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

Consumption of a high-fat diet decreases hypothalamic neuropeptide Y (NPY) and increases proopiomelanocortin (POMC) and brown adipose uncoupling protein (UCP)-1 mRNA in obesity-resistant SWR/J but not obesity-prone C57Bl/6J mice. Although leptin was elevated in both strains in response to a high-fat diet, its role in the development of diet-induced obesity has remained unclear since insulin and other factors that affect similar tissue targets are altered. Thus, we administered recombinant leptin by subcutaneous infusion to chow-fed mice to mimic the changes in plasma leptin across its broad physiologic range. We observed strain differences in responsiveness to reduced and elevated leptin levels. A reduction in leptin during fasting evoked a greater response in C57Bl/6J mice by decreasing energy expenditure and thyroxin, increasing corticosterone and stimulating food intake and weight gain during refeeding. However, C57Bl/6J mice were less responsive to an increase in leptin in the fed state. Conversely, the leptin-mediated response to fasting was blunted in SWR/J mice, whereas an increase in leptin profoundly reduced food intake and body weight in SWR/J mice fed ad libitum. Sensitivity to fasting in C57Bl/6J mice was associated with higher hypothalamic NPY mRNA and reduced POMC and UCP-1 mRNA expression, while the robust response to high leptin levels in SWR/J mice was associated with suppression of NPY mRNA. These results indicate that differences in leptin responsiveness between strains might occur centrally or peripherally, leading to alteration in the patterns of food intake, thermogenesis and energy storage.
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PMID:Divergent effects of leptin in mice susceptible or resistant to obesity. 1266 Aug 84

Corticolimbic circuits involving the prefrontal cortex, amygdala, and ventral striatum determine the reward value of food and might play a role in environmentally induced obesity. Chemical manipulation of the nucleus accumbens shell (AcbSh) has been shown to elicit robust feeding and Fos expression in the hypothalamus and other brain areas of satiated rats. To determine the neurochemical phenotype of hypothalamic neurons receiving input from the AcbSh, we carried out c-Fos/peptide double-labeling immunohistochemistry in various hypothalamic areas known to contain feeding peptides, from rats that exhibited a significant feeding response after AcbSh microinjection of the GABA(A) agonist muscimol. In the perifornical area, a significantly higher percentage of orexin neurons expressed Fos after muscimol compared with saline injection. In contrast, Fos expression was not induced in melanin-concentrating hormone and cocaine-amphetamine-related transcript (CART) neurons. In the arcuate nucleus, Fos activation was significantly lower in neurons coexpressing CART and proopiomelanocortin, and there was a tendency for higher Fos expression in neuropeptide Y neurons. In the paraventricular nucleus, no significant activation of oxytocin and CART neurons was found. Thus AcbSh manipulation may elicit food intake through coordinated stimulation of hypothalamic neurons expressing orexigenic peptides and suppression of neurons expressing anorexigenic peptides. However, activation of many neurons not expressing these peptides suggests that additional peptides/transmitters in the lateral hypothalamus and accumbens projections to other brain areas might also be involved.
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PMID:Peptides that regulate food intake: appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons. 1273 70

Hypothalamic neuronal histamine and its H(1) receptor (H(1)-R) form a part of the leptin-signaling pathway in the brain and have been shown to regulate body weight and adiposity in diabetic (db/db) and diet-induced obese mice by affecting food intake and uncoupling protein mRNA expression. The proopiomelanocortin (POMC) melanocortin-4 receptor (MC-4R) is also important for leptin signaling. The present study had two aims: first, to clarify the antiobesity action of neuronal histamine in agouti yellow (A(y)/a) obese mice, a model of obesity in which POMC/MC-4R signaling is disrupted by blockade of MC-4R and second, to investigate the functional relationship between neuronal histamine and POMC/MC-4R signaling. Central administration of histamine into the lateral cerebroventricle decreased cumulative food intake and body weight in A(y)/a obese mice. Histamine treatment also decreased mRNA expression of ob gene in epididymal white adipose tissue and up-regulated uncoupling protein 1 mRNA expression in brown adipose tissue. These effects were attenuated in A(y)/a obese mice with histamine H(1)-receptor (H(1)-R) knockout. Histamine treatment induced c-Fos-like immunoreactivity in both paraventricular and arcuate nucleus. There was no significant difference in histamine-induced c-Fos-like immunoreactivity in the hypothalamus between A(y)/a obese mice and lean littermates, indicating histamine signaling was not disrupted at the hypothalamic level in A(y)/a obese mice. These results suggest that neuronal histamine have an antiobese action, even in A(y)/a obese mice despite a deficiency in POMC/MC-4R signaling. In addition, it appears that the histamine H(1)-R signaling pathway may be independent or downstream of the POMC/MC-4R signaling.
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PMID:Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice. 1274 38

