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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital deficiency of proopiomelanocortin (POMC) results in a syndrome of hypoadrenalism, severe obesity, and altered skin and hair pigmentation. The concept that subtle variation in POMC expression and/or function might contribute to common obesity is suggested by studies reporting linkage of obesity-related traits to a locus on chromosome 2p22 encompassing the POMC gene. We identified a novel homozygous frameshift (C6906del) mutation in POMC in a child of Turkish origin with severe obesity and hypoadrenalism. This mutation would be predicted to lead to the loss of all POMC-derived peptides. The availability of a large extended pedigree provided the opportunity to address whether loss of one copy of the POMC gene was sufficient to alter obesity risk. Twelve relatives were heterozygous for the mutation and 7 were wild type. Of the heterozygotes, 11 of 12 heterozygotes were obese or overweight compared with only 1 of 7 of the wild-type relatives. The mean BMI SD score was 1.7 +/- 0.5 in heterozygotes and 0.4 +/- 0.4 in the wild-type relatives. Parametric linkage analysis of the trait "overweight" provided statistically significant evidence of linkage with this locus, with a maximum "location score" (comparable with multipoint logarithm of odds scores) of 3.191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity.
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PMID:Heterozygosity for a POMC-null mutation and increased obesity risk in humans. 1693 3

As the incidence of obesity continues to increase, adequate animal models acquire increased importance for the investigation of energy homeostatic mechanisms. Understanding the central mechanism of action of the adiposity hormones, insulin and leptin, has become particularly important as researchers examine ways to treat or prevent obesity. Although the intra-3rd-ventricular (i3vt) administration of insulin reduces food intake in several species, its effects on food intake and body weight have not been previously been assessed in mice. Male C57BL/6J mice were administered insulin i3vt (0.05, 0.1 or 0.4 microU) or leptin i3vt (5 microg/1 microl) as a positive control. As it occurs in other species, i3vt insulin dose-dependently reduced 24-h food intake and body weight, and increased hypothalamic proopiomelanocortin (POMC) mRNA. Hence, genetic manipulations that influence brain insulin sensitivity in mice can now more easily be integrated with the broader literature on energy homeostasis.
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PMID:Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice. 1697 94

Data are reviewed that support the hypothesis that the neural control of energy expenditure is distributed among several brain sites. This view contrasts with that expressed most commonly in literature, that a single site-the arcuate hypothalamic nucleus-receives and integrates signals of relevance to energy status assessment and engages the effector circuits that orchestrate responses that maintain energy balance. The data reviewed support a contribution from medullary neurons, including those of the nucleus of the solitary tract, in the integration of signals of relevance to energy balance and in the issuing of commands to local behavioral and autonomic effectors. Experimental evidence is discussed that supports the following specific conclusions: hindbrain neurons integrate oral and gastrointestinal signals and issue commands to local motor circuits that control meal size; leptin's effect on food intake may be mediated, in part, by a direct action on the hindbrain neurons that respond to gastric distention; deprivation signals, such as the fall in leptin level, affect gene expression outside of the hypothalamus with reductions in proglucagon and proopiomelanocortin message seen in nucleus of the solitary tract-rich tissue; and that hindbrain neurons contribute to the control of energy expenditure seen with food deprivation and increases in expenditure after cold exposure or starvation. Future work is needed to define how the nucleus of the solitary tract and arcuate nodes of the central energy balance control network interact to collectively, or separately, influence specific aspects of energy balance control in the intact brain.
Obesity (Silver Spring) 2006 Aug
PMID:Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. 1702 70

Recent research has identified a number of genes playing critical roles in the central regulation of energy homeostasis. Subsequently, models of the neurocircuitry regulating energy balance have been suggested, although their physiological relevance remains mostly untested. Using the Cre/loxP system, we can now genetically dissect these neurocircuits and establish the specific roles of these genes in small neuronal subpopulations. Here we focus on two receptors shown to be critical in the central regulation of energy homeostasis: leptin (LepR) and melanocortin-4 receptors (MC4R). Mice and humans deficient in either leptin or melanocortin signaling are severely obese. A prominent model of leptin action places the arcuate nucleus of the hypothalamus, and in particular arcuate proopiomelanocortin (POMC) neurons, at the center stage of energy balance regulation. By deleting LepR specifically from POMC neurons in mice, we showed that LepR on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis. Thus, LepR on other neurons must also be critically important in leptin-mediated regulation of body weight homeostasis. Data from MC4R-deficient mice have shown that MC4Rs regulate both sides of the energy intake/energy expenditure balance. Our recent experiments used MC4R-deficient mice with restored MC4R expression only in the paraventricular hypothalamus and a subpopulation of amygdala neurons. We showed that MC4Rs in the paraventricular hypothalamus and/or amygdala are sufficient to control food intake but that MC4Rs elsewhere control energy expenditure, thereby discovering the novel concept of functional and anatomical divergence of MC4Rs.
Obesity (Silver Spring) 2006 Aug
PMID:Genetic dissection of neuronal pathways controlling energy homeostasis. 1702 71

