of the melanocortin system by ARC Y1 receptors and antagonism of MC3R/MC4R activation by AgRP in the PVN. However, it has been demonstrated that NPY/AgRP-knockout mice have no obvious feeding or body-weight defects. Furthermore, AgRP is absent from hypothalamic nuclei known to be involved in energy homeostasis, such as the VMH (Broberger et al. 1998a). This suggests there must be other signalling pathways which are capable of regulating energy homeostasis (Qian et al. 2002).

CART

CART is co-expressed with α-MSH in the ARC (Elias et al. 1998a, Kristensen et al. 1998). Neurons expressing CART are also found in the LHA and PVN (Couceyro et al. 1997). Food-deprived animals show a pronounced reduction in CART mRNA within the ARC, whereas peripheral administration of leptin to leptin-deficient ob/ob mice results in a stimulation of CART mRNA expression (Kristensen et al. 1998). An antiserum against CART peptide (1–102) and CART peptide fragment (82–103), injected icv in rats, increases feeding, suggesting that it is part of the physiological control of energy homeostasis (Kristensen et al. 1998, Lambert et al. 1998). CART(1–102) and CART(82–103) injected icv into rats inhibit both the normal and NPY-stimulated feeding response, but result in abnormal behavioural responses at high dose (Kristensen et al. 1998, Lambert et al. 1998). However, administration of CART(55–102) into discrete hypothalamic nuclei such as the ARC and ventromedial nucleus is able to increase food intake (Abbott et al. 2001). Thus, there may be more than one population of CART-expressing neurons which have different roles in feeding behaviour. For instance, NPY release could stimulate a population of CART neurons in the ARC which are orexigenic, producing positive orexigenic feedback (Dhillo et al. 2002).

Downstream pathways

Hypothalamic nuclei such as the PVN, dorsomedial hypothalamus (DMH), LHA and perifornical area receive NPY/AgRP and POMC/CART neuronal projections from the ARC (Elias et al. 1998b, Elmquist et al. 1998b, Kalra et al. 1999). These areas contain secondary neurons which process information regarding energy homeostasis. A number of signalling molecules which are expressed in these regions have been shown to be physiologically involved in energy homeostasis (see Figure 2).

PVN

The PVN integrates NPY, AgRP, melanocortin and other signals via projections it receives from a number of sites in the brain, including the ARC and nucleus of the solitary tract (NTS) (Sawchenko & Swanson 1983). The PVN is highly sensitive to administration of many peptides implicated in feeding, e.g. cholecystokinin (CCK) (Hamamura et al. 1991), NPY (Lambert et al. 1995), ghrelin (Lawrence et al. 2002), orexin-A (Edwards et al. 1999, Shirasaka et al. 2001), leptin (Van Dijk et al. 1996, Elmquist et al. 1997) and glucagon-like peptide 1 (GLP-1) (Van Dijk et al. 1996). Administration of a melanocortin agonist directly into the PVN results in potent inhibition of food intake (Giraudo et al. 1998, Kim et al. 2000a), and inhibits the orexigenic effect of NPY administration (Wirth et al. 2001), whereas, the administration of a melanocortin antagonist to the PVN results in a potent increase in food intake (Giraudo et al. 1998). Electro-physiological studies in the PVN have shown that neurons expressing NPY/AgRP attenuate inhibitory GABA-ergic signalling, whereas POMC neurons potentiate GABA-ergic signalling (Cowley et al. 1999). GABA-ergic signalling also occurs in a subpopulation of ARC NPY neurons which release GABA locally and inhibit POMC neurons.

Neuropeptides involved in appetite regulation in the PVN may also signal via AMP-activated protein kinase (AMPK), a heterodimer consisting of catalytic α-subunits and regulatory β- and γ-subunits. Multiple anorectic factors including leptin, insulin and MT-II (an MC3R/MC4R agonist) suppress α2 AMPK activity in the ARC and PVN, whereas the α2 AMPK activity is stimulated by orexigenic factors such as AgRP (Andersson et al. 2004, Minokoshi et al. 2004). A pharmacologically induced increase in the level of AMPK in the PVN results in increased food intake (Andersson et al. 2004). α2 AMPK activity may be regulated by the MC4R, as peripheral signals of energy status are unable to modulate α2 AMPK activity in MC4R-knockout mice (Minokoshi et al. 2004).

The integration of signals within the PVN intiates changes in other neuroendocrine systems. NPY/AgRP and melanocortin projections from the ARC innervate thyrotropin-releasing hormone neurons in the PVN (Legradi & Lechan 1999, Fekete et al. 2000). These projections have an inhibitory effect on prothyrotropin-releasing hormone gene expression in the PVN (Fekete et al. 2002), whereas α-MSH projections have a stimulatory effect and prevent fasting-induced inhibition of thyrotropin-releasing hormone (Fekete et al. 2000). NPY projections to the PVN also act on corticotrophin-releasing hormone-expressing neurons influencing energy homeostasis (Sarkar & Lechan 2003).

DMH

The DMH has extensive connections with other hypothalamic nuclei, including the ARC, from which it receives AgRP/NPY projections (Kalra et al. 1999). Integration of signals may also take place in the DMH, as α-MSH-positive fibres are in close proximity to NPY-expressing cells in the DMH, and melanocortin agonists attenuate DMH NPY expression and suckling-induced hyperphagia in rats (Chen et al. 2004b).

LHA/perifornical area

Other hypothalamic sites such as the LHA/perifornical area are also involved in second-order signalling. Indeed, the perifornical area has been found to be more sensitive to NPY-elicited feeding than the PVN (Stanley et al. 1993). The LHA/perifornical area contains neurons expressing melanin-concentrating hormone (MCH) (Marsh et al. 2002). Fasting increases MCH mRNA, and repeated icv administration of MCH increases food intake (Qu et al. 1996) and results in mild obesity in rats (Marsh et al. 2002). Conversely, MCH-1 receptor antagonists reduce feeding and result in a sustained reduction in body weight if administered chronically (Borowsky et al. 2002). Transgenic mice over-expressing precursor MCH are hyperphagic and develop central obesity (Marsh et al. 2002), whereas mice with a disruption of the MCH gene are hypophagic, lean and have increased energy expenditure, despite reduced ARC POMC and circulating leptin (Shimada et al. 1998, Marsh et al. 2002). Crosses of leptin-deficient ob/ob mice with MCH-null mice result in an attenuation in weight gain and adiposity compared with ob/ob mice (Segal-Lieberman et al. 2003). This perhaps infers that MCH acts downstream of leptin and POMC, and demonstrates that not all orexigenic peptides show redundancy.

Orexin A and B (or hypocretin 1 and 2) are peptide products of prepro-orexin. The peptides are produced in the LHA/perifornical area and zona incerta by neurons distinct from those which produce MCH (De Lecea et al. 1998, Sakurai et al. 1998). Orexin neurons exert their effects via wide projections throughout the brain, for example to the PVN, ARC, NTS and dorsal motor nucleus of the vagus (De Lecea et al. 1998, Peyron et al. 1998). The orexin-1 receptor, which is highly expressed in the VMH, has a much greater affinity for orexin A, whereas the orexin-2 receptor, which is highly expressed in the PVN, has comparable affinity for both orexin A and B (Sakurai et al. 1998). The prepro-orexin mRNA level is increased in the fasting state and central administration has been found to result in both orexigenic behaviour and generalized arousal (Sakurai et al. 1998, Hagan et al. 1999). Central administration of orexin A has a potent effect on feeding (Haynes et al. 1999) and vagally mediated gastric acid secretion (Takahashi et al. 1999), whereas orexin B does not. However, although icv administration of orexin A results in increased daytime feeding, there is no overall change in 24-h food intake (Haynes et al. 1999). Furthermore, chronic administration of orexin A alone does not increase body weight (Yamanaka et al. 1999).

Orexin neurons project to areas associated with arousal and attention as well as feeding, and orexin-knockout mice are thought to be a model of human narcolepsy (Chemelli et al. 1999). In circumstances of starvation, the orexin neuropeptides may mediate both an arousal response and a feeding response in order to initiate food-seeking behaviour.

Orexin may also play a role as a peripheral hormone involved in energy homeostasis. Orexin neurons, expressing both orexin and leptin receptors, have been identified in the gastrointestinal tract, and appear to be activated during starvation (Kirchgessner & Liu 1999). Orexin is also expressed in the endocrine cells in the gastric mucosa, intestine and pancreas (Kirchgessner & Liu 1999) and peripheral administration increases blood insulin levels (Nowak et al. 2000).

NPY, AgRP and α-MSH terminals are abundant in the LHA and are in contact with MCH- and orexin-expressing cells (Broberger et al. 1998b, Elias et al. 1998b, Horvath et al. 1999). Central orexin neurons also express NPY (Campbell et al. 2003) and leptin receptors (Horvath et al. 1999) and are thus able to integrate adiposity signals. Further integration of peripheral signals is provided by the large number of glucose-sensing neurons in the LHA (Bernardis & Bellinger 1996). Some studies have hypothesized a role for orexin neurons in sensing glucose levels within this region, and these have shown that hypogly-caemia induces c-Fos expression in orexin neurons (Moriguchi et al. 1999) and increases orexin mRNA levels (Cai et al. 1999). Glucose signalling also occurs in other hypothalamic nuclei such as the VMH (Dunn-Meynell et al. 1997) and in the ARC, where glucose-sensing neurons express NPY (Muroya et al. 1999). The mechanism by which the MCH and orexin neurons exert their effects on energy homeostasis has not been fully elucidated. However, it is clear that major targets are the endocrine and autonomic nervous system, the cranial nerve motor nuclei and cortical structures (Saper et al. 2002).

VMH

The VMH has long been known to play a role in energy homeostasis. Bilateral VMH lesions produce hyperphagia and obesity. The VMH receives projections from arcuate NPY-, AgRP- and POMC-immunoreactive neurons and in turn VMH neurons project to other hypothalamic nuclei (e.g. DMH) and to brain stem regions such as the NTS. NPY expression is altered in the VMH of obese mice (Guan et al. 1998) and MC4R expression is upregulated in the VMH of diet-induced obese rats (Huang et al. 2003). Recent work has demonstrated that brain-derived neurotrophic factor (BDNF) is highly expressed within the VMH, where its expression is reduced markedly by food deprivation (Xu et al. 2003), and also regulated by melanocortin agonists. Mice with reduced BDNF receptor expression or reduced BDNF signalling have significantly increased food intake and body weight (Rios et al. 2001, Xu et al. 2003). Thus, VMH BDNF neurons may form another downstream pathway through which the melanocortin system regulates appetite and body weight.

The brainstem pathways

There are extensive reciprocal connections between the hypothalamus and brainstem, particularly the NTS (Ricardo & Koh 1978, van der Kooy et al. 1984, Ter Horst et al. 1989). In addition to interacting with hypothalamic circuits, the brainstem also plays a principal role in the regulation of energy homeostasis. Like the ARC, the NTS is in close anatomical proximity to a circumventricular organ with an incomplete blood–brain barrier – the area postrema (Ellacott & Cone 2004) – and is therefore in an ideal position to respond to peripheral circulating signals, in addition to receiving vagal afferents from the gastrointestinal tract (Kalia & Sullivan 1982, Sawchenko 1983).

The NTS has a high density of NPY-binding sites (Harfstrand et al. 1986), including Y1 receptors (Glass et al. 2002) and Y5 receptors (Dumont et al. 1998). Extracellular NPY levels within the NTS fluctuate with feeding (Yoshihara et al. 1996), and NPY neurons from this region project forward to the PVN (Sawchenko et al. 1985).

There is also evidence for a melanocortin system in the NTS, separate from that of the ARC (Kawai et al. 1984). POMC-derived peptides are synthesized in the NTS of the rat (Kawai et al. 1984, Bronstein et al. 1992, Fodor et al. 1996), and caudal medulla in humans (Grauerholz et al. 1998), and these POMC neurons are activated by feeding and by peripheral CCK administration (Fan et al. 1997). The MC4R is present in the NTS (Mountjoy et al. 1994). Food intake is reduced by the administration of a MC3R/MC4R agonist to the fourth ventricle or dorsal motor nucleus of the vagus nerve, whereas MC3R/MC4R antagonists increase intake (Williams et al. 2000).

The reward pathways

The rewarding nature of food may act as a stimulus to feeding, even in the absence of an energy deficit. The sensation of reward is, however, influenced by energy status, as the subjective palatability of food is altered in the fed, compared with the fasting, states (Berridge 1991). Thus, signals of energy status, such as leptin, are able to influence the reward pathways (Fulton et al. 2000).

The reward circuitry is complex and involves interactions between several signalling systems. Opioids play an important role, as a lack of either enkephalin or β-endorphin in mice abolishes the reinforcing property of food, regardless of the palatability of the food tested. This reinforcing effect is lost in the fasted state, indicating that homeostatic mechanisms can override the hedonistic mechanisms (Hayward et al. 2002). In man, opiate antagonists are found to reduce food palatability without reducing subjective hunger (Yeomans et al. 1990, Drewnowski et al. 1992).

The dopaminergic system is integral to reward-induced feeding behaviour. The influence of central dopamine signalling on feeding is thought to be mediated by the D1 and D2 receptors (Schneider 1989, Kuo 2002). Mice which lack dopamine, due to the absence of the tyrosine hydroxylase gene, have fatal hypophagia. Dopamine replacement, by gene therapy, into the caudate putamen restores feeding, whereas replacement into the caudate putamen or nucleus accumbens restores preference for a palatable diet (Szczypka et al. 2001).

The nucleus accumbens is an important component of reward circuitry. Injections of opioid agonists and dopamine agonists into this region preferentially stimulate the ingestion of highly palatable foods such as sucrose and fat (Zhang & Kelley 2000, Zhang et al. 2003). Conversely, opioid receptor antagonists injected into the nucleus accumbens reduce the ingestion of sucrose rather than less palatable substances (Zhang et al. 2003). The reciprocal GABA-ergic connections between the nucleus accumbens and LHA may mediate hedonistic feeding by disinhibition of LHA neurons (Stratford & Kelley 1999). The MCH neurons in the LHA may reciprocally influence the reward circuitry, as the nucleus accumbens is a site which expresses MCH receptors (Saito et al. 2001).

Other systems, including those mediated by endocan-nabinoids and serotonin, may also be able to modulate both reward circuitry and homeostatic mechanisms controlling feeding. Endocannabinoids in the hypothalamus may maintain food intake via CB1 receptors, which co-localize with CART, MCH and orexin peptides (Cota et al. 2003). Defective leptin signalling is associated with high hypothalamic endocannabinoid levels in animal models (Di et al. 2001). CB1 receptors are also present on adipocytes where they appear to act directly in order to increase lipogenesis (Cota et al. 2003). CB1 receptor antagonists are currently in phase III clinical trials, and have been found to reduce appetite and body weight in humans (for a review see Black 2004). Serotonin may directly influence the melanocortin pathway in the ARC via 5-hydroxytryptamine receptors (Heisler et al. 2002). See Figure 3.

Peripheral signals of adiposity

Leptin

Leptin (Greek: thin) is a peptide hormone, secreted from adipose tissue, which influences energy homeostasis, immune and neuroendocrine function. Restriction of food intake, over a period of days, results in a suppression of leptin levels, which can be reversed by refeeding (Frederich et al. 1995, Maffei et al. 1995) or administration of insulin (Saladin et al. 1995). Production of leptin correlates positively with adipose tissue mass (Maffei et al. 1995). Circulating leptin levels thus reflect both energy stores and food intake. Exogenous leptin replacement decreases fast-induced hyperphagia (Ahima et al. 1996), and chronic peripheral administration of leptin to wild-type rodents results in reduced food intake, loss of body weight and fat mass (Halaas et al. 1995).

In addition to its effects on appetite, circulating leptin levels also affect energy expenditure in rodents (Halaas et al. 1995, Pelleymounter et al. 1995), the hypothalamo-pituitary control of the gonadal, adrenal and thyroid axes (Ahima et al. 1996, Chehab et al. 1996) and the immune response (Lord et al. 1998). A replacement dose of leptin is able to reverse the starvation-induced changes of the neuroendocrine axes in both rodents (Ahima et al. 1996) and humans (Chan et al. 2003). Thus, leptin signalling is able to integrate the body’s response to a decrease in energy stores.

