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)

The melanocortin-3 receptor (MC3R) is an important regulator of energy homeostasis, inflammation, and cardiovascular function. Inactivating mutations in MC3R gene are associated with childhood obesity. How MC3R binds to its ligands has rarely been studied. In the present study, we systematically mutated all ten acidic residues in transmembrane (TM) domains and measured the cell surface expression levels as well as ligand binding and signaling properties of these mutants. Our results showed that of the 19 mutants stably expressed in HEK293 cells, all were expressed on the cell surface, although some mutants had decreased levels of cell surface expression. We showed that with the superpotent analog [Nle(4), D-Phe(7)]-alpha-melanocyte stimulating hormone (MSH), E92, E131, D154, D158, D178, and D332 are important for ligand binding. D121 and D332 are important for binding and signaling. Further experiments using other ligands such as D-Trp(8)-gamma-MSH, alpha-MSH and gamma-MSH showed that different ligands induce or select different conformations. In summary, we showed that acidic residues in TMs 1 and 3 are important for ligand binding whereas the acidic residues in TMs 2 and 7 are important for both ligand binding and signaling.
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PMID:Functions of acidic transmembrane residues in human melanocortin-3 receptor binding and activation. 1861 55

The melanocortin (MC) receptor type-1 (MC1-R) is the only one of the five MC receptor subtypes expressed in human adipose tissue explants, human mesenchymal stem cells (MSCs), and MSC-derived adipocytes. Following our recent expression studies (Obesity 2007, 15, 40-49), we now investigated the functional role of MC1-R in these tissues and cells to deduce the coupling state of MC1-R to intracellular output signals in human fat cells and tissue. Expression of MC1-R by undifferentiated and differentiated MSCs was quantified by real-time TaqMan PCR. Intracellular output signals (cAMP, lipolysis, secretion of IL-6, IL-10, and TNF-alpha), as well as effects on the metabolic rate and proliferation of human MSCs were analyzed by standard assays, exposing undifferentiated and differentiated MSCs and, in part, human adipose tissue explants to the potent MC1-R agonist, [Nle(4), D-Phe(7)]-alpha-MSH (NDP-MSH). This agonist induced a weak cAMP signal in MSC-derived adipocytes. However, it did not affect lipolysis in these cells or in adipose tissue explants, nor did it modulate cytokine release and mRNA expression of IL-6, IL-8, and TNF-alpha upon LPS stimulation. In undifferentiated MSCs, NDP-MSH did not alter the metabolic rate, but it showed a significant antiproliferative effect. Therefore, it appears that MC1-R-effector coupling in (differentiated) human adipocytes is too weak to induce a regulatory effect on lipolysis or inflammation; by contrast, MC1-R stimulation in undifferentiated MSCs induces an inhibitory signal on cell proliferation.
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PMID:Weak functional coupling of the melanocortin-1 receptor expressed in human adipocytes. 1894 69

Rodent experiments raise the possibility of a regulatory role of peripheral alpha-melanocyte-stimulating hormone (alpha-MSH) in obesity and metabolism, but human data on peripheral alpha-MSH levels remain fragmentary. Because of the possible relationship between alpha-MSH and obesity, we endeavored to test the hypothesis that higher levels of alpha-MSH in obese patients would correlate with leptin levels and with other markers of obesity. Sixty normal-weight to obese healthy men and women participated. Weight, measures of body composition, and diet diaries were obtained; fasting blood was analyzed for alpha-MSH, lipids, glucose, insulin, leptin, and adiponectin. To begin to understand the source of peripherally measured hormones, alpha-MSH was also measured in serum samples from 5 individuals with untreated Addison disease. Levels of alpha-MSH were higher in men vs women (10.1 +/- 4.3 vs 7.6 +/- 3.4 pmol/L, P = .019), and alpha-MSH levels were higher in patients with Addison disease vs controls (17.7 +/- 2.3 vs 8.7 +/- 0.52 pmol/L, P < .001). Measures of adiposity correlated with insulin and leptin in men and women, and with adiponectin in women. alpha-Melanocyte-stimulating hormone levels did not correlate significantly with any parameter of adiposity or diet composition. The elevated alpha-MSH levels in patients with untreated Addison disease suggest possible pituitary secretion of alpha-MSH to the periphery. The lack of correlation between peripheral alpha-MSH and parameters of adiposity suggests that endogenous plasma alpha-MSH levels are not a metric for body composition per se.
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PMID:Plasma alpha-melanocyte-stimulating hormone: sex differences and correlations with obesity. 1905 26

The anorexigenic neuromodulator alpha-melanocyte-stimulating hormone (alpha-MSH; referred to here as alpha-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of alpha-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into alpha-MSH1-13 inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Real-time PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of alpha-MSH1-13, producing alpha-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where alpha-MSH1-13 is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of alpha-MSH1-13 in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet-induced obesity. Our results suggest that PRCP is an important component of melanocortin signaling and weight maintenance via control of active alpha-MSH1-13 levels.
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PMID:Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents. 1962 Jul 79

