Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity.
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PMID:Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance. 1043 52

Mechanisms mediating genetic susceptibility to diet-induced obesity have not been completely elucidated. Elevated hypothalamic neuropeptide Y (NPY) and decreased hypothalamic proopiomelanocortin (POMC) are thought to promote the development and maintenance of obesity. To assess the potential role of hypothalamic neuropeptide gene expression in diet-induced obesity, the present study examined effects of a high-fat diet on hypothalamic NPY and POMC mRNA in three strains of mice that differ in susceptibility to develop diet-induced obesity. C57BL/6J, CBA, and A/J mice were fed either normal rodent chow or a high-fat diet for 14 weeks after which hypothalamic gene expression was measured. On the high-fat diet, C57BL/6J mice gained the most weight, whereas A/J mice gained the least weight. On the high-fat diet, NPY mRNA significantly decreased as body weight increased in CBA and A/J mice, but not in C57BL/6J mice. In addition, POMC mRNA significantly increased as body weight increased in A/J mice, but not in CBA and C57BL/6J mice. Since decreased NPY mRNA and increased POMC mRNA would presumably attenuate weight gain, these results suggest that a high-fat diet produces compensatory changes in hypothalamic gene expression in mice resistant to diet-induced obesity but not in mice susceptible to diet-induced obesity.
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PMID:Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus. 1064 44

The recent discovery of the contribution of proopiomelanocortin (POMC)-derived peptides to the regulation of energy homeostasis and exocrine gland secretion in mice aroused new interest in the complex function of the endocrine POMC network. In addition, the first mutations in the gene encoding POMC have been identified in two patients affected by adrenal insufficiency, early onset severe obesity and red hair pigmentation. Therefore, the focus of this brief review will be the detailed discussion of the implications of these new findings in the physiology of the human POMC ligand-receptor system.
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PMID:Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. 1065 1

We have investigated whether interactions between leptin and hypothalamic melanocortin-4 receptors (MC4-Rs) determine individual susceptibility to dietary obesity in rats. Animals with relatively high plasma leptin levels 1 week after presentation of palatable food, before weight increased significantly, subsequently showed lower food intake and weight gain after 8 weeks of palatable feeding than those with low early leptin levels. The rats with lesser weight gain also showed significantly greater down-regulation of MC4-Rs, which mediate hypophagia, in specific hypothalamic areas, namely, the arcuate, dorsomedial, and ventromedial (VMH) nuclei and the median eminence. We suggest that this reflects enhanced receptor exposure to endogenous alpha-melanocyte-stimulating hormone, an appetite-suppressing peptide produced by hypothalamic proopiomelanocortin neurones. It is striking that plasma leptin levels at 1 week were inversely correlated with MC4-R density in the VMH, suggesting that this is a key site of leptin action. The early leptin response to palatable feeding may therefore "program" subsequent feeding behaviour and weight gain by regulating neurones that project selectively to the VMH.
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PMID:Early leptin response to a palatable diet predicts dietary obesity in rats: key role of melanocortin-4 receptors in the ventromedial hypothalamic nucleus. 1069 55

Food intake is regulated via neural circuits located in the hypothalamus. During the past decade our knowledge on the specific mediators and neuronal networks that regulate food intake and body weight has increased dramatically. An important contribution to the understanding of hypothalamic control of food intake has been the characterization of the ob gene product (leptin) via positional cloning. Absence of circulating, functionally active, leptin hormone results in massive obesity as seen in ob/ob mice. Leptin inhibits food intake and increases energy expenditure via an interaction with specific leptin receptors located in the hypothalamus. Leptin receptors, of which there are several splice variants (Ob-Ra through Ob-Re), belong to the superfamily of cytokine receptors, which use the JAK-STAT pathway of signal transduction. Obese db/db mice, which have a mutation in the db locus, are unable to perform JAK-STAT signal transduction due to absence of functionally active (long form; Ob-Rb) leptin receptors. Ob-Rb is primarily expressed in the hypothalamus, with particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei and in the lateral hypothalamic area. The abundance of leptin receptors in the ventromedial and lateral hypothalamus supports early observations that these two regions are intimately associated with the regulation of food intake. Leptin receptors have been identified in neuropeptide Y (NPY)/lagouti-related peptide (AgRP)- and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-containing neurons of the ventromedial and ventrolateral arcuate nucleus, respectively, and in melanin-concentrating hormone (MCH)- and hypocretin/orexin-containing neurons of the lateral hypothalamus, suggesting that the above-mentioned messengers are mediators of leptin's action in the hypothalamus. Indeed, functional studies show that NPY, AgRP, POMC-derived peptides, CART, MCH, and hypocretins/orexins all are important regulators of food intake. Leptin is essential for normal body weight balance, but the exact mechanisms by which leptin activates hypothalamic neuronal circuitries is known to a limited extent. In order to find pharmaceutical approaches to treat obesity, further studies will be needed to reveal the exact mechanisms by which leptin lowers body weight and which role leptin and leptin receptors have in the pathogenesis of human obesity.
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PMID:Control of food intake via leptin receptors in the hypothalamus. 1071 43