Leptin is a product of the ob gene expressed predominantly by adipocytes (Zhang et al. 1994) but also at lower levels in gastric epithelium (Bado et al. 1998) and placenta (Masuzaki et al. 1997). A mutation in the ob gene, resulting in the absence of circulating leptin, leads to the hyperphagic obese phenotype of the ob/ob mouse, which can be normalized by the administration of leptin (Campfield et al. 1995, Halaas et al. 1995, Pelleymounter et al. 1995). Similarly, mutations resulting in the absence of leptin in humans cause severe obesity and hypogonadism (Montague et al. 1997, Strobel et al. 1998), which can be ameliorated with recombinant leptin therapy in both children (Farooqi et al. 1999) and adults (Licinio et al. 2004). There is a higher prevalence of obesity than expected in humans with heterozygous leptin deficiency, compared with controls. These subjects also have a greater percentage of body fat, but a lower than expected leptin level (Farooqi et al. 2001). Studies from animal models also demonstrate that one deficient copy of the leptin gene can affect body weight (Chung et al. 1998, Coleman 1979).

The leptin receptor has a single transmembrane domain and is a member of the cytokine receptor family (Tartaglia et al. 1995). The leptin receptor (Ob-R) has multiple isoforms which result from alternative mRNA splicing and post-translational processing (Chua et al. 1997, Tartaglia 1997). The different splice forms of the receptor can be divided into three classes: long, short and secreted (Tartaglia 1997, Ge et al. 2002). The long - form Ob-Rb receptor differs from the other forms of the receptor by having a long intracellular domain, which is necessary for the action of leptin on appetite (Lee et al. 1996). This intracellular domain binds to Janus kinases (JAK) (Lee et al. 1996) and to STAT3 (signal transduction and activators of transcription 3) transcription factors (Vaisse et al. 1996) required for signal transduction. The JAK/STAT pathway induces expression of a suppressor of cytokine signalling-3 (SOCS-3), one of a family of cytokine-inducible inhibitors of signalling.

Obesity in the db/db mouse is the result of a mutation within the intracellular portion of the Ob-Rb receptor, which prevents signalling (Chen et al. 1996, Lee et al. 1996). Similarly, mutations within the human leptin receptor result in early-onset morbid obesity, though less severe than that seen with leptin deficiency, and a failure to undergo puberty (Clement et al. 1998).

Circulating leptin is transported across the blood–brain barrier via a saturable process (Banks et al. 1996). Regulation of transport may be an important modulator of the effects of leptin on food intake. Starvation reduces transport, whereas refeeding increases the transport of leptin across the blood–brain barrier (Kastin & Pan 2000). The short forms of the receptor have been proposed to have a role in the transport of leptin across the blood–brain barrier (El Haschimi et al. 2000), whereas the secreted form is thought to bind to circulating leptin thus modulating its biological activity (Ge et al. 2002).

The Ob-Rb receptor is expressed within the hypothalamus (particularly ARC, VMH, DMH and LHA) (Fei et al. 1997, Elmquist et al. 1998a). Ob-Rb mRNA is expressed in the ARC by NPY/AgRP neurons (Mercer et al. 1996) and POMC/CART neurons (Cheung et al. 1997). The orexigenic NPY/AgRP neurons are inhibited by leptin, and therefore activated in conditions of low circulating leptin (Stephens et al. 1995, Schwartz et al. 1996, Hahn et al. 1998, Elias et al. 1999). Conversely, leptin activates anorexigenic POMC/CART neurons (Schwartz et al. 1997, Thornton et al. 1997, Kristensen et al. 1998, Cowley et al. 2001). The anorexic response of leptin is attenuated by administration of an MC4R antagonist, demonstrating that the melanocortin pathway is perhaps an important downstream mediator of leptin signalling (Seeley et al. 1997). Mice lacking leptin signalling in POMC neurons are mildly obese and hyperlepti-naemic, but less so than mice with a complete deletion of the leptin receptor (Balthasar et al. 2004). This suggests that POMC are important, but not essential, for leptin signalling in vitro.

The PVN, LHA VMH and medial preoptic area may be direct targets for leptin signalling as leptin receptors are found in these nuclei (Hakansson et al. 1998). Chronic hypothalamic over-expression of the leptin gene, using a recombinant adeno-associated virus vector, has demonstrated distinct actions of leptin in different hypothalamic nuclei. Leptin over-expression in the ARC, PVN and VMH results in a reduction of food intake and energy expenditure, whereas leptin over-expression in the medial preoptic area results in reduced energy expenditure alone (Bagnasco et al. 2002).

The NTS, like the ARC, contains leptin receptors (Mercer et al. 1998) and leptin administration to the fourth ventricle results in a reduction in food intake and bodyweight gain (Grill & Kaplan 2002). Peripheral administration of leptin also results in neuronal activation within the NTS (Elmquist et al. 1997, Hosoi et al. 2002). Thus leptin appears to exert its effect on appetite via both the hypothalamus and brainstem.

Although a small subset of obese human subjects have a relative leptin deficiency, the majority of obese animals and humans have a proportionally high circulating leptin (Maffei et al. 1995, Considine et al. 1996), suggesting leptin resistance. Indeed, recombinant leptin administered subcutaneously to obese human subjects has only shown a modest effect on body weight (Heymsfield et al. 1999, Fogteloo et al. 2003). Administration of peripheral leptin to rodents with diet-induced obesity fails to result in a reduction in food intake, although these rodents retain the capacity to respond to icv leptin (Van Heek et al. 1997). Exogenous leptin in mice is transported across the blood–brain barrier less rapidly in obese animals (Banks et al. 1999). Leptin resistance may be the result of a signalling defect in leptin-responsive hypothalamic neurons, as well as impaired transport into the brain. Resistance to the effects of leptin has been shown to develop in NPY neurons following chronic central leptin exposure (Sahu 2002). Furthermore, the magnitude of hypothalamic STAT3 activation in response to icv leptin is reduced in rodents with diet-induced obesity (El Haschimi et al. 2000). Leptin upregulates expression of SOCS-3 in hypothalamic nuclei expressing the Ob-Rb receptor. SOCS-3 acts as a negative regulator of leptin signalling. Therefore, increased or excessive SOCS-3 expression may be an important mechanism for obesity-related leptin resistance. Consistent with this, neuron-specific conditional SOCS-3-knockout mice are resistant to diet-induced obesity (Mori et al. 2004). Mice with heterozygous SOCS-3 deficiency are also resistant to obesity and demonstrate both enhanced weight loss and increased hypothalamic leptin receptor signalling in response to exogenous leptin administration (Howard et al. 2004). Although as yet untested, SOCS-3 suppression may be a potential target for the treatment of leptin-resistant obesity.

Leptin resistance seems to occur as a result of obesity, but a lack of sensitivity to circulating leptin may also contribute to the aetiology of obesity. Leptin sensitivity can predict the subsequent development of diet-induced obesity when rodents are placed on a high-energy diet (Levin & Dunn-Meynell 2002). Furthermore, it may be that the high-fat diet itself induces leptin resistance prior to any change in body composition, as rodents on a high-fat diet rapidly demonstrate an attenuated response to leptin administration before they gain weight (Lin et al. 2001).

Although leptin deficiency has profound effects on body weight, the effect of high leptin levels seen in obesity are much less potent at restoring body weight. Thus, leptin may be primarily important in periods of starvation, and have a lesser role in times of plenty.

Insulin

Insulin is a major metabolic hormone produced by the pancreas and the first adiposity signal to be described (Schwartz et al. 1992a). Like leptin, levels of plasma insulin vary directly with changes in adiposity (Bagdade et al. 1967) so that plasma insulin increases at times of positive energy balance and decreases at times of negative energy balance (Woods et al. 1974). Levels of insulin are determined to a great extent by peripheral insulin sensitivity, and this is related to total body fat stores and fat distribution, with visceral fat being a key determinant of insulin sensitivity (Porte et al. 2002). However, unlike leptin, insulin secretion increases rapidly after a meal, whereas leptin levels are relatively insensitive to meal ingestion (Polonsky et al. 1988).

Insulin penetrates the blood–brain barrier via a saturable, receptor-mediated process, at levels which are proportional to the circulating insulin (Baura et al. 1993). Recent findings suggest that little or no insulin is produced in the brain itself (Woods et al. 2003, Banks 2004). Once insulin enters the brain, it acts as an anorexigenic signal, decreasing intake and body weight. An infusion of insulin into the lateral cerebral ventricles in primates (Woods et al. 1979) or third ventricle in rodents (Ikeda et al. 1986) results in a dose-dependent decrease in food intake and, over a period of weeks, decreases body weight. Injections of insulin directly into the hypothalamic PVN also decrease food intake and rate of weight gain in rats (Menendez & Atrens 1991). Consistent with these data, an injection of antibodies to insulin into the VMH of rats increases food intake (Strubbe & Mein 1977) and repeated antiserum injections increase food intake and rate of weight gain (McGowan et al. 1992). Thus, the VMH and PVN seem therefore to play an important part in the ability of centrally administered insulin to reduce food intake.

Male mice with neuron-specific deletion of the insulin receptor in the CNS are obese and dyslipidaemic with increased peripheral levels of insulin (Bruning et al. 2000). Reduction of insulin receptor proteins in the medial ARC, by administration of an antisense RNA directed against the insulin receptor precursor protein, results in hyperphagia and increased fat mass (Obici et al. 2002).

i.c.v. administration of an insulin mimetic dose-dependently reduces food intake and body weight in rats, and alters the expression of hypothalamic genes known to regulate food intake and body weight (Air et al. 2002). Treatment of mice with orally available insulin mimetics decreases the weight gain produced by a high-fat diet as well as adiposity and insulin resistance (Air et al. 2002).

If insulin elicits changes in feeding behaviour at the level of the hypothalamus, then levels of circulating insulin should reflect the effect of centrally administered insulin. Studies of systemic insulin administration have been complicated by the fact that increasing circulating insulin causes hypoglycaemia which in itself potently stimulates food intake. Experiments where glucose levels have been controlled in the face of elevated plasma insulin levels have indeed shown a reduction in food intake in both rodents and baboons (Nicolaidis & Rowland 1976, Woods et al. 1984). Thus peripheral and central data are consistent with the insulin system acting as an endogenous controller of appetite.

The insulin receptor is composed of an extracellular α-subunit which binds insulin, and an intracellular β-subunit which tranduces the signal and has intrinsic tyrosine kinase activity. The insulin receptor exists as two splice variants resulting in subtype A, with higher affinity for insulin and more widespread expression, and subtype B with lower affinity and expression in classical insulin-responsive tissues such as fat, muscle and liver. There are several insulin receptor substrates (IRSs) including IRS-1 and IRS-2, both identified in neurons (Baskin et al. 1994, Burks et al. 2000). The phenotype of IRS-1-knockout mice does not show differences in food intake or body weight (Araki et al. 1994), but that of IRS-2-knockout mice is associated with an increase in food intake, increased fat stores and infertility (Burks et al. 2000). IRS-2 mRNA is highly expressed in the ARC, suggesting that neuronal insulin may be coupled to IRS-2 (Burks et al. 2000). There is also evidence to suggest that insulin and leptin, along with other cytokines, share common intracellular signalling pathways via IRS and the enzyme phoshoinositide 3-kinase, resulting in downstream signal transduction (Niswender et al. 2001, Porte et al. 2002).

Insulin receptors are widely distributed in the brain, with highest concentrations found in the olfactory bulbs and the hypothalamus (Marks et al. 1990). Within the hypothalamus, there is particularly high expression of insulin receptors in the ARC; they are also present in the DMH, PVN, and suprachiasmatic and periventricular regions (Corp et al. 1986). This is consistent with the hypothesis that peripheral insulin acts on hypothalamic nuclei to control energy homeostasis.

The mechanisms by which insulin acts as an adiposity signal remain to be fully elucidated. Earlier studies pointed to hypothalamic NPY as a potential mediator of the regulatory effects of insulin. i.c.v. administration of insulin during food deprivation in rats prevents the fasting-induced increase in hypothalamic levels of both NPY in the PVN and NPY mRNA in the ARC (Schwartz et al. 1992b). NPY expression is increased in insulin-deficient, streptozocin-induced diabetic rats and this effect is reversed with insulin therapy (Williams et al. 1989, White et al. 1990). More recently, the melanocortin system has been implicated as a mediator of insulin’s central actions. Insulin receptors have been found on POMC neurons in the ARC (Benoit et al. 2002). Administration of insulin into the third ventricle of fasted rats increases POMC mRNA expression and the reduction of food intake caused by i.c.v. injection of insulin is blocked by a POMC antagonist (Benoit et al. 2002). Furthermore, POMC mRNA is reduced by 80% in rats with untreated diabetes, and this can be attenuated by peripheral insulin treatment which partially reduces the hyperglycaemia (Sipols et al. 1995). Taken together, these experiments suggest that both the NPY and melanocortin systems are important downstream targets for the effects of insulin on food intake and body weight.

Adiponectin

Adiponectin is a complement-like protein, secreted from adipose tissue, which is postulated to regulate energy homeostasis (Scherer et al. 1995). The plasma concentration of adiponectin is inversely correlated with adiposity in rodents, primates and humans (Hu et al. 1996, Arita et al. 1999, Hotta et al. 2001). Adiponectin is significantly increased after food restriction in rodents (Berg et al. 2001) and after weight loss induced by a calorie-restricted diet (Hotta et al. 2000) or gastric partition surgery in obese humans (Yang et al. 2001). Peripheral administration of adiponectin to rodents has been shown to attenuate body-weight gain, by increased oxygen consumption, without affecting food intake (Berg et al. 2001, Fruebis et al. 2001, Yamauchi et al. 2001). The effect of peripheral adiponectin on energy expenditure seems to be mediated by the hypothalamus, since adiponectin induced expression of the early gene c-fos in the PVN, and may involve the melanocortin system (Qi et al. 2004). It is perhaps counterintuitive for a factor that increases energy expenditure to increase following weight loss; however, reduced adiponectin could perhaps contribute to the pathogenesis of obesity.

Studies show that plasma adiponectin levels correlate negatively with insulin resistance (Hotta et al. 2001), and treatment with adiponectin can reduce body-weight gain, increase insulin sensitivity and decrease lipid levels in rodents (Berg et al. 2001, Yamauchi et al. 2001, Qi et al. 2004). Adiponectin-knockout mice demonstrate severe diet-induced insulin resistance (Maeda et al. 2002) and a propensity towards atherogenesis in response to intimal injury (Kubota et al. 2002). Thus adiponectin, as well as increasing energy expenditure, may also provide protection against insulin resistance and atherogenesis.

In addition to leptin and adiponectin, adipose tissue produces a number of factors which may influence adiposity. Resistin is an adipocyte-derived peptide which appears to act on adipose tissue to decrease insulin resistance. Circulating resistin levels are increased in rodent models of obesity (Steppan et al. 2001) and fall after weight loss in humans (Valsamakis et al. 2004). Although resistin may be a mechanism through which obesity contributes to the development of diabetes (Steppan et al. 2001), the role of resistin in the pathogenesis of obesity remains to be defined.

Peripheral signals from the gastrointestinal tract

Ghrelin

Ghrelin is an orexigenic factor released primarily from the oxyntic cells of the stomach, but also from duodenum, ileum, caecum and colon (Date et al. 2000a, Sakata et al. 2002). It is a 28-amino-acid peptide with an acyl side chain, n-octanoic acid, which is essential for its actions on appetite (Kojima et al. 1999). In humans on a fixed feeding schedule, circulating ghrelin levels are high during a period of fasting, fall after eating (Ariyasu et al. 2001, Cummings et al. 2001, Tschop et al. 2001) and are thought to be regulated by both calorie intake and circulating nutritional signals (Tschop et al. 2000, Sakata et al. 2002). Ghrelin levels fall in response to the ingestion of food or glucose, but not following ingestion of water, suggesting that gastric distension is not a regulator (Tschop et al. 2000). In rats, ghrelin shows a bimodal peak, which occurs at the end of the light and dark periods (Murakami et al. 2002). In humans, ghrelin levels vary diurnally in phase with leptin, which is high in the morning and low at night (Cummings et al. 2001).

