Leptin is involved in regulating food intake, energy balance and bone formation. Increasing evidence suggests that leptin is also involved in fetal growth and development. The aim of this study was to determine if increased maternal leptin is followed by changes in body composition, skeletal growth or hormonal regulation in the adult rat offspring. Pregnant rats were given injections of either human recombinant leptin (3.5 mg/kg, i.p.) or vehicle on days 8, 10 and 12 of gestation. Both genders of leptin-exposed offspring showed significantly reduced adipose tIssue weight at adult age. Skeletal growth and cortical bone dimensions were significantly reduced. Circulating testosterone levels were significantly increased in female leptin-exposed offspring, and male leptin-exposed offspring had significant testicular enlargement. No significant effects were seen on circulating leptin levels or hypothalamic protein levels of the leptin receptor. The results demonstrate that maternally administered leptin is involved in fetal growth and development, leading to lean offspring with reduced skeletal growth.
C Nilsson, D Swolin-Eide, C Ohlsson, E Eriksson, HP Ho, P Bjorntorp, and A Holmang
RG Denis, G Williams, and RG Vernon
The factors regulating serum leptin concentration and its relationship to the hyperphagia of lactation have been investigated in rats. Lactation results in hypoleptinaemia and loss, or at least marked attenuation, of the nocturnal rise in serum leptin. Litter removal resulted in a fall in food intake and restoration of the nocturnal rise in serum leptin. Returning the litter to the mother after a 48-h absence increased food intake and began to reinitiate milk production, but the nocturnal serum leptin levels were still increased at 48 h after litter restoration. Adjusting litter size to four, eight, ten or fourteen pups at parturition resulted in different rates of litter growth and food intake during the subsequent lactation, but had no effect on the degree of hypoleptinaemia. Reducing litter size from ten to four pups at mid-lactation resulted in a transient increase in both serum leptin and pup growth rate, while food intake fell to a level found in rats suckling four pups throughout lactation. Reducing milk production by injection of bromocriptine increased serum leptin, but did not restore the nocturnal rise in serum leptin; food intake decreased, but remained much higher than in non-lactating rats. Feeding a varied, high-energy diet resulted in a decrease in the weight of food ingested, but no change in calorie intake, and had no effect on the hypoleptinaemia. These studies suggested that the hypoleptinaemia of lactating rats is due to negative energy balance, but the loss of the nocturnal rise in serum leptin is due to the suckling stimulus. The negative energy balance of lactation does not appear to be caused by a physical constraint on food intake. While the hypoleptinaemia should facilitate the hyperphagia of lactation, other orexigenic signals must also be involved.
C Fernandez-Galaz, T Fernandez-Agullo, F Campoy, C Arribas, N Gallardo, A Andres, M Ros, and JM Carrascosa
Leptin interacts with specific receptors in hypothalamic nuclei and modulates energy balance. Growing evidence has shown the association of obesity and hyperleptinaemia with non-insulin-dependent diabetes mellitus and insulin resistance. The aged Wistar rat shows peripheral insulin resistance in the absence of obesity and alterations of glucose homeostasis. However, it is not known whether, in these animals, the leptin action is altered. Here we studied the effect of ageing on plasma leptin concentration and the ability of hypothalamic nuclei to capture i.c.v.-injected digoxigenin-labelled leptin. Our data indicate that 24-month-old animals are hyperleptinaemic. However, daily food intake was greater in old animals, suggesting that they are leptin resistant. Leptin uptake in the hypothalamus was reduced in old rats. This uptake was a receptor-mediated process as demonstrated by displacement. Leptin accumulation in hypothalamic nuclei was partially colocalized with neuropeptide Y fibres. Immunohistochemical and western blot analyses showed a lower amount of the long form of leptin receptors in the hypothalamus of aged rats. Analysis by RT-PCR also demonstrated a decreased expression of leptin receptor mRNA in old animals. We conclude that the lower leptin uptake may be explained, at least in part, by a decreased amount of receptors in hypothalamic neurones of the aged rats.