The co-existence of hyperinsulinemia and hyperleptinemia of obesity is well established. Additionally, both insulin resistance and leptin resistance are also characteristic of these states. Possible central nervous system (CNS) mechanisms could mediate these responses in that leptin receptors are located on hypothalamic neurons that coexpress neuropeptide-Y (NPY) or proopiomelanocortin (POMC) and both peptides that have been implicated as mediators of the CNS action of leptin. Leptin has been demonstrated to decrease or down regulate NPY expression and increase POMC expression. Insulin also has been demonstrated to decrease NPY and insulin insufficiency is associated with an increased POMC. Since both leptin and insulin share and modulate the same effector systems, we investigated the effect of CNS-induced hyperinsulinemia on the subsequent cardiovascular and sympathetic nervous response to leptin. Normal rats were implanted with intracerebroventricular (i.c.v.) cannula and allowed to recover. They were treated with insulin via i.c.v. cannula for 3 days. Following treatment, they were instrumented for the recording of cardiovascular and sympathetic nervous responses. Intracerebroventricular leptin administration in normal animals result in a progressive increase in both lumbar sympathetic nerve activity and mean arterial pressure. However, in animals pretreated with insulin for 3 days the leptin-induced response was completely attenuated. However, insulin treatment did not affect the POMC peptide product, alpha-melanocyte stimulating hormone (alphaMSH), mediated sympathetic nervous and cardiovascular responses. From these studies we conclude that CNS hyperinsulinemia can act to attenuate the leptin-induced increases in sympathetic nervous and cardiovascular system activity. The decreased responsiveness is not due to decreased sensitivity of the melanocortin, alphaMSH, mediated pathway.We suggest that the hyperinsulinemia of obesity may play a role in the obesity-induced leptin resistance.
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PMID:Chronic intracerebroventricular insulin attenuates the leptin-mediated but not alpha melanocyte stimulating hormone increase in sympathetic and cardiovascular responses. 1080 82

Obesity is a common problem in Western society and is associated with significant morbidity and mortality. Energy homeostasis is regulated by a complex system involving both peripheral signals such as leptin and a number of orexigenic and anorectic neuropeptides. Obesity can result from dysregulation of the peripheral and/or central signals. Melanin-concentrating hormone (MCH) is a hypothalamic peptide that is important in the regulation of feeding behavior, primarily via uncharacterized signaling pathways in the central nervous system. Leptin, expressed in adipose tissue, mediates some of its actions through several hypothalamic neuropeptides, notably agouti-related peptide, proopiomelanocortin, and neuropeptide Y. Expression of leptin is regulated by dietary status, insulin, and glucocorticoids. Furthermore, certain neuropeptides may act on adipocytes. However, the potential effect of MCH has not been investigated. We report that MCH stimulates leptin mRNA expression and leptin secretion. MCH stimulated a 2-fold increase in leptin secretion by isolated rat adipocytes after 4 h of treatment. This increase in secreted leptin was preceded by a rapid and transient increase in ob mRNA levels; MCH stimulated a 2.5-fold increase in ob mRNA within 1 h of treatment, followed by a decline to basal levels within 4 h. In addition, we demonstrate that the MCH receptor SLC-1 is expressed in adipocytes, suggesting that fat cells may be targets of MCH or an MCH-like peptide under physiological conditions. Finally, using a radioimmunoassay, MCH/MCH-like peptide was detected in rat plasma. This study establishes a novel in vitro mammalian system for examining MCH signaling pathways.
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PMID:Melanin-concentrating hormone regulates leptin synthesis and secretion in rat adipocytes. 1090 60