An increase in circulating ghrelin levels may occur as a consequence of the anticipation of food, or may have a physiological role in initiating feeding. Administration of ghrelin, either centrally or peripherally, increases food intake and body weight and decreases fat utilization in rodents (Tschop et al. 2000, Wren et al. 2001a). Furthermore, central infusion of anti-ghrelin antibodies in rodents inhibits the normal feeding response after a period of fasting, suggesting that ghrelin is an endogenous regulator of food intake (Nakazato et al. 2001). Human subjects who receive ghrelin intravenously demonstrate a potent increase in food intake of 28% (Wren et al. 2001b), and rising pre-prandial levels correlate with hunger scores in humans initiating meals spontaneously (Cummings et al. 2004). The severe hyperphagia seen in Prader–Willi syndrome is associated with elevated ghrelin levels (Cummings et al. 2002a), and the fall in plasma ghrelin concentration after bariatric surgery, despite weight loss, is thought to be partly responsible for the suppression of appetite and weight loss seen after these operations (Cummings et al. 2002b). However, one study has failed to show a correlation between the ghrelin level and the spontaneous initiation of a meal in humans (Callahan et al. 2004), and an alteration of feeding schedule in sheep has been shown to modify the timing of ghrelin peaks (Sugino et al. 2002). Thus ghrelin secretion may be a conditioned response which occurs to prepare the metabolism for an influx of calories. Whatever the precise physiological role of ghrelin, it appears not to be an essential regulator of food intake, as ghrelin-null animals do not have significantly altered body weight or food intake on a normal diet (Sun et al. 2003).

Plasma ghrelin levels are inversely correlated with body mass index. Anorexic individuals have high circulating ghrelin which falls to normal levels after weight gain (Otto et al. 2001). Obese subjects have a suppression of plasma ghrelin levels which normalize after diet-induced weight loss (Cummings et al. 2002b, Hansen et al. 2002). Unlike lean individuals, obese subjects do not demonstrate the same rapid post-prandial drop in ghrelin levels (English et al. 2002), which may result in increased food intake and contribute to obesity. Variations within the ghrelin gene may contribute to early-onset obesity (Korbonits et al. 2002, Miraglia et al. 2004) or be protective against fat accumulation (Ukkola et al. 2002), but the role of ghrelin polymorphisms in the control of body weight continues to be controversial (Hinney et al. 2002, Wang et al. 2004).

Ghrelin is the endogenous agonist of the growth hormone secretagogue receptor (GHS-R), and stimulates growth hormone (GH) release via its actions on the type 1a receptor in the hypothalamus (Kojima et al. 1999, Date et al. 2000b, Tschop et al. 2000, Wren et al. 2000). However, the orexigenic action of ghrelin is independent of its effects on GH (Tschop et al. 2000, Shintani et al. 2001, Tamura et al. 2002). Ghrelin administration does not increase food intake in mice lacking GHS-R type 1a, suggesting that the orexigenic effects may be mediated by this receptor; however, these mice have normal appetite and body composition (Chen et al. 2004a, Sun et al. 2004). This lack of a phenotype suggests that ghrelin receptor antagonists may not be an effective therapy for obesity. GHS-R type 1a is found in the hypothalamus, pituitary myocardium, stomach, small intestine, pancreas, colon, adipose tissue, liver, kidney, placenta and peripheral T-cells (Date et al. 2000a, 2002a, Gualillo et al. 2001, Hattori et al. 2001, Murata et al. 2002). Some studies have also described ghrelin analogues which show dissociation between the feeding effects and stimulation of GH, suggesting that GHS-R type 1a may not be the only receptor mediating the effects of ghrelin on food intake (Torsello et al. 2000).

Ghrelin is thought to exert its orexigenic action via the ARC of the hypothalamus. c-Fos expression increases within ARC NPY-synthesizing neurons after peripheral administration of ghrelin (Wang et al. 2002), and ghrelin fails to increase food intake following ablation of the ARC (Tamura et al. 2002). Studies of knockout mice demonstrate that both NPY and AgRP signalling mediate the effect of ghrelin, although neither neuropeptide is obligatory (Chen et al. 2004a). GHS-R are also found on the vagus nerve (Date et al. 2002b), and administration of ghrelin leads to c-Fos expression in the area postrema and NTS (Nakazato et al. 2001, Lawrence et al. 2002), suggesting that the brainstem may also participate in ghrelin signalling.

Ghrelin is also expressed centrally, in a group of neurons adjacent to the third ventricle, between the dorsomedial hypothalamic nucleus (DMH), VMH, PVN and ARC. These neurons terminate on NPY/AgRP, POMC and corticotrophin-releasing hormone neurons, and are able to stimulate the activity of ARC NPY neurons, forming a central circuit which could mediate energy homeostasis (Cowley et al. 2003). The central ghrelin neurons also terminate on orexin-containing neurons within the LHA (Toshinai et al. 2003), and icv administration of ghrelin stimulates orexin-expressing neurons (Lawrence et al. 2002, Toshinai et al. 2003). The feeding response to centrally administered ghrelin is attenuated after administration of anti-orexin antibody and in orexin-null mice (Toshinai et al. 2003).

PP-fold peptides

The PP-fold peptides include PYY, PP and NPY. They all share significant sequence homology and contain several tyrosine residues (Conlon 2002). They have a common tertiary structure which consists of an α-helix and polyproline helix, connected by a β-turn, resulting in a characteristic U-shaped peptide, the PP-fold (Glover et al. 1983).

PYY is secreted predominantly from the distal gastrointestinal tract, particularly the ileum, colon and rectum (Adrian et al. 1985a, Ekblad & Sundler 2002). The L-cells of the intestine release PYY in proportion to the amount of calories ingested at a meal. Post-prandially, the circulating PYY levels rise rapidly to a plateau after 1–2 h and remain elevated for up to 6 h (Adrian et al. 1985a). However, PYY release occurs before the nutrients reach the cells in the distal tract, thus release may be mediated via a neural reflex as well as direct contact with nutrients (Fu-Cheng et al. 1997). The levels of PYY are also influenced by meal composition: higher levels are seen following fat intake rather than carbohydrate or protein (Lin & Chey 2003). Other signals, such as gastric acid, CCK and luminal bile salts, insulin-like growth factor 1, bombesin and calcitonin-gene-related peptide increase PPY levels, whereas gastric distension has no effect, and levels are reduced by GLP-1 (Pedersen-Bjergaard et al. 1996, Lee et al. 1999, Naslund et al. 1999a).

Circulating PYY exists in two major forms: PYY1–36 and PYY3–36. PYY3–36, the peripherally active anorectic signal, is created by cleavage of the N-terminal Tyr-Pro residues by dipeptidyl peptidase IV (DPP-IV) (Eberlein et al. 1989). DPP-IV is involved in the cleavage of multiple hormones including products of the proglucagon gene (Boonacker & Van Noorden 2003).

Administration of PYY causes a delay in gastric emptying, a delay in secretions from the pancreas and stomach, and increases the absorption of fluids and electrolytes from the ileum after a meal (Allen et al. 1984, Adrian et al. 1985b, Hoentjen et al. 2001). Peripheral administration of PYY3–36 to rodents has been shown to inhibit food intake, reduce weight gain (Batterham et al. 2002, Challis et al. 2003) and improve glycaemic control in rodent models of diabetes (Pittner et al. 2004). The effect on appetite may be dependent on a minimization of environmental stress, which in itself can result in a decrease in food intake (Halatchev et al. 2004). Acute stress has been shown to activate the NPY system (Conrad & McEwen 2000, Makino et al. 2000), which may render the system insensitive to the inhibitory effect of PYY3–36, resulting in masking of the anorectic effect of the peptide.

Intravenous administration of PYY3–36 to normal-weight human subjects also has potent effects on appetite, resulting in a 30% reduction in food intake (Batterham et al. 2002, 2003a). The reduction in calories is accompanied by a reduction in subjective hunger without an alteration in gastric emptying. This effect persists for up to 12 h after the infusion is terminated, despite circulating PYY3–36 returning to basal levels (Batterham et al. 2002). Thus, PYY3–36 may be physiologically important as a post-prandial satiety signal.

Obese human subjects have a relatively low circulating PYY and a relative deficiency of post-prandial secretion (Batterham et al. 2003a), although these subjects retain sensitivity to exogenous administration. Obese patients treated by jejunoileal bypass surgery (Naslund et al. 1997) or vertical-banded gastroplasty (Alvarez et al. 2002) have elevated PYY levels, which may contribute to their appetite loss. Thus long-term administration of PYY3–36 could be an effective obesity therapy. After chronic peripheral administration of PYY3–36, rodents do indeed demonstrate reduced weight gain (Batterham et al. 2002).

PP is produced by cells at the periphery of the islets of the endocrine pancreas, and to a lesser extent in the exocrine pancreas, colon and rectum (Larsson et al. 1975). The release of PP occurs in proportion to the number of calories ingested, and levels remain elevated for up to 6 h post-prandially (Adrian et al. 1976). The release of PP is biphasic, with the contribution of the smaller first phase increasing with consecutive meals, although the total release remains proportional to the caloric load (Track et al. 1980). The circulating levels of PP are increased by gastric distension, ghrelin, motilin and secretin (Christofides et al. 1979, Mochiki et al. 1997, Peracchi et al. 1999, Arosio et al. 2003) and reduced by somatostatin (Parkinson et al. 2002). There is also a background diurnal rhythm, with circulating PP low in the early hours of the morning and highest in the evening (Track et al. 1980). The levels of PP have been found to reflect long-term energy stores, with lower levels (Lassmann et al. 1980, Glaser et al. 1988) and reduced second phase of release (Lassmann et al. 1980) in obese subjects, and higher levels in anorexic subjects (Uhe et al. 1992, Fujimoto et al. 1997). However, conflicting studies have found no difference between lean and obese subjects (Wisen et al. 1992), or between obese subjects before and after weight loss (Meryn et al. 1986).

Peripheral administration of PP reduces food intake, body weight and energy expenditure, and ameliorates insulin resistance and dyslipidaemia in rodent models of obesity (Malaisse-Lagae et al. 1977, Asakawa et al. 2003). However, it has been suggested that obese rodents are less sensitive to the effects of PP than normal-weight rodents (McLaughlin & Baile 1981). Transgenic mice that over-express PP also have a lean phenotype with reduced food intake (Ueno et al. 1999).

Normal-weight human volunteers given an infusion of PP demonstrate decreased appetite, and a 25% reduction in food intake over the following 24 h (Batterham et al. 2003b). Unlike rodents, humans do not seem to have altered gastric emptying in response to PP (Adrian et al. 1981). Further investigation of the administration of PP to obese subjects may indicate whether it could be an effective therapy for obesity. PP does appear to be an efficacious treatment for hyperphagia secondary to Prader–Willi syndrome. These patients have blunted basal and post-prandial PP responses which may contribute to their hyperphagia and obesity (Zipf et al. 1981, 1983). A twice-daily ‘replacement’ of PP by infusion results in a 12% reduction in food intake during the therapy (Berntson et al. 1993).

The PP-fold family bind to Y1–Y5 receptors, which are seven-transmembrane-domain, G-protein-coupled receptors (Larhammar 1996). The receptors differ in their distribution and are classified according to their affinity for PYY, PP and NPY. Whereas NPY and PYY bind with high affinity to all Y receptors, PYY3–36 shows high affinity for Y2 and some affinity for Y1 and Y5 receptors. PP binds with greatest affinity to Y4 and Y5 receptors (Larhammar 1996).

The N-terminal of PYY allows it to cross the blood–brain barrier freely from the circulation, whereas PP cannot (Nonaka et al. 2003). It is thought that the effect of peripheral PYY3–36 on appetite may be mediated by the arcuate Y2 receptor, a pre-synaptic inhibitory receptor expressed on NPY neurons (Broberger et al. 1997). Electrophysiological studies have shown that administration of PYY3–36 inhibits NPY neurons (Batterham et al. 2002), and NPY mRNA expression levels are reduced after peripheral PYY3–36 administration (Batterham et al. 2002, Challis et al. 2003). The anorectic effect of PYY3–36 is abolished in Y2 receptor-knockout mice and reduced by a selective Y2 agonist (Batterham et al. 2002). Inhibition of NPY neurons also results in increased activity with the POMC neurons which may contribute to reduced food intake. Immunohistochemical studies have demonstrated that peripherally administered PYY3–36 induces c-fos expression (Batterham et al. 2002, Halatchev et al. 2004) and POMC mRNA expression (Challis et al. 2003) in ARC POMC neurons. However, the melanocortin system does not appear to be obligatory for the effects of PYY3–36 on appetite, as PYY3–36 continues to be effective in MC4R-knockout mice (Halatchev et al. 2004) and POMC-null mice (Challis et al. 2004). Recently, it has been suggested that CART may mediate the effect of PYY3–36 on appetite (Coll et al. 2004). The peripheral administration of PYY3–36 has also been shown to decrease ghrelin levels (Batterham et al. 2003a), and this effect on circulating gut hormone levels may also contribute to its effect on appetite.

In contrast to peripheral PYY3–36, the central actions of PYY1–36 and PYY3–36 are orexigenic. PYY administered into the third, lateral or fourth cerebral ventricles (Clark et al. 1987, Corpa et al. 2001), into the PVN (Stanley et al. 1985) or into the hippocampus (Hagan et al. 1998) potently stimulates food intake in rodents. This orexigenic effect is reduced in both Y1 and Y5 receptor-knockout mice (Kanatani et al. 2000). Therefore these lower-affinity receptors may mediate the central feeding effect of PYY3–36, whereas peripheral PYY3–36 is able to access the higher-affinity ARC Y2 receptors (Batterham et al. 2002).

Circulating PP is unable to cross the blood–brain barrier, but may exert its anorectic effect on the ARC via the area postrema (Whitcomb et al. 1990). This effect may occur via the Y5 receptor as there is no response in Y5 receptor-knockout mice, although the anorectic effect is not reduced by Y5 receptor antisense oligonucleotides (Katsuura et al. 2002). Following the peripheral administration of PP, the expression of hypothalamic NPY and orexin mRNA is significantly reduced (Asakawa et al. 2003). PP may also exert some anorectic action via the vagal pathway to the brainstem, as vagotomy seems to reduce its efficacy (Asakawa et al. 2003). Like PYY3–36, PP is also able to reduce gastric ghrelin mRNA expression, and this has been postulated to mediate its efficacy in the treatment of hyperphagia secondary to Prader–Willi syndrome (Asakawa et al. 2003). Thus PP sends anorectic signals via brainstem pathways, hypothalamic neuropeptides and by modulating expression of other gut hormones such as ghrelin. In contrast to the peripheral effects, when administered centrally into the third ventricle PP causes increased food intake (Clark et al. 1984). However, the mechanism of this orexigenic effect following central injection is unclear.

Proglucagon products

The proglucagon gene product is expressed in the L-cells of the small intestine, pancreas and central nervous system. A small group of neurons expressing pre-proglucagon are present in the NTS (Tang-Christensen et al. 2001). The enzymes prohormone convertase 1 and 2 cleave proglucagon into different products depending on the tissue (Holst 1999). In the pancreas, glucagon is the major product, whereas in the brain and intestine oxyntomodulin (OXM) and GLP-1 and GLP-2 are the major products.

The L-cells of the small intestine release GLP-1 in response to nutrients (Herrmann et al. 1995). Central administration of GLP-1, into the third or fourth ventricles and into the PVN, reduces acute calorie intake (Turton et al. 1996), and decreases weight gain when given chronically to rodents (Meeran et al. 1999). Peripheral administration also inhibits food intake and activates c-Fos in the brainstem (Tang-Christensen et al. 2001, Yamamoto et al. 2003). Thus, GLP-1 may influence energy homeostasis via the brainstem pathways.

In humans, intravenous administration of GLP-1 decreases food intake in both lean and obese individuals in a dose-dependent manner (Verdich et al. 2001a). However, the effect is small when infusions achieve post-prandial circulating levels (Flint et al. 2001, Verdich et al. 2001b). Some evidence suggests GLP-1 secretion is reduced in obese subjects (Holst et al. 1983, Ranganath et al. 1996, Naslund et al. 1999b) and weight loss normalizes the levels (Verdich et al. 2001b). Obese subjects, given subcutaneous GLP-1 prior to each meal, reduce their calorie intake by 15% and lose 0·5 kg in weight over 5 days (Naslund 2003). Reduced secretion of GLP-1 could therefore contribute to the pathogenesis of obesity and replacement may restore satiety.

In addition to its effect on appetite, GLP-1 is an incretin hormone (Kreymann et al. 1987), and potentiates all steps of insulin biosynthesis (MacDonald et al. 2002). GLP-1 has been found to normalize blood glucose levels, in poorly controlled type 2 diabetes, during both a short-term intravenous infusion (Nauck et al. 1993) and after a 6-week subcutaneous infusion (Zander et al. 2002). Body weight was also reduced by 2 kg after the subcutaneous infusion (Zander et al. 2002). GLP-1 is broken down rapidly by the enzyme DPP-IV resulting in a short half-life in the circulation. However, resistant albumin-bound GLP-1, exendin-4 (a naturally occurring peptide from the lizard Heloderma) and inhibitors of the enzyme DPP-IV are all currently in development for the treatment of diabetes (see the review by Holst 2004). Although GLP-1 may be useful in type 2 diabetic patients, it has been reported to cause hypoglycaemia in non-diabetic subjects (Todd et al. 2003), which could limit its usefulness as an obesity therapy.