Leptin regulates energy balance, in part, by modulating the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus. Leptin-deficient (ob/ob) mice differ from wild-type mice in the number of excitatory and inhibitory post-synaptic densities and currents onto NPY and POMC neurons. When leptin was delivered to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. Synaptic currents were also shifted toward wild-type values in leptin-replaced ob/ob mice. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects. In an effort to determine whether the observed synaptic plasticity is leptin specific, we analyzed the effects of an orexigenic hormone, ghrelin, and anorexigenic hormone, estradiol. Ghrelin rearranged synapses in wild type animals to support suppressed POMC tone, whereas the estradiol triggered a robust increase in the number of excitatory, glutamate inputs of POMC neurons. The rearrangement of synapses by estradiol was leptin independent, because it was also evident in leptin- (ob/ob) and leptin receptor-deficient (db/db) mice and was paralleled with decreased food intake and increased energy expenditure in these mutant, obese animals. Such plasticity was also observed in other hypothalamic regions and extrahypothalamic sites. These observations raise the notion that synaptic plasticity is a major way through which peripheral metabolic hormones influence brain functions.
Obesity (Silver Spring) 2006 Aug
PMID:Synaptic plasticity in energy balance regulation. 1702 72

The role of cholecystokinin (CCK) as a satiety factor has been extensively documented. Although most work implies that CCK1 receptor mediates the control of food intake, a contributing role for CCK2 receptor (CCK2R) in the CCK-induced satiety cannot be totally excluded. The hypothesis that CCK2R invalidation disrupts regulatory pathways with impact on feeding behavior was examined in CCK2R(-/-) mice. CCK2R(-/-) mice developed obesity that was associated with hyperphagia. Obesity was related with increased fat deposition resulting from adipocyte hypertrophy. Expression of several adipokines was dysregulated consistently with obesity. Moreover, obesity was associated with disturbed glucose homeostasis as revealed by increased fasting glycemia and insulinemia, impaired glucose tolerance, and hepatic insulin resistance in CCK2R(-/-) mice. In vitro analysis of isolated adipocytes metabolism was consistent with increased storage but preserved insulin sensitivity. Suppression of feeding and concomitant increased expression of hypothalamic proopiomelanocortin after intracerebroventricular injection of gastrin into control mice demonstrates that hypothalamic CCK2 receptors mediate inhibition of food intake. Comparative analysis of hypothalamic mediator gene expression in fed knockout and control mice demonstrated overexpression of ghrelin receptors in CCK2R(-/-) mice, indicating up-regulation of orexigenic pathways. This effect was also observed after body weight normalization, indicating a causative role in the development of hyperphagia and obesity of CCK2R(-/-) mice. Our results give evidence that CCK2 receptor activity plays a contributing regulatory role in the control of food intake.
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PMID:Involvement of cholecystokinin 2 receptor in food intake regulation: hyperphagia and increased fat deposition in cholecystokinin 2 receptor-deficient mice. 1712 76

The alpha-melanocyte-stimulating hormone (alpha-MSH), derived from proopiomelanocortin (POMC), is generated by a posttranslational processing mechanism involving the prohormone convertases (PCs) PC1/3 and PC2. In the brain, alpha-MSH is produced in the arcuate nucleus (ARC) of the hypothalamus and in the nucleus of the solitary tract (NTS) of the medulla. This peptide is key in controlling energy balance, as judged by changes observed at transcriptional level. However, little information is available regarding the biosynthesis of the precursor POMC and the production of its processed peptides during feeding, fasting, and fasting plus leptin in the ARC compared with the NTS in conjunction with the PC activity. In this study we found that, in the ARC, pomc mRNA, POMC-derived peptides, and PC1/3 all decreased during fasting, and administration of leptin reversed these effects. In contrast, in the NTS, where there is a large amount of a 28.1-kDa peptide similar in size to POMC, the 28.1-kDa peptide and other POMC-derived peptides, including alpha-MSH, were further accumulated in fasting conditions, whereas pomc mRNA decreased. These changes were not reversed by leptin. We also observed that, during fasting, PC2 levels decreased in the NTS. These data suggest that, in the NTS, fasting induced changes in POMC biosynthesis, and processing is independent of leptin. These observations indicate that changes in energy status affect POMC in the brain in a tissue-specific manner. This represents a novel aspect in the regulation of energy balance and may have implications in the pathophysiology of obesity.
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PMID:Differential effects of fasting and leptin on proopiomelanocortin peptides in the arcuate nucleus and in the nucleus of the solitary tract. 1722 63