Long-term regulation of energy balance involves two major trends: first age-related obesity develops in the middle-aged, later it is followed by anorexia of aging (sarcopenia and/or cachexia). A dynamic balance between orexigenic and anorexigenic neuropeptides is essential for the regulation of energy homeostasis. Special imbalances of neuropeptide effects may be assumed corresponding to different age-periods. Anorexia induced by acute alpha-MSH (alpha-melanocyte stimulating hormone; endogenous melanocortin agonist) injections was analyzed in male Wistar rats aged 6-9 weeks (juvenile), 3-4 months (young adult), 6 or 12 months (two middle-aged groups), 18 months (aging) and 24-26 months (old). Alpha-MSH injected through a preimplanted intracerebroventricular (ICV) cannula (compared with saline injection) dose-dependently suppressed spontaneous food intake and also re-feeding following 24-h fasting, but the rate of suppression varied between age-groups. An ICV injection of 5 microg alpha-MSH attenuated the 2-h re-feeding by 21.9+/-3.2% in juvenile rats, strongly (68.7+/-2.5%) suppressed it in young adults, the suppression became progressively weaker in the two middle-aged groups (55.7+/-4.9%, vs. 26.4+/-4.9%, respectively), but it turned extreme in aging (94.7+/-4.2%) and old (74.3+/-4.5%) rats. Body composition also changed with age: unlike the tibialis anterior muscle, the epididymal and retroperitoneal fat pads increased until middle-age and remained large even in old animals, while the measured indicator of muscle mass decreased in the oldest group. The food intake suppressing and body weight decreasing effects of a 7-day-long ICV infusion of 1 microg/h alpha-MSH were weakest in the 12-month-old and most pronounced in the 24 month-old rats. In conclusion, responsiveness to the anorexic effect of alpha-MSH varies with age, with a nadir of the curve in the middle-aged, and a peak in the aging and old animals. This age-related nadir of melanocortin-responsiveness may promote obesity in middle-aged rats, while the tendency for anorexia and incipient sarcopenia of old (still obese) rats may result from age-related melanocortin-hypersensitivity rather than from adiposity.
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PMID:Age-dependence of alpha-MSH-induced anorexia. 2038 26

Because rearing rats in large litters (LLs) protects them from becoming obese, we postulated that LL rearing would protect rats selectively bred to develop diet-induced obesity (DIO) from becoming obese by overcoming their inborn central leptin resistance. Male and female DIO rats were raised in normal litters (NLs; 10 pups/dam) or LLs (16 pups/dam) and assessed for anatomical, biochemical, and functional aspects of leptin sensitivity at various ages when fed low-fat chow or a 31% fat high-energy (HE) diet. LL rearing reduced plasma leptin levels by postnatal day 2 (P2) and body weight gain by P8. At P16, LL DIO neonates had increased arcuate nucleus (ARC) binding of leptin to its extracellular receptors and at P28 an associated increase of their agouti-related peptide and alpha-MSH axonal projections to the paraventricular nucleus. Reduced body weight persisted and was associated with increased ARC leptin receptor binding and sensitivity to the anorectic effects of leptin, reduced adiposity, and enhanced insulin sensitivity in LL DIO rats fed chow until 10 wk of age. The enhanced ARC leptin receptor binding and reduced adiposity of LL DIO rats persisted after an additional 5 wk on the HE diet. Female LL DIO rats had similar reductions in weight gain on both chow and HE diet vs. normal litter DIO rats. We postulate that LL rearing enhances DIO leptin sensitivity by lowering plasma leptin levels and thereby increasing leptin receptor availability and that this both enhances the ARC-paraventricular nucleus pathway development and protects them from becoming obese.
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PMID:Large litter rearing enhances leptin sensitivity and protects selectively bred diet-induced obese rats from becoming obese. 2066 22

Energy homeostasis and fuel metabolism undergo significant modifications in the course of aging. This presents in elderly subjects either as increased body mass and glucose intolerance - which may lead to obesity and type 2 diabetes - or loss of appetite, which may also seriously compromise health. The hypothalamic expression of neuropeptide Y (NPY), the most potent orexigen, and its receptors, was highly suppressed in old rats. Moreover, induction of the NPY-dependent responses was severely blunted in old animals. Similar reductions, although of a lower magnitude, were reported for other hypothalamic orexigens, A and orexins. Orexigenic activity of ghrelin, the only peripheral orexigen, was clearly suppressed in old humans and rats. However, aging did not alter hypothalamic expression of key anorexigens, alpha-MSH and CART. Age-related decrease of central anorexigenic action of leptin was likely caused by the impaired leptin signal transduction. Thus, aging in rodents is associated with the general down-regulation of orexigenic hypothalamic pep-tides - and unchanged expression of anorexigenic hypothalamic peptides - which may lead to weight loss at the end of life. If similar changes at the level of CNS underlie the 'anorexia of aging' observed in some elderly, therapeutic interventions at this regulatory level may be possible in the future.
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PMID:Central control of food intake in aging. 2070 54


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