OXM is released from the L-cells of the small intestine in proportion to nutrient ingestion (Ghatei et al. 1983, Le Quellec et al. 1992), and shows a diurnal variation with lowest values early in the morning, rising to a peak in the evening (Le Quellec et al. 1992). Administration of OXM centrally or peripherally acutely inhibits food intake in rodents (Dakin et al. 2001, 2004), and chronic administration via these routes results in reduced body weight gain and adiposity (Dakin et al. 2002, 2004). OXM may also increase energy expenditure, as OXM-treated animals lose more weight than pair-fed animals, an effect which is postulated to be mediated by the thyroid axis (Dakin et al. 2002). An infusion of OXM to normal-weight human subjects reduces hunger and decreases calorie intake by 19·3%, an effect which persists up to 12 h post-infusion (Cohen et al. 2003). Anorexia occurs in human conditions associated with high OXM levels, such as tropical sprue (Besterman et al. 1979) and jejunoileal bypass surgery (Holst et al. 1979, Sarson et al. 1981). Thus OXM may be a physiological regulator of energy homeostasis. However, the circulating concentrations of OXM in obese subjects and its potential to decrease weight in humans remain unknown.

It has been suggested that the effects of GLP-1 and OXM on energy homeostasis are mediated by the GLP-1 receptor. The anorexigenic effects of GLP-1 and OXM are blocked by the antagonist, exendin(9–39), when administered centrally (Turton et al. 1996, Dakin et al. 2001). GLP-1 receptors are present in both the NTS and hypothalamus (Uttenthal et al. 1992, Shughrue et al. 1996), and are also widespread in the periphery: in the pancreas, lung, brain, kidney, gastrointestinal tract and heart (Wei & Mojsov 1995, Bullock et al. 1996).

The effect of OXM on appetite may not simply be mediated via GLP-1 receptors. Peripheral administration of OXM results in increased c-Fos in the ARC, but not in the brainstem region (Dakin et al. 2004), a pattern of neuronal activation which is different from that seen with GLP-1. Furthermore, the affinity of OXM for GLP-1 receptor is approximately two orders of magnitude less than that of GLP-1 yet they appear to be similarly efficacious at reducing food intake (Fehmann et al. 1994). Although exendin(9–39) can block the appetite effects of centrally administered OXM and GLP-1, antagonist administered into the ARC is able to abolish the effect of peripheral OXM, but not peripheral GLP-1. There may thus be distinct receptors mediating the physiological effects of the two peripheral gut hormones. The peripheral administration of OXM reduces circulating ghrelin by 20% in rodents (Dakin et al. 2004) and 44% in human subjects (Cohen et al. 2003), an effect which is also likely to contribute to its effects on appetite.

CCK

CCK is found predominantly in the duodenum and jejunum, although it is widely distributed in the gastrointestinal tract (Larsson & Rehfeld 1978). It is present in multiple bioactive forms, including CCK-58, CCK-33 and CCK-8, all derived from the same gene product (Reeve et al. 1994). CCK is rapidly released locally and into the circulation in response to nutrients, and remains elevated for up to 5 h (Liddle et al. 1985). CCK is also found within the brain where it functions as a neurotransmitter involved in diverse processes such as reward behaviour, memory and anxiety, as well as satiety (Crawley & Corwin 1994).

CCK coordinates digestion by stimulating the release of enzymes from the pancreas and gall bladder, increasing intestinal motility and inhibiting gastric emptying (Liddle et al. 1985, Moran & Schwartz 1994). Administration of CCK, to both humans and animals, has long been known to inhibit food intake by reducing meal size and duration (Gibbs et al. 1973, Kissileff et al. 1981), an effect which is enhanced by gastric distension (Kissileff et al. 2003). Although CCK exerts its effect on food intake rapidly, its duration of action is brief. It has a half-life of only 1–2 min, and it is not effective at reducing meal size if the peptide is administered more than 15 min before a meal (Gibbs et al. 1973). In animals, chronic pre-prandial administration of CCK does reduce food intake, but is seen to increase meal frequency, with no resulting effect on body weight (West et al. 1984, West et al. 1987). A continuous infusion of CCK becomes ineffective after the first 24 h (Crawley & Beinfeld 1983). Thus, the efficacy of CCK as a potential treatment for human obesity is in doubt.

CCK exerts its effect via binding to CCKA and CCKB receptors; these are G-protein-coupled receptors with seven transmembrane domains (Wank et al. 1992a). CCKA receptors are found throughout the brain, including areas such as the NTS, DMH and area postrema. Peripherally, CCKA receptors are found in the pancreas, on vagal afferent and enteric neurons. CCKB receptors are also distributed widely in the brain, are present in the afferent vagus nerve, and are found within the stomach (Moran et al. 1986, 1990, Wank et al. 1992a, 1992b).

The CCKA receptor subtype is thought to mediate the effect of the endogenous agonist on appetite (Asin et al. 1992). Suppression of food intake is only seen in response to the sulphated form of CCK which binds with high affinity to CCKA receptors (Gibbs et al. 1973). Further-more, administration of a CCKA receptor antagonist increases calorie intake and reduces satiety (Hewson et al. 1988, Beglinger et al. 2001).

Circulating CCK sends satiety signals via activation of vagal fibres (Schwartz & Moran 1994, Moran et al. 1997). The action of CCK on the vagal nerve may partly be a paracrine or neurocrine effect, as there is evidence that locally released CCK may activate vagal fibres without a significant increase in plasma CCK level (Reidelberger & Solomon 1986). The vagal nerve projects to the NTS, which in turn relays information to the hypothalamus (Schwartz et al. 2000). Peripheral CCK may act both on the vagal nerve and directly on the CNS by crossing the blood–brain barrier (Reidelberger et al. 2003). Evidence from the CCKA receptor-knockout (OLETF) rat suggests that CCK may act on the DMH to suppress NPY levels (Bi et al. 2001). This is supported by data which demonstrate that administration of CCK to the DMH inhibits food intake significantly (Blevins et al. 2000).

CCK may also act as a longer-term indicator of nutritional status: the CCKA receptor-knockout (OLETF) rat (but not the CCKA receptor-knockout mouse) is hyper-phagic and obese (Moran et al. 1998, Schwartz et al. 1999). Chronic administration of both CCK antibodies and CCKA antagonists also results in weight gain in rodent models, although not with a significant increase in food intake (McLaughlin et al. 1985, Meereis-Schwanke et al. 1998). The long-term effect of CCK on body weight may partially result from an interaction with signals of adiposity such as leptin, which enhance the satiating effect of CCK (Matson et al. 2000). See Figure 4.

Future direction

The brain integrates peripheral signals of nutrition in order to maintain a stable body weight. However, in some individuals, genetic and environmental factors interact to result in obesity. Understanding of the complex system which regulates energy homeostasis is progressing rapidly, enabling new obesity therapies to emerge. Available pharmacological agents, such as sibutramine and orlistat, have limited efficacy and are restricted to 1 or 2 years of therapy respectively (see review by Finer 2002). Currently, the only obesity treatment in clinical use that has shown significant long-term weight loss is gastrointestinal bypass surgery (Frandsen et al. 1998, Mitchell et al. 2001). However, because of its complications, this procedure is restricted to patients with morbid obesity. Post-surgical weight loss is not caused by malabsorption, but is due to a loss of appetite (Atkinson & Brent 1982), which may be secondary to elevated PYY and OXM (Sarson et al. 1981, Naslund et al. 1997) and/or suppressed ghrelin levels (Cummings et al. 2002b). This suggests that therapies based on these hormones may be effective in the long term, without the need for surgical intervention. As mechanisms of disordered energy homeostasis are clarified, treatments based on peripheral hormones or central neuropeptide signals could be tailored to the individual; just as leptin deficiency is treated successfully with leptin replacement. Therapeutic strategies may thus significantly impact on the enormous morbidity and mortality associated with obesity, as even modest weight loss can reduce the risk of diabetes, cancer and cardiovascular disease.

Figure 1
Figure 1

The ARC and the control of appetite. α-MSH, α-melanocyte-stimulating hormone; GHS-R, growth hormone secretagogue receptor.

Citation: Journal of Endocrinology 184, 2; 10.1677/joe.1.05866

Figure 2
Figure 2

Schematic of the hypothalamic nuclei (coronal section). BDNF, brain-derived neurotrophic factor; CRH, corticotrophin-releasing hormone; MCH, melanin-concentrating hormone; ME; median eminence; PFA, perifornical area; TRH, thyrotropin-releasing hormone.

Citation: Journal of Endocrinology 184, 2; 10.1677/joe.1.05866

Figure 3
Figure 3

The central control of appetite. AP, area postrema; ME; median eminence; NAc, nucleus accumbens; PFA, perifornical area.

Citation: Journal of Endocrinology 184, 2; 10.1677/joe.1.05866

Figure 4
Figure 4

Peripheral control of appetite.

Citation: Journal of Endocrinology 184, 2; 10.1677/joe.1.05866

K W is supported by the Wellcome Trust, B M is supported by the Wellcome Trust and S S is supported by the Medical Research Council.

References

  • Abbott CR, Rossi M, Kim M, AlAhmed SH, Taylor GM, Ghatei MA, Smith DM & Bloom SR 2000 Investigation of the melanocyte stimulating hormones on food intake. Lack of evidence to support a role for the melanocortin-3-receptor. Brain Research 869 203–210.

    • Search Google Scholar
    • Export Citation
  • Abbott CR, Rossi M, Wren AM, Murphy KG, Kennedy AR, Stanley SA, Zollner AN, Morgan DG, Morgan I, Ghatei MA et al. 2001 Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 142 3457–3463.

    • Search Google Scholar
    • Export Citation
  • Adrian TE, Bloom SR, Bryant MG, Polak JM, Heitz PH & Barnes AJ 1976 Distribution and release of human pancreatic polypeptide. Gut 17 940–944.

    • Search Google Scholar
    • Export Citation
  • Adrian TE, Greenberg GR, Fitzpatrick ML & Bloom SR 1981 Lack of effect of pancreatic polypeptide in the rate of gastric emptying and gut hormone release during breakfast. Digestion 21 214–218.

    • Search Google Scholar
    • Export Citation
  • Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM & Bloom SR 1985a Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89 1070–1077.

    • Search Google Scholar
    • Export Citation
  • Adrian TE, Savage AP, Sagor GR, Allen JM, Bacarese-Hamilton AJ, Tatemoto K, Polak JM & Bloom SR 1985b Effect of peptide YY on gastric, pancreatic, and biliary function in humans. Gastroenterology 89 494–499.

    • Search Google Scholar
    • Export Citation
  • Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E & Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382 250–252.

    • Search Google Scholar
    • Export Citation
  • Air EL, Strowski MZ, Benoit SC, Conarello SL, Salituro GM, Guan XM, Liu K, Woods SC & Zhang BB 2002 Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nature Medicine 8 179–183.

    • Search Google Scholar
    • Export Citation
  • Allen YS, Adrian TE, Allen JM, Tatemoto K, Crow TJ, Bloom SR & Polak JM 1983 Neuropeptide Y distribution in the rat brain. Science 221 877–879.

    • Search Google Scholar
    • Export Citation
  • Allen JM, Fitzpatrick ML, Yeats JC, Darcy K, Adrian TE & Bloom SR 1984 Effects of peptide YY and neuropeptide Y on gastric emptying in man. Digestion 30 255–262.

    • Search Google Scholar
    • Export Citation
  • Alvarez BM, Borque M, Martinez-Sarmiento J, Aparicio E, Hernandez C, Cabrerizo L & Fernandez-Represa JA 2002 Peptide YY secretion in morbidly obese patients before and after vertical banded gastroplasty. Obesity Surgery 12 324–327.

    • Search Google Scholar
    • Export Citation
  • Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D & Small CJ 2004 AMP-activated protein kinase plays a role in the control of food intake. Journal of Biological Chemistry 279 12005–12008.

    • Search Google Scholar
    • Export Citation
  • Araki E, Lipes MA, Patti ME, Bruning JC, Haag B, III, Johnson RS & Kahn CR 1994 Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372 186–190.

    • Search Google Scholar
    • Export Citation
  • Argyropoulos G, Rankinen T, Neufeld DR, Rice T, Province MA, Leon AS, Skinner JS, Wilmore JH, Rao DC & Bouchard C 2002 A polymorphism in the human agouti-related protein is associated with late-onset obesity. Journal of Clinical Endocrinology and Metabolism 87 4198–4202.

    • Search Google Scholar
    • Export Citation
  • Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K et al. 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257 79–83.

    • Search Google Scholar
    • Export Citation
  • Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S et al. 2001 Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. Journal of Clinical Endocrinology and Metabolism 86 4753–4758.

    • Search Google Scholar
    • Export Citation
  • Arosio M, Ronchi CL, Gebbia C, Cappiello V, Beck-Peccoz P & Peracchi M 2003 Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels. Journal of Clinical Endocrinology and Metabolism 88 701–704.

    • Search Google Scholar
    • Export Citation
  • Asakawa A, Inui A, Ueno N, Fujimiya M, Fujino MA & Kasuga M 1999 Mouse pancreatic polypeptide modulates food intake, while not influencing anxiety in mice. Peptides 20 1445–1448.

    • Search Google Scholar
    • Export Citation
  • Asakawa A, Inui A, Yuzuriha H, Ueno N, Katsuura G, Fujimiya M, Fujino MA, Niijima A, Meguid MM & Kasuga M 2003 Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology 124 1325–1336.

    • Search Google Scholar
    • Export Citation
  • Asin KE, Gore PA Jr, Bednarz L, Holladay M & Nadzan AM 1992 Effects of selective CCK receptor agonists on food intake after central or peripheral administration in rats. Brain Research 571 169–174.

    • Search Google Scholar
    • Export Citation
  • Atkinson RL & Brent EL 1982 Appetite suppressant activity in plasma of rats after intestinal bypass surgery. American Journal of Physiology –Regulatory, Integrative and Comparative Physiology 243 R60–R64.

    • Search Google Scholar
    • Export Citation
  • Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Marchand-Brustel Y & Lewin MJ 1998 The stomach is a source of leptin. Nature 394 790–793.

    • Search Google Scholar
    • Export Citation
  • Bagdade JD, Bierman EL & Porte D Jr 1967 The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. Journal of Clinical Investigation 46 1549–1557.

    • Search Google Scholar
    • Export Citation
  • Bagnasco M, Dube MG, Kalra PS & Kalra SP 2002 Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy. Endocrinology 143 4409–4421.

    • Search Google Scholar
    • Export Citation
  • Bai FL, Yamano M, Shiotani Y, Emson PC, Smith AD, Powell JF & Tohyama M 1985 An arcuato-paraventricular and -dorsomedial hypothalamic neuropeptide Y-containing system which lacks noradrenaline in the rat. Brain Research 331 172–175.

    • Search Google Scholar
    • Export Citation
  • Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC Jr, Elmquist JK & Lowell BB 2004 Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42 983–991.

    • Search Google Scholar
    • Export Citation
  • Banks WA 2004 The source of cerebral insulin. European Journal of Pharmacology 490 5–12.

  • Banks WA, Kastin AJ, Huang W, Jaspan JB & Maness LM 1996 Leptin enters the brain by a saturable system independent of insulin. Peptides 17 305–311.

    • Search Google Scholar
    • Export Citation
  • Banks WA, DiPalma CR & Farrell CL 1999 Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 20 1341–1345.

  • Bannon AW, Seda J, Carmouche M, Francis JM, Norman MH, Karbon B & McCaleb ML 2000 Behavioral characterization of neuropeptide Y knockout mice. Brain Research 868 79–87.

    • Search Google Scholar
    • Export Citation
  • Baskin DG, Schwartz MW, Sipols AJ, D’Alessio DA, Goldstein BJ & White MF 1994 Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology 134 1952–1955.

    • Search Google Scholar
    • Export Citation
  • Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD & Bloom SR 2002 Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 418 650–654.

    • Search Google Scholar
    • Export Citation
  • Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA & Bloom SR 2003a Inhibition of food intake in obese subjects by peptide YY3–36. New England Journal of Medicine 349 941–948.

    • Search Google Scholar
    • Export Citation
  • Batterham RL, Le Roux CW, Cohen MA, Park A, Ellis SM, Patterson M, Frost GS, Ghatei MA & Bloom SR 2003b Pancreatic polypeptide reduces appetite and food intake in humans. Journal of Clinical Endocrinology and Metabolism 88 3989–3992.

