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Background:The ␣-MSH peptide is essential in regulating food intake and energy expenditure. Results: ER stress induced by obesity reduces ␣-MSH, accumulates POMC, and decreases the enzyme PC2. Conclusion: There is a direct link between obesity and ER stress, resulting in altered POMC processing. Significance: These studies bring a new perspective to how ER stress can regulate energy balance by altering POMC processing.

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We determined baseline and capture-induced glucocorticoid concentrations during two different seasons in three species of wild free-living rodents: brown lemmings (Lemmus trimucronatus), golden-mantled ground squirrels (Spermophilus saturatus), and yellow-pine chipmunks (Tamias amoenus). Initial blood samples were obtained within 3 min of capture, so that initial glucocorticoid levels reflect baseline titers of undisturbed animals. Animals were held for an additional 30 min, when a second blood sample was taken to measure stress-induced glucocorticoid titers. The primary glucocorticoid differed in each species. Lemmings secreted extremely large amounts of corticosterone (as high as 8,000 ng/ml). These high concentrations were accompanied by high corticosterone-binding globulin capacity and resistance to negative feedback. Squirrels and chipmunks secreted a mixture of cortisol and corticosterone (10-400 ng/ml). In males of all three species and female squirrels and chipmunks, glucocorticoid levels were significantly elevated 30 min after capture. Baseline and 30-min glucocorticoid levels differed seasonally in each species. Levels were higher during summer (with no snow cover) than in spring (with approximately 60% snow cover) in female lemmings, higher during breeding than before hibernation in squirrels, and higher postreproductively than during breeding in chipmunks. Together, these data indicate that glucocorticoid responses to stress in these free-living species are similar to those in laboratory species, but the magnitude of the response appears to depend on life-history features specific to each species.

Although the glucocorticoid response to acute short-term stress is an adaptive physiological mechanism that aids in the response to and survival of noxious stimuli, chronic stress is associated with a negative impact on health. In wild-caught European starlings (Sturnus vulgaris), chronic stress alters the responsiveness of hypothalamic-pituitary-adrenal (HPA) axis as measured by the acute corticosterone response. In the present study, we investigated potential underlying neuroendocrine mechanisms by comparing glucocorticoid receptor and mineralocorticoid receptor mRNA expression in the brains of chronically and nonchronically-stressed starlings. Hypothalamic paraventricular nucleus, but not hippocampal, glucocorticoid receptor mRNA expression in chronically-stressed birds was significantly lower compared to controls, suggesting changes in the efficacy of corticosterone negative feedback. In addition, chronically-stressed birds showed a significant decrease in hippocampal MR mRNA expression. Together, these results suggest that chronic stress changes the brain physiology of wild birds and provides important information for the understanding of the underlying mechanisms that result in dysregulation of the HPA axis in wild animals by chronic stress.

The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintaining energy expenditure and body weight, and the adipocyte hormone leptin regulates this axis by increasing TRH levels in the fed state. Leptin stimulates TRH directly in the hypothalamic paraventricular nucleus (PVN; direct pathway) and indirectly by regulating proopiomelnocortin neurons in the hypothalamic arcuate nucleus (ARC; indirect pathway). Whereas the indirect pathway is fully functional in lean animals, it is inactive during diet-induced obesity (DIO) because of the establishment of leptin resistance. Despite this, the HPT axis activity in obese humans and rodents remains within the normal levels or slightly higher. Therefore, in this study, we aimed to determine the mechanism(s) by which the HPT axis is still active despite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears a mutation in the leptin receptor, we were able to demonstrate that under DIO conditions the HPT axis is regulated at the central level, but only through the direct pathway of leptin action on TRH neurons. Deiodinase enzymes, which are present in many tissues and responsible for converting thyroid hormones, were not statistically different between lean and DIO animals. These data suggest that the increase in T(4/3) seen in obese animals is due mostly to central leptin action. We also found that T(3) feedback inhibition on the prepro-TRH gene is controlled partially by leptin-induced pSTAT3 signaling via the TRH promoter. This interactive relationship between T(3) and pSTAT3 signaling appears essential to maintain the HPT axis at normal levels in conditions such as obesity.