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

Genetic knockout and null mutations of melanocortin system components lead to phenotypes that recapitulate the metabolic syndrome such as obesity, hypertension and insulin resistance. Since stress is known to modify metabolic and cardiovascular function, we hypothesized the involvement of the neural melanocortin system in the stress response. Male rats were subjected to rapid-eye-movement sleep deprivation stress and the levels of proopiomelanocortin (POMC), MC3R, MC4R and MC5R transcripts in the hypothalamic-pituitary-adrenal axis (HPA) determined by real-time PCR. Increased levels of POMC transcripts were observed in the hypothalamus and adrenal gland tissues but there were no significant changes in the expression of the receptors genes. Whereas MC3R and MC5R are expressed in all HPA tissues, MC4R seems to be restricted mainly to the hypothalamus. It is possible that melanocortin receptors function in different aspects of the neuron. In vitro studies showed similar cellular distribution patterns for MC3R and MC4R and sequence analyses revealed strong conservation of the putative G-protein coupled receptors (GPCR) C-terminal membrane localization signal, EX(3-7)II/L motif, in MC3R, MC4R and MC5R. These data suggest that the physiological roles of neural melanocortin receptors, MC3R and MC4R, are likely determined by distinct tissue distribution patterns and suggest a role for hypothalamic and intra-adrenal melanocortin systems in the manifestation of stress related pathologies.
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PMID:Neural melanocortin receptors are differentially expressed and regulated by stress in rat hypothalamic-pituitary-adrenal axis. 1564 Nov 61

Exposure to maternal diabetes in utero (GD) may 'program' for obesity. Orexigenic neuropeptides, like neuropeptide Y (NPY) and agouti-related peptide (AGRP), and anorexigenic neuropeptides, like proopiomelanocortin (POMC) and alpha-melanocyte-stimulating hormone (MSH), are decisively involved in body weight regulation. We investigated consequences of GD and its treatment by pancreatic islet transplantation in rats for development of neuropeptidergic neurons in the arcuate hypothalamic nucleus (ARC) in weanling offspring. In GD, islet transplantation on d15 of pregnancy led to normalized blood glucose. Sham-transplanted GD mothers (TSGD) remained hyperglycemic. Twenty-one-day-old TSGD offspring developed hypothalamic 'malorganization'. Despite of normal leptin and insulin levels in TSGD offspring, increased immunopositivity of NPY and AGRP appeared. TSGD offspring showed unchanged POMC, but decreased MSH-immunopositivity. In conclusion, untreated diabetes in pregnant rats leads to 'malprogramming' of hypothalamic neuropeptidergic neurons in offspring, probably contributing to later development of overweight. These acquired alterations are preventable by treatment of maternal GD.
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PMID:'Programming' of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats. 1564 53

The adipocyte hormone leptin binds to its receptors in hypothalamic neurons and decreases appetite and food consumption. Its effect on appetite is mediated by melanocortines (MC) that are derivative of proopiomelanocortin (POMK) and their receptor (MC4-R). The knock-out of POMC gene or MC4-R gene causes obesity in animals. However, the growth of the animals intensifies and their reproductive function does not cease. The paper covers consequences of mutations in genes responsible for leptin regulation of various functions.
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PMID:[The role of leptin and its peptide mediators in neurophysiology]. 1577 67

The proopiomelanocortin (POMC) gene is expressed in the pituitary and arcuate neurons of the hypothalamus. POMC arcuate neurons play a central role in the control of energy homeostasis, and rare loss-of-function mutations in POMC cause obesity. Moreover, POMC is the prime candidate gene within a highly significant quantitative trait locus on chromosome 2 associated with obesity traits in several human populations. Here, we identify two phylogenetically conserved neuronal POMC enhancers designated nPE1 (600 bp) and nPE2 (150 bp) located approximately 10 to 12 kb upstream of mammalian POMC transcriptional units. We show that mouse or human genomic regions containing these enhancers are able to direct reporter gene expression to POMC hypothalamic neurons, but not the pituitary of transgenic mice. Conversely, deletion of nPE1 and nPE2 in the context of the entire transcriptional unit of POMC abolishes transgene expression in the hypothalamus without affecting pituitary expression. Our results indicate that the nPEs are necessary and sufficient for hypothalamic POMC expression and that POMC expression in the brain and pituitary is controlled by independent sets of enhancers. Our study advances the understanding of the molecular nature of hypothalamic POMC neurons and will be useful to determine whether polymorphisms in POMC regulatory regions play a role in the predisposition to obesity.
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PMID:Identification of neuronal enhancers of the proopiomelanocortin gene by transgenic mouse analysis and phylogenetic footprinting. 1579 95