    • Search Google Scholar
    • Export Citation
  • Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C & Schwartz MW 1993 Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. Journal of Clinical Investigation 92 1824–1830.

    • Search Google Scholar
    • Export Citation
  • Beglinger C, Degen L, Matzinger D, D’Amato M & Drewe J 2001 Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 280 R1149–R1154.

    • Search Google Scholar
    • Export Citation
  • Benoit SC, Schwartz MW, Lachey JL, Hagan MM, Rushing PA, Blake KA, Yagaloff KA, Kurylko G, Franco L, Danhoo W & Seeley RJ 2000 A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences. Journal of Neuroscience 20 3442–3448.

    • Search Google Scholar
    • Export Citation
  • Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ & Woods SC 2002 The catabolic action of insulin in the brain is mediated by melanocortins. Journal of Neuroscience 22 9048–9052.

    • Search Google Scholar
    • Export Citation
  • Berg AH, Combs TP, Du X, Brownlee M & Scherer PE 2001 The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature Medicine 7 947–953.

    • Search Google Scholar
    • Export Citation
  • Bernardis LL & Bellinger LL 1996 The lateral hypothalamic area revisited: ingestive behavior. Neuroscience and Biobehavioral Reviews 20 189–287.

    • Search Google Scholar
    • Export Citation
  • Berntson GG, Zipf WB, O’Dorisio TM, Hoffman JA & Chance RE 1993 Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome. Peptides 14 497–503.

    • Search Google Scholar
    • Export Citation
  • Berridge KC 1991 Modulation of taste affect by hunger, caloric satiety, and sensory-specific satiety in the rat. Appetite 16 103–120.

  • Besterman HS, Cook GC, Sarson DL, Christofides ND, Bryant MG, Gregor M & Bloom SR 1979 Gut hormones in tropical malabsorption. Bristish Medical Journal 2 1252–1255.

    • Search Google Scholar
    • Export Citation
  • Bi S, Ladenheim EE, Schwartz GJ & Moran TH 2001 A role for NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 281 R254–R260.

    • Search Google Scholar
    • Export Citation
  • Billington CJ, Briggs JE, Grace M & Levine AS 1991 Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 260 R321–R327.

    • Search Google Scholar
    • Export Citation
  • Black SC 2004 Cannabinoid receptor antagonists and obesity. Current Opinion in Investigational Drugs 5 389–394.

  • Blevins JE, Stanley BG & Reidelberger RD 2000 Brain regions where cholecystokinin suppresses feeding in rats. Brain Research 860 1–10.

  • Boonacker E & Van Noorden CJ 2003 The multifunctional or moonlighting protein CD26/DPPIV. European Journal of Cell Biology 82 53–73.

  • Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR , DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I et al. 2002 Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nature Medicine 8 825–830.

    • Search Google Scholar
    • Export Citation
  • Broadwell RD & Brightman MW 1976 Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. Comparative Journal of Neurology 166 257–283.

    • Search Google Scholar
    • Export Citation
  • Broberger C, Landry M, Wong H, Walsh JN & Hokfelt T 1997 Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 66 393–408.

    • Search Google Scholar
    • Export Citation
  • Broberger C, Johansen J, Johansson C, Schalling M & Hokfelt T 1998a The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. PNAS 95 15043–15048.

    • Search Google Scholar
    • Export Citation
  • Broberger C, De Lecea L, Sutcliffe JG & Hokfelt T 1998b Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. Comparative Journal of Neurology 402 460–474.

    • Search Google Scholar
    • Export Citation
  • Bronstein DM, Schafer MK, Watson SJ & Akil H 1992 Evidence that beta-endorphin is synthesized in cells in the nucleus tractus solitarius: detection of POMC mRNA. Brain Research 587 269–275.

    • Search Google Scholar
    • Export Citation
  • Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D & Kahn CR 2000 Role of brain insulin receptor in control of body weight and reproduction. Science 289 2122–2125.

    • Search Google Scholar
    • Export Citation
  • Bullock BP, Heller RS & Habener JF 1996 Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology 137 2968–2978.

    • Search Google Scholar
    • Export Citation
  • Burks DJ, de Mora JF, Schubert M, Withers DJ, Myers MG, Towery HH, Altamuro SL, Flint CL & White MF 2000 IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407 377–382.

    • Search Google Scholar
    • Export Citation
  • Butler AA 2004 Studies defining the role of the melanocortin-3 receptor in the development of obesity and insulin resistance. American Endocrine Society, New Orleans 2004, Abstract OR17-1.

  • Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M & Cone RD 2000 A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141 3518–3521.

    • Search Google Scholar
    • Export Citation
  • Cai XJ, Widdowson PS, Harrold J, Wilson S, Buckingham RE, Arch JR, Tadayyon M, Clapham JC, Wilding J & Williams G 1999 Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes 48 2132–2137.

    • Search Google Scholar
    • Export Citation
  • Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC & Weigle DS 2004 Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. Journal of Clinical Endocrinology and Metabolism 89 1319–1324.

    • Search Google Scholar
    • Export Citation
  • Campbell RE, Smith MS, Allen SE, Grayson BE, Ffrench-Mullen JM & Grove KL 2003 Orexin neurons express a functional pancreatic polypeptide Y4 receptor. Journal of Neuroscience 23 1487–1497.

    • Search Google Scholar
    • Export Citation
  • Campfield LA, Smith FJ, Guisez Y, Devos R & Burn P 1995 Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269 546–549.

    • Search Google Scholar
    • Export Citation
  • Challis BG, Pinnock SB, Coll AP, Carter RN, Dickson SL & O’Rahilly S 2003 Acute effects of PYY3–36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochemical and Biophysical Research Communications 311 915–919.

    • Search Google Scholar
    • Export Citation
  • Challis BG, Coll AP, Yeo GS, Pinnock SB, Dickson SL, Thresher RR, Dixon J, Zahn D, Rochford JJ, White A et al. 2004 Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY (3–36). PNAS 101 4695–4700.

    • Search Google Scholar
    • Export Citation
  • Chan JL, Heist K, DePaoli AM, Veldhuis JD & Mantzoros CS 2003 The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. Journal of Clinical Investigation 111 1409–1421.

    • Search Google Scholar
    • Export Citation
  • Chehab FF, Lim ME & Lu R 1996 Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics 12 318–320.

    • Search Google Scholar
    • Export Citation
  • Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y et al. 1999 Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98 437–451.

    • Search Google Scholar
    • Export Citation
  • Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI & Morgenstern JP 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84 491–495.

    • Search Google Scholar
    • Export Citation
  • Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM et al. 2004a Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP). Endocrinology 145 2607–2612.

    • Search Google Scholar
    • Export Citation
  • Chen P, Williams SM, Grove KL & Smith MS 2004b Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y expression in the dorsomedial hypothalamus during lactation. Journal of Neuroscience 24 5091–5100.

    • Search Google Scholar
    • Export Citation
  • Cheng X, Broberger C, Tong Y, Yongtao X, Ju G, Zhang X & Hokfelt T 1998 Regulation of expression of neuropeptide Y Y1 and Y2 receptors in the arcuate nucleus of fasted rats. Brain Research 792 89–96.

    • Search Google Scholar
    • Export Citation
  • Cheung CC, Clifton DK & Steiner RA 1997 Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138 4489–4492.

    • Search Google Scholar
    • Export Citation
  • Christofides ND, Sarson DL, Albuquerque RH, Adrian TE, Ghatei MA, Modlin IM & Bloom SR 1979 Release of gastrointestinal hormones following an oral water load. Experientia 35 1521–1523.

    • Search Google Scholar
    • Export Citation
  • Chua SC Jr, Koutras IK, Han L, Liu SM, Kay J, Young SJ, Chung WK & Leibel RL 1997 Fine structure of the murine leptin receptor gene: splice site suppression is required to form two alternatively spliced transcripts. Genomics 45 264–270.

    • Search Google Scholar
    • Export Citation
  • Chung WK, Belfi K, Chua M, Wiley J, Mackintosh R, Nicolson M, Boozer CN & Leibel RL 1998 Heterozygosity for Lep(ob) or Lep(rdb) affects body composition and leptin homeostasis in adult mice. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 274 R985–R990.

    • Search Google Scholar
    • Export Citation
  • Clark JT, Kalra PS, Crowley WR & Kalra SP 1984 Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115 427–429.

    • Search Google Scholar
    • Export Citation
  • Clark JT, Sahu A, Kalra PS, Balasubramaniam A & Kalra SP 1987 Neuropeptide Y (NPY)-induced feeding behavior in female rats: comparison with human NPY ([Met17]NPY), NPY analog ([norLeu4]NPY) and peptide YY. Regulatory Peptides 17 31–39.

    • Search Google Scholar
    • Export Citation
  • Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM et al. 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392 398–401.

    • Search Google Scholar
    • Export Citation
  • Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA & Bloom SR 2003 Oxyntomodulin suppresses appetite and reduces food intake in humans. Journal of Clinical Endocrinology and Metabolism 88 4696–4701.

    • Search Google Scholar
    • Export Citation
  • Coleman DL 1979 Obesity genes: beneficial effects in heterozygous mice. Science 203 663–665.

  • Coll AP, Challis BG & ORahilly S 2004 Peptide YY3–36 and satiety: clarity or confusion? Endocrinology 145 2582–2584.

  • Cone RD, Cowley MA, Butler AA, Fan W, Marks DL & Low MJ 2001 The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. International Journal of Obesity and Related Metabolic Disorders 25 Suppl 5 S63–S67.

    • Search Google Scholar
    • Export Citation
  • Conlon JM 2002 The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP). Peptides 23 269–278.

  • Conrad CD & McEwen BS 2000 Acute stress increases neuropeptide Y mRNA within the arcuate nucleus and hilus of the dentate gyrus. Brain Research Molecular Brain Research 79 102–109.

    • Search Google Scholar
    • Export Citation
  • Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL et al. 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine 334 292–295.

    • Search Google Scholar
    • Export Citation
  • Corp ES, Woods SC, Porte D Jr, Dorsa DM, Figlewicz DP & Baskin DG 1986 Localization of 125I-insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neuroscience Letters 70 17–22.

    • Search Google Scholar
    • Export Citation
  • Corpa ES, McQuade J, Krasnicki S & Conze DB 2001 Feeding after fourth ventricular administration of neuropeptide Y receptor agonists in rats. Peptides 22 493–499.

    • Search Google Scholar
    • Export Citation
  • Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S et al. 2003 The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. Journal of Clinical Investigations 112 423–431.

    • Search Google Scholar
    • Export Citation
  • Couceyro PR, Koylu EO & Kuhar MJ 1997 Further studies on the anatomical distribution of CART by in situ hybridization. Journal of Chemical Neuroanatomy 12 229–241.

    • Search Google Scholar
    • Export Citation
  • Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF & Cone RD 1999 Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24 155–163.

    • Search Google Scholar
    • Export Citation
  • Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD & Low MJ 2001 Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411 480–484.

    • Search Google Scholar
    • Export Citation
  • Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML et al. 2003 The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37 649–661.

    • Search Google Scholar
    • Export Citation
  • Crawley JN & Beinfeld MC 1983 Rapid development of tolerance to the behavioural actions of cholecystokinin. Nature 302 703–706.

  • Crawley JN & Corwin RL 1994 Biological actions of cholecystokinin. Peptides 15 731–755.

  • Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE & Weigle DS 2001 A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50 1714–1719.

    • Search Google Scholar
    • Export Citation
  • Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A & Weigle DS 2002a Elevated plasma ghrelin levels in Prader Willi syndrome. Nature Medicine 8 643–644.

    • Search Google Scholar
    • Export Citation
  • Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP & Purnell JQ 2002b Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New England Journal of Medicine 346 1623–1630.

    • Search Google Scholar
    • Export Citation
  • Cummings DE, Frayo RS, Marmonier C, Aubert R & Chapelot D 2004 Plasma ghrelin levels and hunger scores among humans initiating meals voluntarily in the absence of time- and food-related cues. American Journal of Physiology – Endocrinology and Metabolism 287 E297–E304.

    • Search Google Scholar
    • Export Citation
  • Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA & Bloom SR 2001 Oxyntomodulin inhibits food intake in the rat. Endocrinology 142 4244–4250.

    • Search Google Scholar
    • Export Citation
  • Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA & Bloom SR 2002 Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. American Journal of Physiology – Endocrinology and Metabolism 283 E1173–E1177.

    • Search Google Scholar
    • Export Citation
  • Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA, Patterson M, Ghatei MA & Bloom SR 2004 Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 145 2687–2695.

    • Search Google Scholar
    • Export Citation
  • Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K & Nakazato M 2000a Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141 4255–4261.

    • Search Google Scholar
    • Export Citation
  • Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K & Nakazato M 2000b Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochemical and Biophysical Research Communications 275 477–480.

    • Search Google Scholar
    • Export Citation
  • Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H et al. 2002a Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes 51 124–129.

    • Search Google Scholar
    • Export Citation
  • Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K & Nakazato M 2002b The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123 1120–1128.

    • Search Google Scholar
    • Export Citation
  • De Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS et al. 1998 The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. PNAS 95 322–327.

    • Search Google Scholar
    • Export Citation
  • Dhillo WS, Small CJ, Stanley SA, Jethwa PH, Seal LJ, Murphy KG, Ghatei MA & Bloom SR 2002 Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats. Journal of Neuroendocrinology 14 725–730.

    • Search Google Scholar
    • Export Citation
  • Di M, V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T & Kunos G 2001 Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410 822–825.

    • Search Google Scholar
    • Export Citation
  • Drewnowski A, Krahn DD, Demitrack MA, Nairn K & Gosnell BA 1992 Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement. Physiology and Behavior 51 371–379.

    • Search Google Scholar
    • Export Citation
  • Dumont Y, Fournier A & Quirion R 1998 Expression and characterization of the neuropeptide Y Y5 receptor subtype in the rat brain. Journal of Neuroscience 18 5565–5574.

    • Search Google Scholar
    • Export Citation
  • Dunn-Meynell AA, Govek E & Levin BE 1997 Intracarotid glucose selectively increases Fos-like immunoreactivity in paraventricular, ventromedial and dorsomedial nuclei neurons. Brain Research 748 100–106.

    • Search Google Scholar
    • Export Citation
  • Eberlein GA, Eysselein VE, Schaeffer M, Layer P, Grandt D, Goebell H, Niebel W, Davis M, Lee TD, Shively JE et al. 1989 A new molecular form of PYY: structural characterization of human PYY(3–36) and PYY(1–36). Peptides 10 797–803.

    • Search Google Scholar
    • Export Citation
  • Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA & Bloom SR 1999 The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. Journal of Endocrinology 160 R7–R12.

    • Search Google Scholar
    • Export Citation
  • Egawa M, Yoshimatsu H & Bray GA 1991 Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 260 R328–R334.

    • Search Google Scholar
    • Export Citation
  • Ekblad E & Sundler F 2002 Distribution of pancreatic polypeptide and peptide YY. Peptides 23 251–261.

  • El Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C & Flier JS 2000 Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Journal of Clinical Investigation 105 1827–1832.

    • Search Google Scholar
    • Export Citation
  • Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB & Elmquist JK 1998a Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21 1375–1385.

    • Search Google Scholar
    • Export Citation
  • Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, Tatro JB, Hoffman GE, Ollmann MM, Barsh GS, Sakurai T, Yanagisawa M & Elmquist JK 1998b Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. Comparative Journal of Neurology 402 442–459.

    • Search Google Scholar
    • Export Citation
  • Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB & Elmquist JK 1999 Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23 775–786.

    • Search Google Scholar
    • Export Citation
  • Ellacott KL & Cone RD 2004 The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. Recent Progress in Hormone Research 59 395–408.

    • Search Google Scholar
    • Export Citation
  • Elmquist JK, Ahima RS , Maratos-Flier E, Flier JS & Saper CB 1997 Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138 839–842.

    • Search Google Scholar
    • Export Citation
  • Elmquist JK, Bjorbaek C, Ahima RS, Flier JS & Saper CB 1998a Distributions of leptin receptor mRNA isoforms in the rat brain. Comparative Journal of Neurology 395 535–547.

    • Search Google Scholar
    • Export Citation
  • Elmquist JK, Maratos-Flier E, Saper CB & Flier JS 1998b Unraveling the central nervous system pathways underlying responses to leptin. Nature Neuroscience 1 445–450.

    • Search Google Scholar
    • Export Citation
  • English PJ, Ghatei MA, Malik IA, Bloom SR & Wilding JP 2002 Food fails to suppress ghrelin levels in obese humans. Journal of Clinical Endocrinology and Metabolism 87 2984.

