The photoperiodic mammal undergoes quite remarkable changes in physiology as part of its natural adaptations to seasonal fluctuations in the environment. Changes in energy balance and body weight are among these adaptations. In some seasonal mammals, such as the Siberian hamster (Phodopus sungorus), these changes in body weight have been explored in detail, and there is evidence for tightly controlled systems of energy balance that are coordinated by photoperiod acting via the temporal pattern of melatonin secretion from the pineal gland. The pathways and systems involved appear to be quite distinct from the hypothalamic pathways identified to regulate energy balance in studies of both mice and rats thus far. Instead it appears that in the Siberian hamster a tightly regulated system under the control of photoperiod is able to reset the tone of the systems involved in energy balance regulation. Understanding how photoperiod and melatonin act within the hypothalamus to regulate energy balance offers potentially fundamental and important new insights into the control of energy balance. This review describes the current state of our knowledge.

MSH is a pituitary hormone derived by post-translational processing from POMC and involved in stress and background adaptation. N-terminal acetylation of MSH to monoacetyl alpha-MSH or diacetyl alpha-MSH increases the bioactivity of the peptide. The aim of this study was to characterize alpha-MSH acetylation in the sea bream (Sparus aurata L.) pituitary gland in response to the stressors air exposure and confinement, as well as in fish adapted for 15 days to a white, gray or black background. Pituitary homogenates were purified by reversed-phase HPLC (RP-HPLC). The alpha-MSH content of fractions was measured by RIA. Immunoreactive RP-HPLC fractions were further analyzed by electrospray mass spectrometry and the peptide sequence determined as SYSMEHFRWGKPV-NH2. In the pituitary gland of sea bream, des-, mono- and diacetyl alpha-MSH were identified. Then plasma alpha-MSH levels were measured in sea bream adapted to different backgrounds. Surprisingly, we found the highest plasma alpha-MSH levels in white-adapted as compared with black-adapted sea bream with intermediate values for gray-adapted fish. This observation is in contrast with results that have been obtained in eel, trout or terrestrial vertebrates. Next, des-, mono- and diacetyl alpha-MSH forms were measured in homogenates of the pituitary gland and in plasma of sea bream exposed to air, to confinement, or to different backgrounds. Monoacetyl alpha-MSH was the predominant form in all control and experimental groups. The lowest content of monoacetyl alpha-MSH relative to des- and diacetyl alpha-MSH was found in white-adapted fish. Levels of des- and diacetyl alpha-MSH forms were similar under all conditions. We observed that monoacetyl alpha-MSH is the most abundant isoform in the pituitary gland after background adaptation, confinement and air exposure, in sea bream. These data indicate that the physiologically most potent isoform of alpha-MSH may vary from species to species.

Nur77 is a member of the steroid receptor superfamily and is known to be expressed in animals under stress. We studied the role of nur77 in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis during the stress response using a murine pituitary corticotrope cell line, AtT-20. Corticotropin-releasing hormone (CRH), a stress mediator in the HPA axis, induced the expression of nur77 transiently in AtT-20 cells. Gel shift assay showed that nur77 bound to negative glucocorticoid responsive element (nGRE) in the promoter of the human proopiomelanocortin (POMC) gene and the formation of the nur77-nGRE complex increased after treatment of the cells with CRH. Negative GRE is known to be necessary for the negative regulation by glucocorticoid of the POMC gene expression. In stable transformants of AtT-20 cells expressing a human homolog of nur77, NAK-1, at a high level, glucocorticoid-mediated inhibition of both POMC mRNA induction and ACTH secretion was significantly lower than that in the NAK-1-non-expressing cells (P < 0.001). These results strongly suggest that nur77 antagonizes the negative feedback effect of glucocorticoid on the synthesis and secretion of ACTH in pituitary corticotropes. This suggests that nur77 plays an important role in the pituitary gland in the biological adaptation to overcome stress.

Mitochondrial heat shock protein 70 (mtHsp70), an important mitochondrial chaperone, is increased in cardiac muscle mitochondria of hyperthyroid rats. To determine the mechanism(s) underlying this increase, we used variations in thyroid status. In Series I, rats were made hyperthyroid by injecting them with 3,3', 5-triiodo-l-thyronine (T(3)) for 5 days, or by treating them with vehicle. In Series II, animals were given 6-n-propyl-2-thiouracil in their drinking water (0.05% w/v) for a period of 32-42 days to make them hypothyroid. During the last 5 days of treatment these animals received injections of either T(3) or vehicle. T(3) treatment resulted in parallel increases in mtHsp70 protein and mRNA levels in a variety of tissues, suggesting transcriptional regulation. However, evidence of tissue-specific post-transcriptional regulation was also apparent. In isolated heart mitochondria, T(3) treatment resulted in a 1.8-fold increase in mtHsp70. This was due to the 1. 6-fold greater import of mtHsp70 into mitochondria in T(3), compared with hypothyroid animals, and it could not be attributed to an altered rate of intramitochondrial mtHsp70 degradation. The rate of processing of mtHsp70 to its mature form, reflecting mitochondrial processing peptidase activity, was unaffected by T(3), but was more rapid than mtHsp70 import. These data indicate a novel mechanism by which T(3) modifies the mitochondrial phenotype via the adaptations in the protein import pathway.