To examine the role of the brain stem melanocortin system in long-term energy regulation, we assessed the effects of overproduction of proopiomelanocortin (POMC) in the caudal brain stem of F344xBN rats with adult-onset obesity. Recombinant adeno-associated viral vector encoding POMC gene was delivered to the nucleus of solitary tract (NTS) in the hindbrain, and food intake, body weight, glucose and fat metabolism, brown adipose tissue thermogenesis, and mRNA levels of neuropeptides and melanocortin receptors were assessed. POMC delivery resulted in sustained reduction in food intake and body weight over 42 days and improved insulin sensitivity. At death, in recombinant adeno-associated viral vector-POMC-treated rats vs. control rats, alpha-melanocyte-stimulating hormone in NTS increased nearly 21-fold, whereas hypothalamic alpha-melanocyte-stimulating hormone remained unchanged. Visceral adiposity decreased by 37%; tissue triglyceride content diminished by 26% and 47% in liver and muscle, respectively; serum triglyceride and nonesterified fatty acids were reduced by 35% and 34%, respectively; phosphorylation of acetyl-CoA carboxylase was elevated by 63% in soleus muscle; brown adipose tissue uncoupling protein 1 increased by 30%; and melanocortin 3 receptor expression declined by 60%, whereas neuropeptide Y, agouti-related protein, and MC4 receptor mRNA levels were unchanged in the NTS. In conclusion, POMC overexpression in the NTS produces a characteristic unabated hypophagia that is uniquely different from the anorexic tachyphylaxis following POMC overexpression in the hypothalamus. The sustained anorectic response may result from absence of compensatory elements in the NTS, such as increased agouti-related protein expression, suggesting melanocortin activation of the brain stem may be a viable strategy to alleviate obesity.
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PMID:Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss. 1738 13

Within the last decade an intensive research led to an identification of several genes which are involved in a regulation of energy balance. In most cases, carriers of these gene mutations do not exhibit further characteristic phenotypic features except for a severe obesity. Obesity based on mutation of one gene product is called monogenic obesity. Mutations in genes for leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1, melanocortin 4 and 3 receptor disrupt the physiological humoral signalization between peripheral signals and the hypothalamic centres of satiety and hunger. Defects of all above mentioned genes lead to phenotype of abnormal eating behaviour followed by a development of severe early-onset obesity. Mutations of melanocortin 4 receptor gene represent the most common cause of monogenic obesity because they are detected in almost 6 % children with early-onset severe obesity. Mutations of the other genes involved in energy homeostasis are very rare. Although these mutations are sporadic we assume that further research of monogenic forms of obesity might lead to our understanding of physiology and pathophysiology of regulation of the energy homeostasis and eating behaviour. Additionally, they may open new approach to the management of eating behaviour and to the treatment of obesity.
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PMID:[Obesity based on mutation of genes involved in energy balance]. 1741 7

Androgen receptor (AR) mediates diverse androgen actions, particularly reproductive processes in males and females. AR-mediated androgen signaling is considered to also control metabolic processes; however, the molecular basis remains elusive. In the present study, we explored the molecular mechanism of late-onset obesity in male AR null mutant (ARKO) mice. We determined that the obesity was caused by a hypercorticoid state. The negative feedback system regulating glucocorticoid production was impaired in ARKO mice. Male and female ARKO mice exhibited hypertrophic adrenal glands and glucocorticoid overproduction, presumably due to high levels of adrenal corticotropic hormone. The pituitary glands of the ARKO males had increased expression of proopiomelanocortin and decreased expression of the glucocorticoid receptor (GR). There were no overt structural abnormalities and no alteration in the distribution of cell types in the pituitaries of male ARKO mice. Additionally, there was normal production of the other hormones within the glucocorticoid feedback system in both the pituitary and hypothalamus. In a cell line derived from pituitary glands, GR expression was under the positive control of the activated AR. Thus, this study suggests that the activated AR supports the negative feedback regulation of glucocorticoid production via up-regulation of GR expression in the pituitary gland.
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PMID:The pituitary function of androgen receptor constitutes a glucocorticoid production circuit. 2369 41


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