    • Search Google Scholar
    • Export Citation
  • Fan W, Boston BA, Kesterson RA, Hruby VJ & Cone RD 1997 Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385 165–168.

    • Search Google Scholar
    • Export Citation
  • Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA & O’Rahilly S 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 341 879–884.

    • Search Google Scholar
    • Export Citation
  • Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T & O’Rahilly S 2000 Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. Journal of Clinical Investigation 106 271–279.

    • Search Google Scholar
    • Export Citation
  • Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY & O’Rahilly S 2001 Partial leptin deficiency and human adiposity. Nature 414 34–35.

    • Search Google Scholar
    • Export Citation
  • Fehmann HC, Jiang J, Schweinfurth J, Wheeler MB, Boyd AE III & Goke B 1994 Stable expression of the rat GLP-I receptor in CHO cells: activation and binding characteristics utilizing GLP-I(7–36)-amide, oxyntomodulin, exendin-4, and exendin(9–39). Peptides 15 453–456.

    • Search Google Scholar
    • Export Citation
  • Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R & Friedman JM 1997 Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. PNAS 94 7001–7005.

    • Search Google Scholar
    • Export Citation
  • Fekete C, Legradi G, Mihaly E, Huang QH, Tatro JB, Rand WM, Emerson CH & Lechan RM 2000 alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. Journal of Neuroscience 20 1550–1558.

    • Search Google Scholar
    • Export Citation
  • Fekete C, Sarkar S, Rand WM, Harney JW, Emerson CH, Bianco AC & Lechan RM 2002 Agouti-related protein (AGRP) has a central inhibitory action on the hypothalamic-pituitary-thyroid (HPT) axis; comparisons between the effect of AGRP and neuropeptide Y on energy homeostasis and the HPT axis. Endocrinology 143 3846–3853.

    • Search Google Scholar
    • Export Citation
  • Finer N 2002 Pharmacotherapy of obesity. Best Practice and Research. Clinical Endocrinology and Metabolism 16 717–742.

  • Flint A, Raben Ai, Ersboll AK, Holst JJ & Astrup A 2001 The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. International Journal of Obesity and Related Metabolic Disorders 25 781–792.

    • Search Google Scholar
    • Export Citation
  • Flynn MC, Turrin NP, Plata-Salaman CR & Ffrench-Mullen JM 1999 Feeding response to neuropeptide Y-related compounds in rats treated with Y5 receptor antisense or sense phosphothio-oligodeoxynucleotide. Physiology and Behavior 66 881–884.

    • Search Google Scholar
    • Export Citation
  • Fodor M, Sluiter A, Frankhuijzen-Sierevogel A, Wiegant VM, Hoogerhout P, De Wildt DJ & Versteeg DH 1996 Distribution of Lys-gamma 2-melanocyte-stimulating hormone- (Lys-gamma 2-MSH)-like immunoreactivity in neuronal elements in the brain and peripheral tissues of the rat. Brain Research 731 182–189.

    • Search Google Scholar
    • Export Citation
  • Fogteloo AJ, Pijl H, Frolich M, McCamish M & Meinders AE 2003 Effects of recombinant human leptin treatment as an adjunct of moderate energy restriction on body weight, resting energy expenditure and energy intake in obese humans. Diabetes, Nutrition & Metabolism 16 109–114.

    • Search Google Scholar
    • Export Citation
  • Frandsen J, Pedersen SB & Richelsen B 1998 Long term follow up of patients who underwent jejunoileal bypass for morbid obesity. European Journal of Surgery 164 281–286.

    • Search Google Scholar
    • Export Citation
  • Frederich RC, Lollmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB & Flier JS 1995 Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. Journal of Clinical Investigation 96 1658–1663.

    • Search Google Scholar
    • Export Citation
  • Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE & Lodish HF 2001 Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. PNAS 98 2005–2010.

    • Search Google Scholar
    • Export Citation
  • Fu-Cheng X, Anini Y, Chariot J, Castex N, Galmiche JP & Roze C 1997 Mechanisms of peptide YY release induced by an intraduodenal meal in rats: neural regulation by proximal gut. Pflugers Archiv 433 571–579.

    • Search Google Scholar
    • Export Citation
  • Fujimoto S, Inui A, Kiyota N, Seki W, Koide K, Takamiya S, Uemoto M, Nakajima Y, Baba S & Kasuga M 1997 Increased cholecystokinin and pancreatic polypeptide responses to a fat-rich meal in patients with restrictive but not bulimic anorexia nervosa. Biological Psychiatry 41 1068–1070.

    • Search Google Scholar
    • Export Citation
  • Fulton S, Woodside B & Shizgal P 2000 Modulation of brain reward circuitry by leptin. Science 287 125–128.

  • Fuxe K, Tinner B, Caberlotto L, Bunnemann B & Agnati LF 1997 NPY Y1 receptor like immunoreactivity exists in a subpopulation of beta-endorphin immunoreactive nerve cells in the arcuate nucleus: a double immunolabelling analysis in the rat. Neuroscience Letters 225 49–52.

    • Search Google Scholar
    • Export Citation
  • Ge H, Huang L, Pourbahrami T & Li C 2002 Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. Journal of Biological Chemistry 277 45898–45903.

    • Search Google Scholar
    • Export Citation
  • Ghatei MA, Uttenthal LO, Christofides ND, Bryant MG & Bloom SR 1983 Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. Journal of Clinical Endocrinology and Metabolism 57 488–495.

    • Search Google Scholar
    • Export Citation
  • Gibbs J, Young RC & Smith GP 1973 Cholecystokinin decreases food intake in rats. Journal of Comparative Physiology and Psychology 84 488–495.

    • Search Google Scholar
    • Export Citation
  • Giraudo SQ, Billington CJ & Levine AS 1998 Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Research 809 302–306.

    • Search Google Scholar
    • Export Citation
  • Glaser B, Zoghlin G, Pienta K & Vinik AI 1988 Pancreatic polypeptide response to secretin in obesity: effects of glucose intolerance. Hormone and Metabolic Research 20 288–292.

    • Search Google Scholar
    • Export Citation
  • Glass MJ, Chan J & Pickel VM 2002 Ultrastructural localization of neuropeptide Y Y1 receptors in the rat medial nucleus tractus solitarius: relationships with neuropeptide Y or catecholamine neurons. Journal of Neuroscience Research 67 753–765.

    • Search Google Scholar
    • Export Citation
  • Glover I, Haneef I, Pitts J, Wood S, Moss D, Tickle I & Blundell T 1983 Conformational flexibility in a small globular hormone: x-ray analysis of avian pancreatic polypeptide at 0·98-A resolution. Biopolymers 22 293–304.

    • Search Google Scholar
    • Export Citation
  • Grauerholz BL, Jacobson JD, Handler MS & Millington WR 1998 Detection of pro-opiomelanocortin mRNA in human and rat caudal medulla by RT-PCR. Peptides 19 939–948.

    • Search Google Scholar
    • Export Citation
  • Grill HJ & Kaplan JM 2002 The neuroanatomical axis for control of energy balance. Frontiers in Neuroendocrinology 23 2–40.

  • Gualillo O, Caminos J, Blanco M, Garcia-Caballero T, Kojima M, Kangawa K, Dieguez C & Casanueva F 2001 Ghrelin, a novel placental-derived hormone. Endocrinology 142 788–794.

    • Search Google Scholar
    • Export Citation
  • Guan XM, Yu H & Van der Ploeg LH 1998 Evidence of altered hypothalamic pro-opiomelanocortin/neuropeptide Y mRNA expression in tubby mice. Brain Research Molecular Brain Research 59 273–279.

    • Search Google Scholar
    • Export Citation
  • Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P et al. 1999 Orexin A activates locus coeruleus cell firing and increases arousal in the rat. PNAS 96 10911–10916.

    • Search Google Scholar
    • Export Citation
  • Hagan MM, Castaneda E, Sumaya IC, Fleming SM, Galloway J & Moss DE 1998 The effect of hypothalamic peptide YY on hippocampal acetylcholine release in vivo: implications for limbic function in binge-eating behavior. Brain Research 805 20–28.

    • Search Google Scholar
    • Export Citation
  • Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van der Ploeg LH, Woods SC & Seeley RJ 2000 Long-term orexigenic effects of AgRP-(83–132) involve mechanisms other than melanocortin receptor blockade. American Journal of Physiology –Regulatory, Integrative and Comparative Physiology 279 R47–R52.

    • Search Google Scholar
    • Export Citation
  • Hagan MM, Rushing PA, Benoit SC, Woods SC & Seeley RJ 2001 Opioid receptor involvement in the effect of AgRP-(83–132) on food intake and food selection. American Journal of Physiology –Regulatory, Integrative and Comparative Physiology 280 R814–R821.

    • Search Google Scholar
    • Export Citation
  • Hahn TM, Breininger JF, Baskin DG & Schwartz MW 1998 Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neuroscience 1 271–272.

    • Search Google Scholar
    • Export Citation
  • Hakansson ML, Brown H, Ghilardi N, Skoda RC & Meister B 1998 Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. Journal of Neuroscience 18 559–572.

    • Search Google Scholar
    • Export Citation
  • Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK & Friedman JM 1995 Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269 543–546.

    • Search Google Scholar
    • Export Citation
  • Halatchev IG, Ellacott KL, Fan W & Cone RD 2004 Peptide YY3–36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 145 2585–2590.

    • Search Google Scholar
    • Export Citation
  • Hamamura M, Leng G, Emson PC & Kiyama H 1991 Electrical activation and c-fos mRNA expression in rat neurosecretory neurones after systemic administration of cholecystokinin. Journal of Physiology 444 51–63.

    • Search Google Scholar
    • Export Citation
  • Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS & Jorgensen JO 2002 Weight loss increases circulating levels of ghrelin in human obesity. Clinical Endocrinology (Oxford) 56 203–206.

    • Search Google Scholar
    • Export Citation
  • Harfstrand A, Fuxe K, Agnati LF, Benfenati F & Goldstein M 1986 Receptor autoradiographical evidence for high densities of 125I-neuropeptide Y binding sites in the nucleus tractus solitarius of the normal male rat. Acta Physiologica Scandinavica 128 195–200.

    • Search Google Scholar
    • Export Citation
  • Harrold JA, Widdowson PS & Williams G 1999 Altered energy balance causes selective changes in melanocortin-4 (MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding. Diabetes 48 267–271.

    • Search Google Scholar
    • Export Citation
  • Hattori N, Saito T, Yagyu T, Jiang BH, Kitagawa K & Inagaki C 2001 GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. Journal of Clinical Endocrinology and Metabolism 86 4284–4291.

    • Search Google Scholar
    • Export Citation
  • Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M & Arch JR 1999 Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20 1099–1105.

    • Search Google Scholar
    • Export Citation
  • Hayward MD, Pintar JE & Low MJ 2002 Selective reward deficit in mice lacking beta-endorphin and enkephalin. Journal of Neuroscience 22 8251–8258.

    • Search Google Scholar
    • Export Citation
  • Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H et al. 2002 Activation of central melanocortin pathways by fenfluramine. Science 297 609–611.

    • Search Google Scholar
    • Export Citation
  • Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R & Goke B 1995 Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 56 117–126.

    • Search Google Scholar
    • Export Citation
  • Hewson G, Leighton GE, Hill RG & Hughes J 1988 The cholecystokinin receptor antagonist L364,718 increases food intake in the rat by attenuation of the action of endogenous cholecystokinin. British Journal of Pharmacology 93 79–84.

    • Search Google Scholar
    • Export Citation
  • Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P & McCamish M 1999 Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. Journal of the American Medical Association 282 1568–1575.

    • Search Google Scholar
    • Export Citation
  • Hinney A, Hoch A, Geller F, Schafer H, Siegfried W, Goldschmidt H, Remschmidt H & Hebebrand J 2002 Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students. Journal of Clinical Endocrinology and Metabolism 87 2716–2719.

    • Search Google Scholar
    • Export Citation
  • Hoentjen F, Hopman WP & Jansen JB 2001 Effect of circulating peptide YY on gallbladder emptying in humans. Scandiavian Journal of Gastroenterology 36 1086–1091.

    • Search Google Scholar
    • Export Citation
  • Holst JJ 1999 Glucagon-like peptide 1 (GLP-1): an intestinal hormone, signalling nutritional abundance, with an unusual therapeutic potential. Trends in Endocrinology and Metabolism 10 229–235.

    • Search Google Scholar
    • Export Citation
  • Holst JJ 2004 Treatment of Type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. Expert Opinion on Emerging Drugs 9 155–166.

    • Search Google Scholar
    • Export Citation
  • Holst JJ, Sorensen TI, Andersen AN, Stadil F, Andersen B, Lauritsen KB & Klein HC 1979 Plasma enteroglucagon after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio. Scandiavian Journal of Gastroenterology 14 205–207.

    • Search Google Scholar
    • Export Citation
  • Holst JJ, Schwartz TW, Lovgreen NA, Pedersen O & Beck-Nielsen H 1983 Diurnal profile of pancreatic polypeptide, pancreatic glucagon, gut glucagon and insulin in human morbid obesity. International Journal of Obesity 7 529–538.

    • Search Google Scholar
    • Export Citation
  • Horvath TL, Diano S & van den Pol AN 1999 Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. Journal of Neuroscience 19 1072–1087.

    • Search Google Scholar
    • Export Citation
  • Hosoi T, Kawagishi T, Okuma Y, Tanaka J & Nomura Y 2002 Brain stem is a direct target for leptin’s action in the central nervous system. Endocrinology 143 3498–3504.

    • Search Google Scholar
    • Export Citation
  • Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K et al. 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis, Thrombosis, and Vascular Biology 20 1595–1599.

    • Search Google Scholar
    • Export Citation
  • Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC & Matsuzawa Y 2001 Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50 1126–1133.

    • Search Google Scholar
    • Export Citation
  • Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C & Flier JS 2004 Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nature Medicine 10 734–738.

    • Search Google Scholar
    • Export Citation
  • Hu E, Liang P & Spiegelman BM 1996 AdipoQ is a novel adipose-specific gene dysregulated in obesity. Journal of Biological Chemistry 271 10697–10703.

    • Search Google Scholar
    • Export Citation
  • Huang XF, Han M, South T & Storlien L 2003 Altered levels of POMC, AgRP and MC4-R mRNA expression in the hypothalamus and other parts of the limbic system of mice prone or resistant to chronic high-energy diet-induced obesity. Brain Research 992 9–19.

    • Search Google Scholar
    • Export Citation
  • Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD et al. 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88 131–141.

    • Search Google Scholar
    • Export Citation
  • Ikeda H, West DB, Pustek JJ, Figlewicz DP, Greenwood MR, Porte D Jr & Woods SC 1986 Intraventricular insulin reduces food intake and body weight of lean but not obese Zucker rats. Appetite 7 381–386.

    • Search Google Scholar
    • Export Citation
  • Inui A 1999 Neuropeptide Y feeding receptors: are multiple subtypes involved? Trends in Pharmacological Sciences 20 43–46.

  • Kalia M & Sullivan JM 1982 Brainstem projections of sensory and motor components of the vagus nerve in the rat. Comparative Journal of Neurology 211 248–265.

    • Search Google Scholar
    • Export Citation
  • Kalra SP, Dube MG, Sahu A, Phelps CP & Kalra PS 1991 Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. PNAS 88 10931–10935.

    • Search Google Scholar
    • Export Citation
  • Kalra SP, Dube MG, Pu S, Xu B, Horvath TL & Kalra PS 1999 Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocrine Reviews 20 68–100.

    • Search Google Scholar
    • Export Citation
  • Kanatani A, Ishihara A, Asahi S, Tanaka T, Ozaki S & Ihara M 1996 Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced and physiological food intake. Endocrinology 137 3177–3182.

    • Search Google Scholar
    • Export Citation
  • Kanatani A, Mashiko S, Murai N, Sugimoto N, Ito J, Fukuroda T, Fukami T, Morin N, MacNeil DJ, Van der Ploeg LH, Saga Y, Nishimura S & Ihara M 2000 Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology 141 1011–1016.

    • Search Google Scholar
    • Export Citation
  • Kastin AJ & Pan W 2000 Dynamic regulation of leptin entry into brain by the blood-brain barrier. Regulatory Peptides 92 37–43.

  • Kastin AJ, Akerstrom V & Pan W 2002 Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. Journal of Molecular Neuroscience 18 7–14.

    • Search Google Scholar
    • Export Citation
  • Katsuura G, Asakawa A & Inui A 2002 Roles of pancreatic polypeptide in regulation of food intake. Peptides 23 323–329.