Outbred Sprague-Dawley rats selectively bred for their propensity to develop diet-induced obesity (DIO) become heavier on low-fat diet than those bred to be diet resistant (DR) beginning at approximately 5 wk of age. Here we assessed the development of metabolic and neural functions for insights into the origins of their greater weight gain. From week 5 to week 10, chow-fed DIO rats gained 15% more body weight and ate approximately 14% more calories but had only slightly greater adiposity and plasma leptin than DR rats. From day 3 through week 10, DIO and DR rats had similar mRNA expression of arcuate nucleus neuropeptide Y, proopiomelanocortin, agouti-related peptide, and all splice variants of the leptin receptor (OB-R). When fed a high-energy (HE; 31% fat) diet, 7-wk-old DIO rats had a 240% increase in plasma leptin levels after only 3 days. Despite this early leptin rise, they maintained a persistent hyperphagia and became more obese than chow-fed DIO rats and DR rats fed chow or HE diet. Their failure to reduce caloric intake, despite high levels of leptin, suggests that selectively bred DIO rats might have reduced leptin sensitivity similar to that seen in the outbred DIO parent strain.
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PMID:Ontogeny of diet-induced obesity in selectively bred Sprague-Dawley rats. 1277 55

We report a 21-year-old woman with ectopic ACTH syndrome due to islet cell carcinoma with multiple liver metastases. On admission, she showed Cushingoid appearance (moon face, central obesity etc.) and had acute respiratory distress syndrome due to pneumocystis carinii pneumonia. Laboratory examination revealed marked elevations of plasma ACTH (735 pg/ml) and cortisol (145 microg/dl) with a profound hypokalemia (2.0 mEq/l). She was found to have multiple masses in the liver and a solid mass in the tail of pancreas by abdominal computerized tomography scanning. Treatment with octreotide successfully reduced elevated plasma ACTH and cortisol levels, and she received frequent transhepatic arterial embolization and chemotherapy. The primary pancreatic tumor was surgically removed, revealing islet cell carcinoma which contained high content of ACTH (100 microg/g wet weight) and abundantly expressed proopiomelanocortin and somatostatin receptor subtype-2 mRNAs as determined by Northern blot analysis. Postoperatively, she was free from symptoms for almost one year. However, progressive enlargement of multiple liver metastases refractory to chemotherapy led her to decide on total hepatectomy and liver transplantation from her father. After liver transplantation, she remained almost free from symptoms for almost one year. However, metastases developed to the mediastinal and paraaortic lymph nodes as detected by 111[In] pentetreotide scintigraphy. Eleven months after liver transplantation, she was again treated with octreotide and, 16 months after, with metyrapone, both of which were effective in reducing ACTH and cortisol levels, respectively, until she died of acute respiratory failure. This case of a young female patient with ectopic ACTH-producing islet cell carcinoma of the pancreas was quite unique in that she survived for 5 years despite the acute onset and rapid progression of the multiple liver metastases at least in part due to the long-lasting favorable response to octreotide and living-related liver transplantation.
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PMID:Octreotide-sensitive ectopic ACTH production by islet cell carcinoma with multiple liver metastases. 1280 33

The hypothalamic melanocortin (MC) system provides a critical inhibitory control on food intake and body weight. Because access to high-fat (HF) diets is associated with the development of obesity, we hypothesized that increased dietary fat attenuates signaling through the MC system. To evaluate this hypothesis, we compared the efficacy of the MC3/4 receptor agonist, MTII, to reduce food intake in rats fed carefully matched HF or low-fat (LF) diets for 12 wk. Rats given the HF diet ad libitum were significantly more obese than rats given the LF diet, and had significantly higher plasma insulin and leptin levels. MTII given into the third cerebral ventricle in doses of 0.1, 0.3, and 1.0 nmol was less effective at reducing food intake in HF rats than in LF rats. Whole-hypothalamic expression of the MC agonist precursor gene, proopiomelanocortin, the MC antagonist agouti-related protein, and the MC4 receptor, were not different between the HF and LF groups. These results indicate that consumption of a HF diet decreases signaling through the melanocortin system, an abnormality that could contribute to diet-induced obesity.
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PMID:Increased dietary fat attenuates the anorexic effects of intracerebroventricular injections of MTII. 1281 May 49

The melanocortin peptides and their receptors represent one of the most complex systems in human endocrinology. Hormonal regulation includes pigmentation, weight maintenance, adrenal function, and exocrine gland secretion via endocrine, paracrine, autocrine, and neurocrine action of melanocortin peptides at five different but homologous melanocortin receptors. Genetic relevance of the melanocortin system for human physiology was initially shown by mutations in the different melanocortin receptor genes, first described in the melanocortin-2 receptor gene in 1993 as one reason for congenital hypocortisolism. Because all ligands within the melanocortin systems are derived from one single precursor hormone, proopiomelanocortin (POMC), a genetic defect in the POMC gene could have been expected to affect all functional components of the melanocortin system. Accordingly, patients with a complete defect of the POMC gene product due to homozygous or compound heterozygous loss of function mutations were shown to be affected mainly by red hair, early-onset obesity, and congenital hypocortisolism. No further obvious clinical problems were described in these patients, suggesting that no additional function of the melanocortin system has escaped recognition. However, whether partial loss of function mutations in the POMC gene might lead to more circumscribed phenotypes, especially common obesity, remains an open question.
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PMID:Mutations in the human proopiomelanocortin gene. 1285 21