Exposure to high-fat diets for prolonged periods results in positive energy balance and obesity, but little is known about the initial physiological and neuroendocrine response of obesity-susceptible strains to high-fat feeding. To assess responses of C57BL/6J mice to high- and low-fat diets, we quantitated the hypothalamic expression of neuropeptides implicated in weight regulation and neuroendocrine function over a 2-wk period. Exposure to high-fat diet increased food consumption over a 2-day period during which leptin levels were increased when assessed by a frequent sampling protocol [area under the curve (AUC): 134.6 +/- 10.3 vs. 100 +/- 12.3, P = 0.03 during first day and 126.5 +/- 8.2 vs. 100 +/- 5.2, P = 0.02 during second day]. During this period, hypothalamic expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased by approximately 30 and 50%, respectively (P < 0.001). After 1 wk, both caloric intake and hypothalamic expression of NPY and AgRP returned toward baseline. After 2 wk, cumulative caloric intake was again higher in the high-fat group, and now proopiomelanocortin (POMC) was elevated by 76% (P = 0.01). This study demonstrates that high-fat feeding induces hyperphagia, hyperleptinemia, and transient suppression of orexigenic neuropeptides during the first 2 days of diet. The subsequent induction of POMC may be a second defense against obesity. Attempts to understand the hypothalamic response to high-fat feeding must examine the changes as they develop over time.
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PMID:Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. 1100 66

Several regulatory substances participate in the regulation of both food intake/energy metabolism and reproduction in mammals. Most of these neuropeptides originate and act in the central nervous system, mainly at specific hypothalamic areas. Leptin represents a signal integrating all these functions, but originating from the periphery (adipose tissue) and carrying information mainly to central structures. Observations in rodent models of leptin deficiency have suggested that leptin participates in the control of reproduction, in conjunction with that of food intake and energy expenditure. Indeed, leptin administration resulted in the restoration of normal body weight, food intake, and fertility in the ob mouse, lacking circulating leptin. Specific targets of leptin in the hypothalamus are neurons expressing neuropeptide Y, proopiomelanocortin and gonadotropin-releasing hormone, but the presence of leptin receptors in peripheral reproductive structures suggests that leptin might also act at these sites. Human obesity is often associated with reproductive disturbances. The situation in humans is more complex than in the animal models of leptin deficit and the presence of leptin resistance in these subjects is suggested. In conclusion, leptin fits many requirements for a molecule linking the regulation of energy balance and the control of reproduction.
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PMID:Leptin: a possible link between food intake, energy expenditure, and reproductive function. 1102 65

Obesity in normal animals has been demonstrated to be associated with a decrease in sensitivity to leptin especially as it relates to leptin's capacity to increase sympathetic nerve activity and enhance cardiovascular dynamics. In normal animals leptin has been demonstrated to exert significant regulatory responses by its capacity to increase proopiomelanocortin (POMC) expression and especially the increase in alpha melanocyte stimulating hormone (alphaMSH). These responses to leptin are blocked by a melanocortin-4 (MC-4) receptor antagonist. In this study we investigated the responsiveness of the sympathetic nervous system and cardiovascular system of high fat fed obese animals to the intracerebroventricular (ICV) administration of the POMC products alphaMSH and beta-endorphin (beta-END). We further investigated these responses in obese animals following leptin administration in the presence of MC-4 receptor and opioid receptor blockade. The ICV administration of leptin resulted in an increase in lumbar sympathetic nerve activity (LSNA) and mean arterial pressure (MAP) in normals but decreased it in the obese. The ICV administration of alphaMSH increased the LSNA and MAP in normal animals but to a lesser degree in obese animals. On the other hand beta-endorphin decreased the LSNA and MAP in normal animals but increased it in obese animals. Additionally ICV leptin administration in obese animals in the presence of MC-4 or opioid receptor blockade resulted in an increase in sympathetic activity and a pressor response. From these studies we conclude that obesity in high fat fed animals is characterized by a decreased sensitivity to alphaMSH and a paradoxical response to beta-endorphin and this altered responsiveness may be a factor in the altered leptin resistance characteristic of obese animals.
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PMID:Leptin resistance in obesity is characterized by decreased sensitivity to proopiomelanocortin products. 1106 94


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