  • Kawai Y, Inagaki S, Shiosaka S, Shibasaki T, Ling N, Tohyama M & Shiotani Y 1984 The distribution and projection of gamma-melanocyte stimulating hormone in the rat brain: an immunohistochemical analysis. Brain Research 297 21–32.

    • Search Google Scholar
    • Export Citation
  • Kim MS, Rossi M, Abusnana S, Sunter D, Morgan DG, Small CJ, Edwards CM, Heath MM, Stanley SA, Seal LJ et al. 2000a Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone. Diabetes 49 177–182.

    • Search Google Scholar
    • Export Citation
  • Kim MS, Small CJ, Stanley SA, Morgan DG, Seal LJ, Kong WM, Edwards CM, Abusnana S, Sunter D, Ghatei MA & Bloom SR 2000b The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. Journal of Clinical Investigation 105 1005–1011.

    • Search Google Scholar
    • Export Citation
  • King PJ, Widdowson PS, Doods HN & Williams G 1999 Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices. Journal of Neurochemistry 73 641–646.

    • Search Google Scholar
    • Export Citation
  • King PJ, Williams G, Doods H & Widdowson PS 2000 Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release. European Journal of Pharmacology 396 R1–R3.

    • Search Google Scholar
    • Export Citation
  • Kirchgessner AL & Liu M 1999 Orexin synthesis and response in the gut. Neuron 24 941–951.

  • Kissileff HR, Pi-Sunyer FX, Thornton J & Smith GP 1981 C-terminal octapeptide of cholecystokinin decreases food intake in man. American Journal of Clinical Nutrition 34 154–160.

    • Search Google Scholar
    • Export Citation
  • Kissileff HR, Carretta JC, Geliebter A & Pi-Sunyer FX 2003 Cholecystokinin and stomach distension combine to reduce food intake in humans. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 285 R992–R998.

    • Search Google Scholar
    • Export Citation
  • Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H & Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402 656–660.

    • Search Google Scholar
    • Export Citation
  • van der Kooy D, Koda LY, McGinty JF, Gerfen CR & Bloom FE 1984 The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat. Comparative Journal of Neurology 224 1–24.

    • Search Google Scholar
    • Export Citation
  • Korbonits M, Gueorguiev M, O’Grady E, Lecoeur C, Swan DC, Mein CA, Weill J, Grossman AB & Froguel P 2002 A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. Journal of Clinical Endocrinology and Metabolism 87 4005–4008.

    • Search Google Scholar
    • Export Citation
  • Kreymann B, Williams G, Ghatei MA & Bloom SR 1987 Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet 2 1300–1304.

  • Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ & Hastrup S 1998 Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393 72–76.

    • Search Google Scholar
    • Export Citation
  • Krude H, Biebermann H, Luck W, Horn R, Brabant G & Gruters A 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics 19 155–157.

    • Search Google Scholar
    • Export Citation
  • Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H et al. 2002 Disruption of adiponectin causes insulin resistance and neointimal formation. Journal of Biological Chemistry 277 25863–25866.

    • Search Google Scholar
    • Export Citation
  • Kuo DY 2002 Co-administration of dopamine D1 and D2 agonists additively decreases daily food intake, body weight and hypothalamic neuropeptide Y level in rats. Journal of Biomedical Science 9 126–132.

    • Search Google Scholar
    • Export Citation
  • Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M & Nakamura M 1998 Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. PNAS 95 15659–15664.

    • Search Google Scholar
    • Export Citation
  • Lambert PD, Phillips PJ, Wilding JP, Bloom SR & Herbert J 1995 c-fos expression in the paraventricular nucleus of the hypothalamus following intracerebroventricular infusions of neuropeptide Y. Brain Research 670 59–65.

    • Search Google Scholar
    • Export Citation
  • Lambert PD, Couceyro PR, McGirr KM, Dall Vechia SE, Smith Y & Kuhar MJ 1998 CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse 29 293–298.

    • Search Google Scholar
    • Export Citation
  • Larhammar D 1996 Structural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide. Regulatory Peptides 65 165–174.

    • Search Google Scholar
    • Export Citation
  • Larsson LI & Rehfeld JF 1978 Distribution of gastrin and CCK cells in the rat gastrointestinal tract. Evidence for the occurrence of three distinct cell types storing COOH-terminal gastrin immunoreactivity. Histochemistry 58 23–31.

    • Search Google Scholar
    • Export Citation
  • Larsson LI, Sundler F & Hakanson R 1975 Immunohistochemical localization of human pancreatic polypeptide (HPP) to a population of islet cells. Cell Tissue Research 156 167–171.

    • Search Google Scholar
    • Export Citation
  • Lassmann V, Vague P, Vialettes B & Simon MC 1980 Low plasma levels of pancreatic polypeptide in obesity. Diabetes 29 428–430.

  • Lawrence CB, Snape AC, Baudoin FM & Luckman SM 2002 Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 143 155–162.

    • Search Google Scholar
    • Export Citation
  • Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI & Friedman JM 1996 Abnormal splicing of the leptin receptor in diabetic mice. Nature 379 632–635.

    • Search Google Scholar
    • Export Citation
  • Lee HM, Udupi V, Englander EW, Rajaraman S, Coffey RJ Jr & Greeley GH Jr 1999 Stimulatory actions of insulin-like growth factor-I and transforming growth factor-alpha on intestinal neurotensin and peptide YY. Endocrinology 140 4065–4069.

    • Search Google Scholar
    • Export Citation
  • Legradi G & Lechan RM 1999 Agouti-related protein containing nerve terminals innervate thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology 140 3643–3652.

    • Search Google Scholar
    • Export Citation
  • Le Quellec A, Kervran A, Blache P, Ciurana AJ & Bataille D 1992 Oxyntomodulin-like immunoreactivity: diurnal profile of a new potential enterogastrone. Journal of Clinical Endocrinology and Metabolism 74 1405–1409.

    • Search Google Scholar
    • Export Citation
  • Levin BE & Dunn-Meynell AA 2002 Reduced central leptin sensitivity in rats with diet-induced obesity. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 283 R941–R948.

    • Search Google Scholar
    • Export Citation
  • Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S et al. 2004 Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. PNAS 101 4531–4536.

    • Search Google Scholar
    • Export Citation
  • Liddle RA, Goldfine ID, Rosen MS, Taplitz RA & Williams JA 1985 Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. Journal of Clinical Investigation 75 1144–1152.

    • Search Google Scholar
    • Export Citation
  • Lin HC & Chey WY 2003 Cholecystokinin and peptide YY are released by fat in either proximal or distal small intestine in dogs. Regulatory Peptides 114 131–135.

    • Search Google Scholar
    • Export Citation
  • Lin L, Martin R, Schaffhauser AO & York DA 2001 Acute changes in the response to peripheral leptin with alteration in the diet composition. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 280 R504–R509.

    • Search Google Scholar
    • Export Citation
  • Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR & Lechler RI 1998 Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394 897–901.

    • Search Google Scholar
    • Export Citation
  • Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO et al. 1994 Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371 799–802.

    • Search Google Scholar
    • Export Citation
  • Lubrano-Berthelier C, Cavazos M, Dubern B, Shapiro A, Stunff CL, Zhang S, Picart F, Govaerts C, Froguel P, Bougneres P et al. 2003a Molecular genetics of human obesity-associated MC4R mutations. Annals of the New York Academy of Sciences 994 49–57.

    • Search Google Scholar
    • Export Citation
  • Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P & Vaisse C 2003b Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Human Molecular Genetics 12 145–153.

    • Search Google Scholar
    • Export Citation
  • MacDonald PE, El Kholy W, Riedel MJ, Salapatek AM, Light PE & Wheeler MB 2002 The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 51 Suppl 3 S434–S442.

    • Search Google Scholar
    • Export Citation
  • Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y et al. 2002 Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nature Medicine 8 731–737.

    • Search Google Scholar
    • Export Citation
  • Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S et al. 1995 Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine 1 1155–1161.

    • Search Google Scholar
    • Export Citation
  • Makimura H, Mizuno TM, Mastaitis JW, Agami R & Mobbs CV 2002 Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neuroscience 3 18.

    • Search Google Scholar
    • Export Citation
  • Makino S, Baker RA, Smith MA & Gold PW 2000 Differential regulation of neuropeptide Y mRNA expression in the arcuate nucleus and locus coeruleus by stress and antidepressants. Journal of Neuroendocrinology 12 387–395.

    • Search Google Scholar
    • Export Citation
  • Malaisse-Lagae F, Carpentier JL, Patel YC, Malaisse WJ & Orci L 1977 Pancreatic polypeptide: a possible role in the regulation of food intake in the mouse. Hypothesis. Experientia 33 915–917.

    • Search Google Scholar
    • Export Citation
  • Marks DL, Boucher N, Lanouette CM, Perusse L, Brookhart G, Comuzzie AG, Chagnon YC & Cone RD 2004 Ala67 Thr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans. American Journal of Medical Genetics 126A 267–271.

    • Search Google Scholar
    • Export Citation
  • Marks JL, Porte D Jr, Stahl WL & Baskin DG 1990 Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127 3234–3236.

    • Search Google Scholar
    • Export Citation
  • Marsh DJ, Hollopeter G, Kafer KE & Palmiter RD 1998 Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nature Medicine 4 718–721.

    • Search Google Scholar
    • Export Citation
  • Marsh DJ, Miura GI, Yagaloff KA, Schwartz MW, Barsh GS & Palmiter RD 1999 Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues. Brain Research 848 66–77.

    • Search Google Scholar
    • Export Citation
  • Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan XM, Jiang MM, Feng Y, Camacho RE et al. 2002 Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. PNAS 99 3240–3245.

    • Search Google Scholar
    • Export Citation
  • Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T & Nakao K 1997 Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nature Medicine 3 1029–1033.

    • Search Google Scholar
    • Export Citation
  • Matson CA, Reid DF, Cannon TA & Ritter RC 2000 Cholecystokinin and leptin act synergistically to reduce body weight. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 278 R882–R890.

    • Search Google Scholar
    • Export Citation
  • McGowan MK, Andrews KM & Grossman SP 1992 Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiology and Behavior 51 753–766.

    • Search Google Scholar
    • Export Citation
  • McLaughlin CL & Baile CA 1981 Obese mice and the satiety effects of cholecystokinin, bombesin and pancreatic polypeptide. Physiology and Behavior 26 433–437.

    • Search Google Scholar
    • Export Citation
  • McLaughlin CL, Baile CA & Buonomo FC 1985 Effect of CCK antibodies on food intake and weight gain in Zucker rats. Physiology and Behavior 34 277–282.

    • Search Google Scholar
    • Export Citation
  • Meeran K, O’Shea D, Edwards CM, Turton MD, Heath MM, Gunn I, Abusnana S, Rossi M, Small CJ, Goldstone AP et al. 1999 Repeated intracerebroventricular administration of glucagon-like peptide-1-(7–36) amide or exendin-(9–39) alters body weight in the rat. Endocrinology 140 244–250.

    • Search Google Scholar
    • Export Citation
  • Meereis-Schwanke K, Klonowski-Stumpe H, Herberg L & Niederau C 1998 Long-term effects of CCK-agonist and -antagonist on food intake and body weight in Zucker lean and obese rats. Peptides 19 291–299.

    • Search Google Scholar
    • Export Citation
  • Menendez JA & Atrens DM 1991 Insulin and the paraventricular hypothalamus: modulation of energy balance. Brain Research 555 193–201.

  • Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Morgan PJ & Trayhurn P 1996 Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. Journal of Neuroendocrinology 8 733–735.

    • Search Google Scholar
    • Export Citation
  • Mercer JG, Moar KM & Hoggard N 1998 Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. Endocrinology 139 29–34.

    • Search Google Scholar
    • Export Citation
  • Meryn S, Stein D & Straus EW 1986 Fasting- and meal-stimulated peptide hormone concentrations before and after gastric surgery for morbid obesity. Metabolism 35 798–802.

    • Search Google Scholar
    • Export Citation
  • Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ & Kahn BB 2004 AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428 569–574.

    • Search Google Scholar
    • Export Citation
  • Miraglia dG, Santoro N, Cirillo G, Raimondo P, Grandone A, D’Aniello A, Di Nardo M & Perrone L 2004 Molecular screening of the ghrelin gene in Italian obese children: the Leu72 Met variant is associated with an earlier onset of obesity. International Journal of Obesity and Related Metabolic Disorders 28 447–450.

    • Search Google Scholar
    • Export Citation
  • Mitchell JE, Lancaster KL, Burgard MA, Howell LM, Krahn DD, Crosby RD, Wonderlich SA & Gosnell BA 2001 Long-term follow-up of patients’ status after gastric bypass. Obesity Surgery 11 464–468.

    • Search Google Scholar
    • Export Citation
  • Mochiki E, Inui A, Satoh M, Mizumoto A & Itoh Z 1997 Motilin is a biosignal controlling cyclic release of pancreatic polypeptide via the vagus in fasted dogs. American Journal of Physiology Gastrointestinal and Liver Physiology 272 G224–G232.

    • Search Google Scholar
    • Export Citation
  • Moltz JH & McDonald JK 1985 Neuropeptide Y: direct and indirect action on insulin secretion in the rat. Peptides 6 1155–1159.

  • Mencarelli M, Maestrini S, Tagliaferri M, Brunani A, Petroni ML, Liuzzi A & DiBlasio AM Identification of three novel melanocortin 3 receptor (MC3R) gene mutations in patients with morbid obesity. American Endocrine Society, New Orleans 2004, Abstract OR45-1.

  • Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA et al. 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387 903–908.

    • Search Google Scholar
    • Export Citation
  • Moran TH & Schwartz GJ 1994 Neurobiology of cholecystokinin. Critical Reviews in Neurobiology 9 1–28.

  • Moran TH, Robinson PH, Goldrich MS & McHugh PR 1986 Two brain cholecystokinin receptors: implications for behavioral actions. Brain Research 362 175–179.

    • Search Google Scholar
    • Export Citation
  • Moran TH, Norgren R, Crosby RJ & McHugh PR 1990 Central and peripheral vagal transport of cholecystokinin binding sites occurs in afferent fibers. Brain Research 526 95–102.

    • Search Google Scholar
    • Export Citation
  • Moran TH, Baldessarini AR, Salorio CF, Lowery T & Schwartz GJ 1997 Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. American Journal of Physiology –Regulatory, Integrative and Comparative Physiology 272 R1245–R1251.

    • Search Google Scholar
    • Export Citation
  • Moran TH, Katz LF, Plata-Salaman CR & Schwartz GJ 1998 Disordered food intake and obesity in rats lacking cholecystokinin A receptors. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 274 R618–R625.

    • Search Google Scholar
    • Export Citation
  • Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H & Yoshimura A 2004 Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature Medicine 10 739–743.

    • Search Google Scholar
    • Export Citation
  • Moriguchi T, Sakurai T, Nambu T, Yanagisawa M & Goto K 1999 Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia. Neuroscience Letters 264 101–104.

    • Search Google Scholar
    • Export Citation
  • Morris BJ 1989 Neuronal localisation of neuropeptide Y gene expression in rat brain. Comparative Journal of Neurology 290 358–368.

  • Mountjoy KG, Mortrud MT, Low MJ, Simerly RB & Cone RD 1994 Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Molecular Endocrinology 8 1298–1308.

    • Search Google Scholar
    • Export Citation
  • Murakami N, Hayashida T, Kuroiwa T, Nakahara K, Ida T, Mondal MS, Nakazato M, Kojima M & Kangawa K 2002 Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats. Journal of Endocrinology 174 283–288.

    • Search Google Scholar
    • Export Citation
  • Murata M, Okimura Y, Iida K, Matsumoto M, Sowa H, Kaji H, Kojima M, Kangawa K & Chihara K 2002 Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. Journal of Biological Chemistry 277 5667–5674.

    • Search Google Scholar
    • Export Citation
  • Muroya S, Yada T, Shioda S & Takigawa M 1999 Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neuroscience Letters 264 113–116.

    • Search Google Scholar
    • Export Citation
  • Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K & Matsukura S 2001 A role for ghrelin in the central regulation of feeding. Nature 409 194–198.

    • Search Google Scholar
    • Export Citation
  • Naslund E 2003 Prandial subcutaneous injections of GLP-1 cause weight loss in obese human subjects. British Journal of Nutrition 91 661–668.

    • Search Google Scholar
    • Export Citation
  • Naslund E, Gryback P, Hellstrom PM, Jacobsson H, Holst JJ, Theodorsson E & Backman L 1997 Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. International Journal of Obesity and Related Metabolic Disorders 21 387–392.