The trafficking of retinoids in the retina represents a model to study soluble hormone-binding proteins in a complex system subject to profound evolutionary adaptations. Although a remarkable illustration of convergent evolution, all visual systems detect light in the same way, that is through the photoisomerization of an 11-cis retinoid to a corresponding trans isomer. What is strikingly different between the systems, is the mechanism by which the 11-cis chromophore is reformed and visual pigment regenerated in a process known as the visual cycle. The variations of the cycle address a problem inherent to retinoids themselves. That is, the properties that make these molecules suited for light detection also account for their susceptibility to oxidative and isomeric degradation, and cellular toxicity. The cycle therefore provides an opportunity to examine the role of soluble hormone-binding proteins within an integrative and evolutionary context. The present review focuses on interphotoreceptor retinoid-binding protein (IRBP), a controversial glycolipoprotein that recruits a protein fold common to Cterminal-processing proteases and the crotonase family. This unorthodox retinoid-binding protein is entrapped in the subretinal compartment of those eyes that translocate visual cycle retinoids between the photoreceptors and the retinal pigment epithelium. Recent studies suggest that we should look beyond a strictly carrier function if we are to appreciate the role of IRBP in the visual cycle. Here we draw lessons from other soluble hormone-binding proteins to anticipate avenues of future research likely to provide insight into the structure and function of IRBP in vision.

Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circulating insulin concentrations are less than 4 microIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH eff! ects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosphorylation, (3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity.

The study of environmental factors affecting vertebrate reproduction has long interested both developmental and evolutionary biologists. Although photoperiod has been considered to be an important environmental parameter for vertebrates such as birds, temperature is probably a primary external factor responsible for reproductive cyclicity in reptiles. In spite of the progress made in the understanding of reptilian reproductive strategies and adaptations, much remains to be learned about the interplay between endocrine physiological factors, such as hormones, and environmental parameters. In this report, we have examined the effects of in vivo administered FSH on oocyte recruitment during the most significant periods of the reproductive cycle of the lizard, Podarcis sicula. The results show that when FSH is administered in proximity to the reproductive period, it stimulates oocyte growth and ovulation; when the hormone is administered at the beginning of the winter stasis it affects ovarian activity without inducing ovulation. Ovarian adenylate cyclase activity is moderately sensitive to in vitro FSH stimulation during the pre- and post-reproductive periods. The sensitivity to hormone stimulation increases significantly during the reproductive period and winter stasis. We have also tested the hypothesis that environmental temperature affects the responsiveness of ovarian adenylate cyclase to FSH stimulation. For such a purpose, we exposed animals to 28 degrees C or 4 degrees C in different periods of the ovarian cycle. The results show that, whenever the temperature applied mimics the thermal regime of the coming season, adenylate cyclase sensitivity to FSH shifts towards levels that anticipate the natural responsiveness.

One of the most remarkable but neglected aspects of osteoclast function is its unique adaptation that allows the cell to function despite its resorbing surface being exposed to extremely high levels of ambient Ca2+. Recently our studies have provided evidence of continuous transcellular Ca2+ disposal, suggesting that osteoclasts are able to prevent Ca2+ accumulation within the resorptive hemivacuole. It has also been shown that matrix protein degradation products that accumulate within the osteoclast resorptive vacuole are also undergoing transcellular transport by transcytosis. However, both experimental evidence and theoretical considerations suggest that transcellular transport of Ca2+ and matrix protein is likely to occur via distinct routes. In light of these considerations, we are able to provide convincing explanations for the apparent anomalies of osteoclast intracellular [Ca2+] responses to a variety of endocrine stimuli. The understanding of the mechanisms involved in Ca2+ handling by osteoclasts indicates the lack of a simple link between osteoclast function and changes in overall cytosolic [Ca2+].

We have previously shown that lambs delivered by caesarean section 1 week prematurely become hypothermic due to reduced brown adipose tissue function in conjunction with low plasma concentrations of cortisol and thyroid hormones. The present study therefore aimed to determine whether maternal dexamethasone (a synthetic corticosteroid) administration could improve thermoregulation in premature lambs to the extent that they become similar to term lambs. Lambs were either delivered by caesarean section into a warm (30 degrees C; WD) or cool (15 degrees C; CD) ambient temperature at 140 days of gestation, 2 days after maternal dexamethasone treatment, or at 146 days for controls. During the first 30 min of life the decline in colonic temperature was greater in dexamethasone treated lambs compared with controls delivered into the same ambient temperature. All lambs then restored colonic temperature although this adaptation took longest in dexamethasone treated lambs CD but these subsequently attained highest plateau colonic temperatures. Oxygen consumption, breathing frequency and plasma free fatty acid concentrations were highest in dexamethasone treated lambs CD. There were no differences in plasma thyroid hormones between groups, but cortisol concentrations were lower in dexamethasone treated lambs irrespective of delivery temperature. Analysis of brown adipose tissue samples at 6 h of life demonstrated that dexamethasone treated lambs WD had more uncoupling protein and, in both dexamethasone treated and control lambs, uncoupling protein content was higher in lambs CD compared with those WD. An effect of ambient temperature on thermogenic activity was only observed in the dexamethasone treated group. It is concluded that maternal dexamethasone treatment can significantly improve thermoregulation after birth following premature delivery by caesarean section. As a consequence, dexamethasone treated lambs delivered 1 week prematurely do not remain hypothermic and have higher or similar colonic temperatures compared with untreated lambs born 1-2 days before term.

Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill health. Neonatally overfed rats have an early increase in leptin that is maintained long term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here, we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in arcuate nucleus (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinaemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short term, but this is partly resolved by adulthood indicating an adaptation to the metabolic mal-programming effects of neonatal overfeeding.