The neuronal circuits involved in the regulation of feeding behavior and energy expenditure are soft-wired, reflecting the relative activity of the postsynaptic neuronal system, including the anorexigenic proopiomelanocortin (POMC)-expressing cells of the arcuate nucleus. We analyzed the synaptic input organization of the melanocortin system in lean rats that were vulnerable (DIO) or resistant (DR) to diet-induced obesity. We found a distinct difference in the quantitative and qualitative synaptology of POMC cells between DIO and DR animals, with a significantly greater number of inhibitory inputs in the POMC neurons in DIO rats compared with DR rats. When exposed to a high-fat diet (HFD), the POMC cells of DIO animals lost synapses, whereas those of DR rats recruited connections. In both DIO rats and mice, the HFD-triggered loss of synapses on POMC neurons was associated with increased glial ensheathment of the POMC perikarya. The altered synaptic organization of HFD-fed animals promoted increased POMC tone and a decrease in the stimulatory connections onto the neighboring neuropeptide Y (NPY) cells. Exposure to HFD was associated with reactive gliosis, and this affected the structure of the blood-brain barrier such that the POMC and NPY cell bodies and dendrites became less accessible to blood vessels. Taken together, these data suggest that consumption of an HFD has a major impact on the cytoarchitecture of the arcuate nucleus in vulnerable subjects, with changes that might be irreversible due to reactive gliosis. synaptic plasticity | brain | inflammation | vulnerability | high-fat diet E fficient and safe pharmacologic options for the prevention and cure of obesity remain elusive. One reason for this failure is the incomplete understanding of the pathogenesis of obesity. A classic example of this is the lack of clarity regarding the molecular reasons why most individuals are prone, but some are resistant, to the obesogenic effects of a high-calorie diet. The currently favored model of molecular body weight control suggests that specific circuitry within the central nervous system (CNS) coordinates peripheral energy metabolism in response to constant input by environmental stimuli, circulating macronutrients, and afferent endocrine signaling (1).Diet-induced obesity in rats recapitulates several features of human obesity, including the fact that obesity-prone (DIO) and -resistant (DR) types are inherited as polygenic traits that can arise from a single population (2-5). Because these rat models are indistinguishably lean before exposure to a high-fat diet (HFD), they can serve as suitable models for studying the pathogenesis of human obesity and the central nervous circuitry that regulates body adiposity (2-5).The CNS melanocortin system is currently regarded as the primum movens of neuroendocrine body weight regulation (reviewed in refs. 1 and 6). Impaired melanocortin receptor signaling or insufficient availability of functional endogenous melanocortin agonists, which are derived from proopiomelanocortin (...

Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity.

Leibel RL. Effects of chronic weight perturbation on energy homeostasis and brain structure in mice. Am J Physiol Regul Integr Comp Physiol 300: R1352-R1362, 2011. First published March 16, 2011 doi:10.1152/ajpregu.00429.2010.-Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weightreduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (Ϫ10 -15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ϳ50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain. obesity; set point; energy metabolism; POMC neurons LONG-TERM MAINTENANCE OF EVEN modest reductions in body weight ameliorates or eliminates many of the comorbidities of obesity (10). The recidivism rate to obesity in formerly obese individuals is 75-85% (59), reflecting the potent metabolic and environmental pressures opposing long-term maintenance of a reduced body weight. We have previously shown that the maintenance of a 10% or greater reduction in body weight in both lean and obese humans is associated with a decrease in energy expenditure (EE) that is 15-20% below what can be accounted for by changes in body mass and body composition.This adaptive thermogenesis does not abate over time (46) and predominantly reflects increased mechanical work efficiency of skeletal muscle, decreased circulating concentrations of bioactive thyroid hormones, and reduced sympathetic autonomic nervous system tone (2,32,46,54).Leptin is an adipocyte-derived hormone whose circulating plasma concentrations are correlated with fat stores at usual (stable) body weight but which rapidly decline during food restriction and/or fasting (1, 52). We have proposed that central nervous system (CNS) en...

Identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with the elucidation of the chemical structure of ghrelin. However, several issues concerning the role of ghrelin in physiological and pathophysiological processes are still under investigation. Most of the ghrelin produced in the body is secreted in the stomach, but it is also expressed in the hypothalamus, pituitary, pancreas, intestine, kidney, heart and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors. Ghrelin secretion in the stomach depends on both acute and chronic changes in nutritional status and energy balance. Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences insulin secretion and glucose metabolism and it may exert potentially important effects on cardiovascular and gastrointestinal functions. Because of its effects on a large number of physiological functions, ghrelin may be involved in the pathomechanism of several human disorders, including disturbances of appetite, energy homeostasis and glucose metabolism. Further research might lead to a better understanding of the pathophysiology of ghrelin and might provide more effective therapy for the above disorders.

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.