    • Search Google Scholar
    • Export Citation
  • Naslund E, Bogefors J, Skogar S, Gryback P, Jacobsson H, Holst JJ & Hellstrom PM 1999a GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 277 R910–R916.

    • Search Google Scholar
    • Export Citation
  • Naslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, Rossner S & Hellstrom PM 1999b Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. International Journal of Obesity and Related Metabolic Disorders 23 304–311.

    • Search Google Scholar
    • Export Citation
  • Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B & Creutzfeldt W 1993 Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36 741–744.

    • Search Google Scholar
    • Export Citation
  • Nicolaidis S & Rowland N 1976 Metering of intravenous versus oral nutrients and regulation of energy balance. American Journal of Physiology 231 661–668.

    • Search Google Scholar
    • Export Citation
  • Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr & Schwartz MW 2001 Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413 794–795.

    • Search Google Scholar
    • Export Citation
  • Nonaka N, Shioda S, Niehoff ML & Banks WA 2003 Characterization of blood-brain barrier permeability to PYY3–36 in the mouse. Journal of Pharmacology and Experimental Therapeutics 306 948–953.

    • Search Google Scholar
    • Export Citation
  • Nowak KW, Mackowiak P, Switonska MM, Fabis M & Malendowicz LK 2000 Acute orexin effects on insulin secretion in the rat: in vivo and in vitro studies. Life Sciences 66 449–454.

    • Search Google Scholar
    • Export Citation
  • Obici S, Feng Z, Karkanias G, Baskin DG & Rossetti L 2002 Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nature Neuroscience 5 566–572.

    • Search Google Scholar
    • Export Citation
  • Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I & Barsh GS 1997 Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278 135–138.

    • Search Google Scholar
    • Export Citation
  • O’Shea D, Morgan DG, Meeran K, Edwards CM, Turton MD, Choi SJ, Heath MM, Gunn I, Taylor GM, Howard JK et al. 1997 Neuropeptide Y induced feeding in the rat is mediated by a novel receptor. Endocrinology 138 196–202.

    • Search Google Scholar
    • Export Citation
  • Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M & Tschop M 2001 Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. European Journal of Endocrinology 145 669–673.

    • Search Google Scholar
    • Export Citation
  • Parkinson C, Drake WM, Roberts ME, Meeran K, Besser GM & Trainer PJ 2002 A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. Journal of Clinical Endocrinology and Metabolism 87 1797–1804.

    • Search Google Scholar
    • Export Citation
  • Pedersen-Bjergaard U, Host U, Kelbaek H, Schifter S, Rehfeld JF, Faber J & Christensen NJ 1996 Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man. Scandinavian Journal of Clinical and Laboratory Investigation 56 497–503.

    • Search Google Scholar
    • Export Citation
  • Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T & Collins F 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269 540–543.

    • Search Google Scholar
    • Export Citation
  • Peracchi M, Tagliabue R, Quatrini M & Reschini E 1999 Plasma pancreatic polypeptide response to secretin. European Journal of Endocrinology 141 47–49.

    • Search Google Scholar
    • Export Citation
  • Peyron C, Tighe DK, van den Pol AN, De Lecea L, Heller HC, Sutcliffe JG & Kilduff TS 1998 Neurons containing hypocretin (orexin) project to multiple neuronal systems. Journal of Neuroscience 18 9996–10015.

    • Search Google Scholar
    • Export Citation
  • Pierroz DD, Ziotopoulou M, Ungsunan L, Moschos S, Flier JS & Mantzoros CS 2002 Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity. Diabetes 51 1337–1345.

    • Search Google Scholar
    • Export Citation
  • Pittner RA, Moore CX, Bhavsar SP, Gedulin BR, Smith PA, Jodka CM, Parkes DG, Paterniti JR, Srivastava VP & Young AA 2004 Effects of PYY[3–36] in rodent models of diabetes and obesity. International Journal of Obesity and Related Metabolic Disorders 28 963–971.

    • Search Google Scholar
    • Export Citation
  • Polonsky KS, Given BD & Van Cauter E 1988 Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. Journal of Clinical Investigation 81 442–448.

    • Search Google Scholar
    • Export Citation
  • Porte D Jr, Baskin DG & Schwartz MW 2002 Leptin and insulin action in the central nervous system. Nutrition Reviews 60 S20–S29.

  • Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE & Ahima RS 2004 Adiponectin acts in the brain to decrease body weight. Nature Medicine 10 524–529.

    • Search Google Scholar
    • Export Citation
  • Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X, Yu H, Shen Z, Feng Y, Frazier E et al. 2002 Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Molecular and Cellular Biology 22 5027–5035.

    • Search Google Scholar
    • Export Citation
  • Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R & Maratos-Flier E 1996 A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380 243–247.

    • Search Google Scholar
    • Export Citation
  • Ranganath LR, Beety JM, Morgan LM, Wright JW, Howland R & Marks V 1996 Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 38 916–919.

    • Search Google Scholar
    • Export Citation
  • Raposinho PD, Pedrazzini T, White RB, Palmiter RD & Aubert ML 2004 Chronic neuropeptide Y infusion into the lateral ventricle induces sustained feeding and obesity in mice lacking either Npy1r or Npy5r expression. Endocrinology 145 304–310.

    • Search Google Scholar
    • Export Citation
  • Reeve JR Jr, Eysselein VE, Ho FJ, Chew P, Vigna SR, Liddle RA & Evans C 1994 Natural and synthetic CCK-58. Novel reagents for studying cholecystokinin physiology. Annals of the New York Academy of Sciences 713 11–21.

    • Search Google Scholar
    • Export Citation
  • Reidelberger RD & Solomon TE 1986 Comparative effects of CCK-8 on feeding, sham feeding, and exocrine pancreatic secretion in rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 251 R97–R105.

    • Search Google Scholar
    • Export Citation
  • Reidelberger RD, Hernandez J, Fritzsch B & Hulce M 2003 Abdominal vagal mediation of the satiety effects of CCK in rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 285 R429–R437.

    • Search Google Scholar
    • Export Citation
  • Ricardo JA & Koh ET 1978 Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Research 153 1–26.

    • Search Google Scholar
    • Export Citation
  • Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, Lechan RM & Jaenisch R 2001 Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Molecular Endocrinology 15 1748–1757.

    • Search Google Scholar
    • Export Citation
  • Roseberry AG, Liu H, Jackson AC, Cai X & Friedman JM 2004 Neuropeptide Y-mediated inhibition of proopiomelanocortin neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice. Neuron 41 711–722.

    • Search Google Scholar
    • Export Citation
  • Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, Abusnana S, Goldstone AP, Russell SH, Stanley SA et al. 1998 A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139 4428–4431.

    • Search Google Scholar
    • Export Citation
  • Sahu A 2002 Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones. Journal of Neuroendocrinology 14 796–804.

    • Search Google Scholar
    • Export Citation
  • Sainsbury A, Schwarzer C, Couzens M, Fetissov S, Furtinger S, Jenkins A, Cox HM, Sperk G, Hokfelt T & Herzog H 2002 Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. PNAS 99 8938–8943.

    • Search Google Scholar
    • Export Citation
  • Saito Y, Cheng M, Leslie FM & Civelli O 2001 Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain. Comparative Journal of Neurology 435 26–40.

    • Search Google Scholar
    • Export Citation
  • Sakata I, Nakamura K, Yamazaki M, Matsubara M, Hayashi Y, Kangawa K & Sakai T 2002 Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides 23 531–536.

    • Search Google Scholar
    • Export Citation
  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S et al. 1998 Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92 573–585.

    • Search Google Scholar
    • Export Citation
  • Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B & Auwerx J 1995 Transient increase in obese gene expression after food intake or insulin administration. Nature 377 527–529.

    • Search Google Scholar
    • Export Citation
  • Sanacora G, Kershaw M, Finkelstein JA & White JD 1990 Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation. Endocrinology 127 730–737.

    • Search Google Scholar
    • Export Citation
  • Saper CB, Chou TC & Elmquist JK 2002 The need to feed: homeostatic and hedonic control of eating. Neuron 36 199–211.

  • Sarkar S & Lechan RM 2003 Central administration of neuropeptide Y reduces alpha-melanocyte-stimulating hormone-induced cyclic adenosine 5′-monophosphate response element binding protein (CREB) phosphorylation in prothyrotropin-releasing hormone neurons and increases CREB phosphorylation in corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology 144 281–291.

    • Search Google Scholar
    • Export Citation
  • Sarson DL, Scopinaro N & Bloom SR 1981 Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity. International Journal of Obesity 5 471–480.

    • Search Google Scholar
    • Export Citation
  • Sawchenko PE 1983 Central connections of the sensory and motor nuclei of the vagus nerve. Journal of the Autonomic Nervous System 9 13–26.

    • Search Google Scholar
    • Export Citation
  • Sawchenko PE & Swanson LW 1983 The organization and biochemical specificity of afferent projections to the paraventricular and supraoptic nuclei. Progress in Brain Research 60 19–29.

    • Search Google Scholar
    • Export Citation
  • Sawchenko PE, Swanson LW, Grzanna R, Howe PR, Bloom SR & Polak JM 1985 Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. Comparative Journal of Neurology 241 138–153.

    • Search Google Scholar
    • Export Citation
  • Schaffhauser AO, Stricker-Krongrad A, Brunner L, Cumin F, Gerald C, Whitebread S, Criscione L & Hofbauer KG 1997 Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 46 1792–1798.

    • Search Google Scholar
    • Export Citation
  • Scherer PE, Williams S, Fogliano M, Baldini G & Lodish HF 1995 A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry 270 26746–26749.

    • Search Google Scholar
    • Export Citation
  • Schneider LH 1989 Orosensory self-stimulation by sucrose involves brain dopaminergic mechanisms. Annals of the New York Academy of Sciences 575 307–319.

    • Search Google Scholar
    • Export Citation
  • Schwartz GJ & Moran TH 1994 CCK elicits and modulates vagal afferent activity arising from gastric and duodenal sites. Annals of the New York Academy of Sciences 713 121–128.

    • Search Google Scholar
    • Export Citation
  • Schwartz MW, Figlewicz DP, Baskin DG, Woods SC & Porte D Jr 1992a Insulin in the brain: a hormonal regulator of energy balance. Endocrine Reviews 13 387–414.

    • Search Google Scholar
    • Export Citation
  • Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD, Scheurink A, Kahn SE, Baskin DG, Woods SC, Figlewicz DP et al. 1992b Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 130 3608–3616.

    • Search Google Scholar
    • Export Citation
  • Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte D Jr, Woods SC, Seeley RJ & Weigle DS 1996 Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45 531–535.

    • Search Google Scholar
    • Export Citation
  • Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P & Baskin DG 1997 Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46 2119–2123.

    • Search Google Scholar
    • Export Citation
  • Schwartz GJ, Whitney A, Skoglund C, Castonguay TW & Moran TH 1999 Decreased responsiveness to dietary fat in Otsuka Long-Evans Tokushima fatty rats lacking CCK-A receptors. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 277 R1144–R1151.

    • Search Google Scholar
    • Export Citation
  • Schwartz MW, Woods SC, Porte D Jr, Seeley RJ & Baskin DG 2000 Central nervous system control of food intake. Nature 404 661–671.

  • Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, Van Dijk G, Baskin DG & Schwartz MW 1997 Melanocortin receptors in leptin effects. Nature 390 349.

    • Search Google Scholar
    • Export Citation
  • Segal-Lieberman G, Bradley RL, Kokkotou E, Carlson M, Trombly DJ, Wang X, Bates S, Myers MG Jr, Flier JS & Maratos-Flier E 2003 Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. PNAS 100 10085–10090.

    • Search Google Scholar
    • Export Citation
  • Shimada M, Tritos NA, Lowell BB, Flier JS & Maratos-Flier E 1998 Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396 670–674.

    • Search Google Scholar
    • Export Citation
  • Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M et al. 2001 Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50 227–232.

    • Search Google Scholar
    • Export Citation
  • Shirasaka T, Miyahara S, Kunitake T, Jin QH, Kato K, Takasaki M & Kannan H 2001 Orexin depolarizes rat hypothalamic paraventricular nucleus neurons. American Journal of Physiology –Regulatory, Integrative and Comparative Physiology 281 R1114–R1118.

    • Search Google Scholar
    • Export Citation
  • Shughrue PJ, Lane MV & Merchenthaler I 1996 Glucagon-like peptide-1 receptor (GLP1-R) mRNA in the rat hypothalamus. Endocrinology 137 5159–5162.

    • Search Google Scholar
    • Export Citation
  • Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R & Stark KL 1997 Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes and Development 11 593–602.

    • Search Google Scholar
    • Export Citation
  • Sipols AJ, Baskin DG & Schwartz MW 1995 Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 44 147–151.

    • Search Google Scholar
    • Export Citation
  • Small CJ, Kim MS, Stanley SA, Mitchell JR, Murphy K, Morgan DG, Ghatei MA & Bloom SR 2001 Effects of chronic central nervous system administration of agouti-related protein in pair-fed animals. Diabetes 50 248–254.

    • Search Google Scholar
    • Export Citation
  • Small CJ, Liu YL, Stanley SA, Connoley IP, Kennedy A, Stock MJ & Bloom SR 2003 Chronic CNS administration of Agouti-related protein (Agrp) reduces energy expenditure. International Journal of Obesity and Related Metabolic Disorders 27 530–533.

    • Search Google Scholar
    • Export Citation
  • Stanley BG, Daniel DR, Chin AS & Leibowitz SF 1985 Paraventricular nucleus injections of peptide YY and neuropeptide Y preferentially enhance carbohydrate ingestion. Peptides 6 1205–1211.

    • Search Google Scholar
    • Export Citation
  • Stanley BG, Kyrkouli SE, Lampert S & Leibowitz SF 1986 Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7 1189–1192.

    • Search Google Scholar
    • Export Citation
  • Stanley BG, Magdalin W, Seirafi A, Thomas WJ & Leibowitz SF 1993 The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Research 604 304–317.

    • Search Google Scholar
    • Export Citation
  • Stellar E 1994 The physiology of motivation. 1954. Psychological Review 101 301–311.

  • Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A et al. 1995 The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377 530–532.

    • Search Google Scholar
    • Export Citation
  • Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS & Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409 307–312.

    • Search Google Scholar
    • Export Citation
  • Stratford TR & Kelley AE 1999 Evidence of a functional relationship between the nucleus accumbens shell and lateral hypothalamus subserving the control of feeding behavior. Journal of Neuroscience 19 11040–11048.

    • Search Google Scholar
    • Export Citation
  • Strobel A, Issad T, Camoin L, Ozata M & Strosberg AD 1998 A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genetics 18 213–215.

    • Search Google Scholar
    • Export Citation
  • Strubbe JH & Mein CG 1977 Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiology and Behavior 19 309–313.

    • Search Google Scholar
    • Export Citation
  • Sugino T, Yamaura J, Yamagishi M, Ogura A, Hayashi R, Kurose Y, Kojima M, Kangawa K, Hasegawa Y & Terashima Y 2002 A transient surge of ghrelin secretion before feeding is modified by different feeding regimens in sheep. Biochemical and Biophysical Research Communications 298 785–788.

    • Search Google Scholar
    • Export Citation
  • Sun Y, Ahmed S & Smith RG 2003 Deletion of ghrelin impairs neither growth nor appetite. Molecular and Cellular Biology 23 7973–7981.

  • Sun Y, Wang P, Zheng H & Smith RG 2004 Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. PNAS 101 4679–4684.

    • Search Google Scholar
    • Export Citation
  • Swart I, Jahng JW, Overton JM & Houpt TA 2002 Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 283 R1020–R1026.

    • Search Google Scholar
    • Export Citation
  • Szczypka MS, Kwok K, Brot MD, Marck BT, Matsumoto AM, Donahue BA & Palmiter RD 2001 Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron 30 819–828.

    • Search Google Scholar
    • Export Citation
  • Takahashi N, Okumura T, Yamada H & Kohgo Y 1999 Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats. Biochemical and Biophysical Research Communications 254 623–627.

    • Search Google Scholar
    • Export Citation
  • Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H & Oikawa S 2002 Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology 143 3268–3275.

    • Search Google Scholar
    • Export Citation
  • Tang-Christensen M, Vrang N & Larsen PJ 2001 Glucagon-like peptide containing pathways in the regulation of feeding behaviour. International Journal of Obesity and Related Metabolic Disorders 25 Suppl 5 S42–S47.

    • Search Google Scholar
    • Export Citation
  • Tartaglia LA 1997 The leptin receptor. Journal of Biological Chemistry 272 6093–6096.

  • Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J et al. 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83 1263–1271.