Resistin is a new adipokine expressed in mouse, rat and human adipose tissue. Resistin may be an important link between obesity and insulin resistance, though this controversial view is complicated by the discovery of multiple sites of resistin expression, including human macrophages, placenta and pancreas. In previous studies we demonstrated that the mouse hypothalamo-pituitary system was also a site of resistin production. Pituitary resistin is developmentally regulated, reduced in the ob/ob mouse and severely down-regulated by food deprivation (24 h). An unexpected finding was that hypothalamic resistin mRNA remained unaffected by fasting. The present experiments examined the localization and possible regulation of hypothalamic resistin protein. Using immunohistochemistry we observed a complex network of resistin+ fibres extending rostrally from the arcuate nucleus of the hypothalamus (ARC) to the preoptic area. Labelled cell bodies occurred only in the ARC and in a periventricular region of the dorsal hypothalamus. Hypothalamic resistin immunoreactivity (ir) was unaffected by fasting (48 h) or by a high fat diet, but the periventricular staining was greatly increased in the lactating mouse. Marked reductions in resistin+ fibres were seen in brain tissue from: (a) ob/ob mice, (b) young mice made underweight for their age by raising them in large litters (20 pups per litter) and (c) mice with hypothalamic lesions induced by monosodium glutamate (MSG) or gold thioglucose (GTG). We speculate that the resistin-ir deficit in genetically obese mice, and in severely underweight mice, could be due to low or absent leptin. In contrast, though MSG- and GTG-treated mice have high levels of circulating leptin, in the presence of excessive visceral fat deposits, we hypothesize that damage to the ARC destroys the resistin+ cell bodies. This latter supposition led us to an additional hypothesis, that resistin-ir would be contained in neurons expressing the proopiomelanocortin (POMC) gene. This proved to be correct. Double label immunofluorescence histochemistry revealed that alpha-MSH-ir, a marker for POMC neurons, was co-localized with resistin-ir. In conclusion, our data reveal a second example of an adipocytokine co-localized with a hypothalamic neuropeptide. We reported previously that leptin was co-localized with oxytocin and vasopressin. RT-PCR analysis confirmed that resistin mRNA is readily detectable in ARC, but further work is required to determine whether the resistin gene is expressed in POMC neurons or if resistin is specifically accumulated by these cells. Nonetheless, our data suggest that the hypothalamus is a target tissue for resistin.
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PMID:Hypothalamic resistin immunoreactivity is reduced by obesity in the mouse: co-localization with alpha-melanostimulating hormone. 1580 9

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.
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PMID:The role of insulin receptor substrate 2 in hypothalamic and beta cell function. 1584 Nov 80

We previously created a novel F-DIO rat strain derived by crossing rats selectively bred for the diet-induced obesity (DIO) phenotype with obesity-resistant Fischer F344 rats. The offspring retained the DIO phenotype through 3 backcrosses with F344 rats but also had exaggerated insulin responses to oral glucose before they became obese on a 31% fat high-energy (HE) diet. Here, we demonstrate that chow-fed rats from the subsequent randomly bred progeny required 57% lower glucose infusions to maintain euglycemia during a hyperinsulinemic clamp in association with 45% less insulin-induced hepatic glucose output inhibition and 80% lower insulin-induced glucose uptake than F344 rats. The DIO phenotype and exaggerated insulin response to oral glucose in the nonobese, chow-fed state persisted in the F6 generation. Also, compared with F344 rats, chow-fed F-DIO rats had 68% higher arcuate nucleus proopiomelanocortin mRNA expression which, unlike the increase in F344 rats, was decreased by 26% on HE diet. Further, F-DIO lateral hypothalamic orexin expression was 18% lower than in F344 rats and was increased rather than decreased by HE diet intake. Finally, both maternal obesity and 30% caloric restriction during the third week of gestation produced F-DIO offspring which were heavier and had higher leptin and insulin levels than lean F-DIO dam offspring. Third-gestational week dexamethasone also produced offspring with higher leptin and insulin levels but with lower body weight. Thus F-DIO rats represent a novel and potentially useful model for the study of DIO, insulin resistance, and perinatal factors that influence the development and persistence of obesity.
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PMID:F-DIO obesity-prone rat is insulin resistant before obesity onset. 1587 56

It is well established that agouti-related protein (AGRP) can act as a competitive antagonist to proopiomelanocortin (POMC)-derived peptides at the melanocortin-4 receptor (MC4R), and that this homeostatic mechanism is important as a means of coordinating appetite with perceived metabolic requirement. However, there are clearly additional facets to the physiological role of AGRP, given that it is active in MC4R knockout mice and it has strikingly long-lasting effects on food intake, compared with MC4R agonists. In this review we focus on: (i) evidence that AGRP is more sensitive to perturbations in energy balance than POMC and is therefore the primary basis of melanocortinergic regulation. (ii) Evidence that the bioactive peptide AGRP83-132, acts by alternate mechanism(s) to elicit its long-term effects on food intake. (iii) Evidence that AGRP is post-translationally cleaved to generate AGRP83-132 and one or more N terminal peptides, which may have an important physiological role(s) that are independent of the melanocortin system. A clear understanding of how proAGRP processing is regulated, and the role of resultant peptides, may define additional therapeutic targets in the treatment of obesity.
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PMID:Agouti-related protein: more than a melanocortin-4 receptor antagonist? 1599 91

Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of Pomc-/- and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc-/- but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc-/- versus 14-fold in wild-type mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc-/- versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc-/- but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8-12 weeks. Thus, Pomc-/- mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc-/- mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state.
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PMID:Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. 1604 91

Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P = 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation.
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PMID:Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study. 1604 20


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