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

The melanocortins, a family of peptides produced from the post-translational processing of pro-opiomelanocortin (POMC), regulate ingestive behavior and energy expenditure. Loss of function mutations of genes encoding POMC, or of either of two melanocortin receptors expressed in the central nervous system (MC3R, MC4R), are associated with obesity. The analyses of MC4R knockout mice indicate that activation of this receptor is involved in the regulation of appetite, the adaptive metabolic response to excess caloric consumption, and negative energy balance associated with cachexia induced by cytokines. In contrast, MC3R knockout mice exhibit a normal, or even exaggerated, response to signals that induce a state of negative energy balance. However, loss of the MC3R also results in an increase in adiposity. This article discusses the regulation of energy balance by the melanocortins. Published and newly presented data from studies analyzing of energy balance of MC3R and MC4R knockout mice indicate that increased adiposity observed in both models involves an imbalance in fat intake and oxidation.
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PMID:The melanocortin system and energy balance. 1643 23

Functional disruption of either MC3R or MC4R results in obesity, implicating both in the control of energy homeostasis. The ligands for these receptors are derived from the prohormone proopiomelancortin (POMC), which is posttranslationally processed to produce a set of melanocortin peptides with a range of activities at the MC3R and MC4R. The relative importance of each of these peptides alpha-MSH, gamma3-MSH, gamma2-MSH, gamma-lipotropin (gamma-LPH) and, in man but not in rodents, beta-MSH] in the maintenance of energy homeostasis is, as yet, unclear. To investigate this further, equimolar amounts (2 nmol) of each peptide were centrally administered to freely feeding, corticosterone-supplemented, Pomc null (Pomc-/-) mice. After a single dose at the onset of the dark cycle, alpha-MSH had the most potent anorexigenic effect, reducing food intake to 35% of sham-treated animals. beta-MSH, gamma-LPH, and gamma3- and gamma2-MSH all reduced food intake but to a lesser degree. The effects of peptide administration over 3 d were also assessed. Only alpha-MSH significantly reduced body weight, affecting both fat and lean mass. Other peptides had no significant effect on body weight. Pair-feeding of sham-treated mice to those treated with alpha-MSH resulted in identical changes in total weight, fat and lean mass indicating that the effects of alpha-MSH were primarily due to reduced food intake rather than increased energy expenditure. Although other melanocortins can reduce food intake in the short-term, only alpha-MSH can reduce the excess fat and lean mass found in Pomc-/- mice, mediated largely through an effect on food intake.
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PMID:A comparative study of the central effects of specific proopiomelancortin (POMC)-derived melanocortin peptides on food intake and body weight in pomc null mice. 1695 30

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

Melanocortins play a central role in autonomic modulation of metabolism by acting through a family of highly homologous G protein-coupled receptors. Studies with gene knockout mice have implicated neural melanocortin receptors, MC3R and MC4R, in the etiology of obesity, insulin resistance, and salt-sensitive hypertension. In an attempt to better understand the mechanisms of function of these receptors, we expressed MC3R and MC4R in neuronal cells and demonstrated their co-localization to several membrane regions. We now show that in cultured neuronal cells, MC3R localizes to lipid rafts and undergoes endocytic internalization upon activation by gamma-MSH through a protein kinase-sensitive pathway. The appearance of the internalized receptor in lysosomes suggests that it is subsequently degraded. The expression of protein kinase A regulatory subunits and of c-Jun and c-Fos was analyzed by either immunoblotting or real-time PCR. No discernable changes were observed in the expression levels of these protein kinase A and protein kinase C responsive genes. Immunohistochemical studies showed a robust expression of MC3R protein in brain nuclei with relevance to cardiovascular function and fluid homeostasis further supporting the notion that the physiological effects of melanocortins on the cardiovascular system arise from effects on the central nervous system.
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PMID:Activation and endocytic internalization of melanocortin 3 receptor in neuronal cells. 1740 38

Melanocortin receptors have been implicated in the confounding factors of cardiovascular diseases such as obesity, insulin resistance and salt-sensitive hypertension. The aim of this study was determine how increased dietary salt intake affects the expression profiles of melanocortin system genes in relevant endocrine tissues. Total RNA was isolated from the pituitary and adrenal glands of Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SP-SHR) and subjected to real-time PCR analysis. Expression levels of pro-opiomelanocortin (POMC), POMC processing enzymes prohormone convertases 1 and 2 (PC1/PC2), melanocortin 3 receptor (MC3R) and melanocortin 5 receptor (MC5R) were not significantly affected by high dietary salt intake in either WKY or SP-SHR tissues. Consistent with known endocrine relationship between the pituitary and adrenal glands, the expression levels of the ACTH receptor, MC2R, were five orders of magnitude higher in adrenal tissues whereas those of POMC were three orders of magnitude higher in the pituitary. MC3R, PC1 and PC2 transcripts were expressed at similar levels in both tissues while MC5R was expressed at a higher level in the adrenal tissues. These results are therefore inconsistent with an endocrine pathway that involves pituitary derived gamma-MSH modulating adrenal function in response to high dietary salt intake.
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PMID:Prevalence of melanocortin system transcripts in rat salt homeostasis endocrine tissues. 1753 Nov 55