ELIZABETH HERVEY and G. R. HERVEY
The effects of progesterone administration on the weight and composition of the body have been studied in rats. Female rats injected with 5 mg. progesterone/day initially gained weight at an average rate of 2 g./day, compared with 0·4 g./day for controls. When treatment was continued for a month or more their weight stabilized at 40–50 g. above the control level. The bodies of the progesterone-treated rats contained increased amounts of water, fat and solids other than fat. These effects were smoothly related to the dose of progesterone.
In terms of percentage composition, fat increased at the expense of the other two constituents. The composition of the fat-free solids did not change, but the proportion of water in the fat-free body increased. About a tenth of the gain of live weight was accounted for by an increase in the contents of the alimentary tract. The composition of the rest was equivalent, typically, to 43% lean tissue, 26% water additional to that in the lean tissue, and 31% fat.
Male rats treated with progesterone showed no changes other than a small gain of water.
It seems likely that in females progesterone reproduces the changes in body composition which occur in pregnancy. The gain of lean tissue seems to reflect increased growth it, and the accumulation of fat, may both be consequences of the production of a positive energy balance.
Mohamed Asrih and François R Jornayvaz
Nonalcoholic fatty liver disease (NAFLD) has become a major health problem in developed countries. It has affected more than 30% of the general population and is commonly associated with insulin resistance, which is a major risk factor for the development of type 2 diabetes and a central feature of the metabolic syndrome. Furthermore, accumulating evidences reveal that NAFLD as well as insulin resistance is strongly related to inflammation. Cytokines and adipokines play a pivotal role in inflammatory processes. In addition, these inflammatory mediators regulate various functions including metabolic energy balance, inflammation, and immune response. However, their role in modulating ectopic lipids involved in the development of insulin resistance, such as diacylglycerols and ceramides, remains unknown. The aim of this review is first to describe the pathophysiology of insulin resistance in NAFLD. In particular, we discuss the role of ectopic lipid accumulation in the liver. Secondly, we also summarize recent findings emphasizing the role of main inflammatory markers in both NAFLD and insulin resistance and their potential role in modulating hepatic fat content in NAFLD and associated hepatic insulin resistance.
SE Snyder, B Peng, JE Pintar, and SR Salton
Analysis of knockout mice suggests that the neurotropin-inducible secreted polypeptide VGF (non-acronymic) plays an important role in the regulation of energy balance. VGF is synthesized by neurons in the central and peripheral nervous systems (CNS, PNS), as well as in the adult pituitary, adrenal medulla, endocrine cells of the stomach and pancreatic beta cells. Thus VGF, like cholecystokinin, leptin, ghrelin and other peptide hormones that have been shown to regulate feeding and energy expenditure, is synthesized in both the gut and the brain. Although detailed developmental studies of VGF localization in the CNS and PNS have been completed, little is known about the ontogeny of VGF expression in endocrine and neuroendocrine tIssues. Here, we report that VGF mRNA is detectable as early as embryonic day 15.5 in the developing rat gastrointestinal and esophageal lumen, pancreas, adrenal, and pituitary, and we further demonstrate that VGF mRNA is synthesized in the gravid rat uterus, together supporting possible functional roles for this polypeptide outside the nervous system and in the enteric plexus.
EE Onal, P Cinaz, Y Atalay, C Turkyilmaz, A Bideci, A Akturk, N Okumus, S Unal, E Koc, and E Ergenekon
Ghrelin is a newly discovered orexigenic peptide originating from the stomach. Circulating ghrelin levels reflect acute and chronic energy balance in humans. However, it is not known whether ghrelin also plays a role in energy homeostasis during fetal life. Forty-one small-for-gestational age (SGA) and 34 appropriate-for-gestational age (AGA) infants were studied in order to determine whether cord blood ghrelin concentrations were different in SGA infants compared with AGA infants and the relationship to anthropometric measurements at delivery. The cord blood ghrelin concentrations of SGA infants (means+/-S.E.M.; 15.20+/-3.08 ng/ml) were significantly greater than of AGA infants (2.19+/-0.24 ng/ml) (P<0.0001). They were negatively correlated with the infants' birth weights (r=-0.481, P<0.0001) and with body mass index values (r=-0.363, P<0.001). The higher ghrelin concentrations were found in female infants (20.42+/-4.55 ng/ml) than in males (7.05+/-2.27 ng/ml) in the SGA group (P=0.042). These data provide the first evidence that cord ghrelin levels of SGA infants are greater than those of AGA infants and it is suggested that ghrelin is also affected by nutritional status in the intrauterine period.