Gold-thioglucose (GTG) induces lesions in the ventromedial nucleus of the hypothalamus, resulting in hyperphagia and obesity. To identify genes involved in the hypothalamic regulation of energy homeostasis, we used a screen for genes that are dysregulated in GTG-induced obese mice. We found that GPR7, the endogenous G protein-coupled receptor for the recently identified ligands neuropeptide B and neuropeptide W, was down-regulated in hypothalamus after GTG treatment. Here we show that male GPR7-/- mice develop an adult-onset obese phenotype that progressively worsens with age and was greatly exacerbated when animals are fed a high-fat diet. GPR7-/- male mice were hyperphagic and had decreased energy expenditure and locomotor activity. Plasma levels of glucose, leptin, and insulin were also elevated in these mice. GPR7-/- male mice had decreased hypothalamic neuropeptide Y RNA levels and increased proopiomelanocortin RNA levels, a set of effects opposite to those evident in ob/ob mice. Furthermore, ob/ob GPR7-/- and Ay/a GPR7-/- double mutant male mice had an increased body weight compared with normal ob/ob or Ay/a male mice, suggesting that the obesity of GPR7-/- mice is independent of leptin and melanocortin signaling. Female mice did not show any significant weight increase or associated metabolic defects. These data suggest a potential role for GPR7 and its endogenous ligands, neuropeptide B and neuropeptide W, in regulating energy homeostasis independent of leptin and melanocortin signaling in a sexually dimorphic manner.
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PMID:Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W, leads to metabolic defects and adult-onset obesity. 1292 42

Prolonged obesity frequently leads to insulin resistance and, eventually, to diabetes. This relationship reflects the integration of fat stores and carbohydrate metabolism and the coordination of central nervous system functions, e.g. appetite, and peripheral metabolism. Recent work suggests that the melanocortin system is involved in this integration; specifically, central administration of melanocyte-stimulating hormone (MSH) decreases, whereas lack of central MSH signaling increases, peripheral insulin resistance. Here we asked whether MSH acting in the periphery has a complementary role in insulin resistance. We tested this in a mouse model where the proopiomelanocortin (POMC) gene encoding all of the melanocortins has been genetically deleted. The homozygous POMC-null mouse lacks central as well as peripheral MSH signaling; in addition, it lacks adrenal glands and thus is devoid of corticosterone and epinephrine. Here we report that homozygous POMC mutants have normal serum levels of insulin, normal fasting levels of glucose, and normal clearance of glucose in glucose tolerance tests. Thus, insulin production and sensitivity and glucose uptake in peripheral tissues are functioning normally. However, we found a striking inability of the homozygous POMC mutants to recover from insulin-induced hypoglycemia. This defect was in the glucagon-mediated counterregulatory response. Both peripheral administration of an MSH analog and supplementation with corticosterone alleviated the hypoglycemia after insulin challenge, but did not make the obese POMC mutant mice diabetic. We conclude that, similar to the regulation of body weight homeostasis, the regulation of glucose homeostasis requires the integration of both central and peripheral melanocortin signaling systems.
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PMID:Altered glucose homeostasis in proopiomelanocortin-null mouse mutants lacking central and peripheral melanocortin. 1297 Jan 57

Neuropeptide Y (NPY) is a powerful orexigenic neurotransmitter. The NPY Y1 and Y5 receptors have been implicated in mediating the appetite-stimulating activity of NPY. To further investigate the importance of these two receptors in NPY-induced hyperphagia after chronic central administration, we used mice lacking either Npy1r or Npy5r expression. NPY infusion into the lateral ventricle of wild-type mice stimulated food intake and induced obesity over a 7-d period. Fat pad weight as well as plasma insulin, leptin, and corticosterone levels were strongly increased in NPY-treated mice. In addition, NPY infusion resulted in a significant decrease in hypothalamic NPY and proopiomelanocortin expression. Interestingly, the lack of either Npy1r or Npy5r expression in knockout mice did not affect such feeding response to chronic NPY infusion. Moreover, the obesity syndrome that developed in these animals was similar to that in wild-type animals. Taken together, these data strongly suggest biological redundancies between Y1 and Y5 receptor signaling in the NPY-mediated control of food intake.
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PMID:Chronic neuropeptide Y infusion into the lateral ventricle induces sustained feeding and obesity in mice lacking either Npy1r or Npy5r expression. 1452 13


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