The melanocortin system has been implicated in regulating various physiological processes including pigmentation, energy homeostasis, obesity, steroidogenesis cardiovascular, and exocrine gland function. The five melanocortin receptors that belong to the super family of G protein-coupled receptors are stimulated by naturally occurring agonists. The aim of this research was focused on the design, synthesis, and pharmacological characterization of melanocortin ligands that contain the 1,2,5-trisubstituted benzimidazole scaffold. A series of benzimidazole analogues, with three points of diversity at positions 1, 2, and 5, were designed, synthesized, pharmacologically assayed at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R and resulted in ligands possessing a range of agonist activity from nm to no stimulation at up to 100 microM concentrations. This study demonstrates that the benzimidazole structure template can be appended with key melanocortin agonist amino acids for the design melanocortin receptor agonist ligands.
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PMID:Structure-activity relationships of melanocortin agonists containing the benzimidazole scaffold. 1753 26

The melanocortin family of receptors (MC 1-5R) and their endogenous peptide ligands (alpha, beta, gamma- MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.
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PMID:Melanocortin-4 receptor agonists for the treatment of obesity. 1758 32

Several mutations in the melanocortin receptor 4 gene have been identified in humans and account for 3-6% of morbid obesity. In contrast, strong evidence of a causative role for melanocortin receptor 3 (MC3R) mutations are still lacking. In MC3R knockout mice, high feed efficiency rather than hyperphagia seems to contribute to increased fat mass. On the basis of this evidence, the objective of the present study was to investigate the presence of MC3R mutations in a group of 290 obese subjects (mean BMI 44.2+/-5.9 kg/m2). As a control, a group of 215 normal-weight subjects (mean BMI 22.4+/-2.7 kg/m2) was also screened. Three novel mutations in the MC3R gene (A293T, I335S and X361S) were identified among the obese patients. The mutations segregated with obesity in the members of the families studied. In vitro expression studies of each mutation demonstrated a loss of function of the I335S-mutated receptor. These findings suggest that, in humans, MC3R mutations may be a cause of a dominantly inherited form of obesity. However, this association as well as the specific phenotypic characteristics resulting from these mutations need to be further evaluated in larger series of obese subjects.
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PMID:Sporadic mutations in melanocortin receptor 3 in morbid obese individuals. 1823 Nov 26

Obesity is a complex disease, which in many cases appears as a polygenic condition affected by environmental factors (mainly unbalanced dietary patterns and physical inactivity). In this context, the weight loss response to dietary interventions varies widely and predictive factors of successful slimming including those concerned with the individual's genetic make-up are poorly understood. Indeed, a number of genes involved in the regulation of energy expenditure, appetite, lipid metabolism and adipogenesis have been reported to affect the risk of treatment failure in some obese subjects. Some candidate genes for the prognosis of weight loss response related to energy expenditure are those codifying for the adrenergic receptors (ADBRs) and uncoupling proteins (UCPs), while genes related to appetite potentially affected by energy restriction are leptin (LEP), leptin receptor (LEPR), melanocortin pathways genes (MC3R, POMC) and the serotonin receptor. Furthermore, adipogenesis related genes such as peroxisome proliferator-activated receptor (PPAR gamma 2) and genes related to cytokines such as interleukin-6 (IL-6) and lipid metabolism including hepatic lipase (LIPC), perilipin (PLIN) and lipoprotein lipase (LPL) have also been associated to the weight lowering outcome induced by hypocaloric diets. Therefore, this review shows preliminary evidence from human studies that support the existence of a genetic component in the fat reduction process associated to a negative energy balance.
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PMID:Genotype-dependent response to energy-restricted diets in obese subjects: towards personalized nutrition. 1829 17

The aim of this study was to investigate a series of single-nucleotide polymorphisms (SNPs) in the genes MC2R, MC3R, MC4R, MC5R, POMC, and ENPP1 for association with obesity. Twenty-five SNPs (2-7 SNPs/gene) were genotyped in 246 Finns with extreme obesity (BMI > or = 40 kg/m2) and in 481 lean subjects (BMI 20-25 kg/m2). Of the obese subjects, 23% had concomitant type 2 diabetes. SNPs and SNP haplotypes were tested for association with obesity and type 2 diabetes. Allele frequencies differed between obese and lean subjects for two SNPs in the ENPP1 gene, rs1800949 (P = 0.006) and rs943003 (P = 0.0009). These SNPs are part of a haplotype (rs1800949 C-rs943003 A), which was observed more frequently in lean subjects compared to obese subjects (P = 0.0007). Weaker associations were detected between the SNPs rs1541276 in the MC5R, rs1926065 in the MC3R genes and obesity (P = 0.04 and P = 0.03, respectively), and between SNPs rs2236700 in the MC5R, rs2118404 in the POMC, rs943003 in the ENPP1 genes and type 2 diabetes (P = 0.03, P = 0.02 and P = 0.02, respectively); these associations did not, however, remain significant after correction for multiple testing. In conclusion, a previously unexplored ENPP1 haplotype composed of SNPs rs1800949 and rs943003 showed suggestive evidence for association with adult-onset morbid obesity in Finns. In this study, we did not find association between the frequently studied ENPP1 K121Q variant, nor SNPs in the MCR or POMC genes and obesity or type 2 diabetes.
Obesity (Silver Spring) 2008 Sep
PMID:Further evidence for the role of ENPP1 in obesity: association with morbid obesity in Finns. 1855 Nov 13


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