M K Piya, P G McTernan, and S Kumar
Adipose tissue is an active endocrine organ, and our knowledge of this secretory tissue, in recent years, has led us to completely rethink how our body functions and becomes dysregulated with weight gain. Human adipose tissue appears to act as a multifunctional secretory organ with the capacity to control energy homoeostasis through peripheral and central regulation of energy homoeostasis. It also plays an important role in innate immunity. However, the capability to more than double its original mass to cope with positive energy balance in obesity leads to many pathogenic changes. These changes arise within the adipose tissue as well as inducing secondary detrimental effects on other organs like muscle and liver, including chronic low-grade inflammation mediated by adipocytokines (adipokine inflammation). This inflammation is modulated by dietary factors and nutrients including glucose and lipids, as well as gut bacteria in the form of endotoxin or LPS. The aim of this current review is to consider the impact of nutrients such as glucose and lipids on inflammatory pathways, specifically within adipose tissue. Furthermore, how nutrients such as these can influence adipokine inflammation and consequently insulin resistance directly through their effects on secretion of adipocytokines (TNFα, IL6 and resistin) as well as indirectly through increases in endotoxin is discussed.
Martina Holubová, Jana Zemenová, Barbora Mikulášková, Vladimíra Panajotova, Jiří Stöhr, Martin Haluzík, Jaroslav Kuneš, Blanka Železná, and Lenka Maletínská
Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood–brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both Prrp-knockout and Prrp receptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague–Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.
A P Santos-Silva, E Oliveira, C R Pinheiro, A L Nunes-Freitas, Y Abreu-Villaça, A C Santana, C C Nascimento-Saba, J F Nogueira-Neto, A M Reis, E G Moura, and P C Lisboa
Exposure to tobacco smoke is related to changes in energy balance regulation and several endocrine dysfunctions. Previously, we showed that maternal nicotine (the main addictive compound of tobacco) exposure exclusively during lactation affects biochemical profiles in mothers, milk, and pups. As the possible consequences for mothers and offspring of maternal smoking during lactation are still unknown, we evaluated the effects of tobacco smoke exposure on nutritional, biochemical, and hormonal parameters in dams and pups at weaning. After 72 h from birth, lactating rats were divided into two groups: smoke-exposed (S) in a cigarette-smoking machine, 4×1 h per day throughout the lactation period without pups; control (C), rats were treated the same as the experimental group but exposed to filtered air. Dams and pups were killed at weaning (21 days of lactation). Body weight and food intake were evaluated. Milk, blood, visceral fat, adrenal, and carcass were collected. S dams showed hyperprolactinemia (+50%), hypoinsulinemia (−40%), hypoleptinemia (−46%), as well as lower triglycerides (−53%) and very low-density lipoprotein cholesterol (−50%). Milk of S dams had higher lactose (+52%) and triglycerides (+78%). S pups presented higher body protein (+17%), lower total (−24%) and subcutaneous fat contents (−25%), hypoglycemia (−11%), hyperinsulinemia (+28%), hypocorticosteronemia (−40%), lower adrenal catecholamine content (−40%), hypertriglyceridemia (+34%), higher high-density lipoprotein cholesterol (+16%), and lower low-density lipoprotein cholesterol (−45%). In conclusion, tobacco smoke exposure leads to changes in nutritional, biochemical, and hormonal parameters in dams and, passively through the milk, may promote several important metabolic disorders in the progeny.