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

Melanocortin receptor agonists act in the brain to regulate food intake and body weight and, independently of these actions, affect insulin sensitivity. These experiments investigated the function of novel non-selective melanocortin receptor agonists (BIM-22493, BIM-22511) that cross the blood-brain barrier when administered peripherally. Treatment of diet induced obese C57BL/6J (B6) mice with melanocortin agonists administered peripherally improved obesity, hyperinsulinemia (approximately 50%) and fatty liver disease. Specificity of function was determined using B6 melanocortin-3 and melanocortin-4 receptor knockout mice (MC3RKO, MC4RKO). Chow fed MC4RKO but not MC3RKO used for these tests exhibited obesity, hyperinsulinemia and severe hepatosteatosis associated with increased expression of insulin-stimulated genes involved in lipogenesis. Reduced food intake associated with acute BIM-22493 treatment, and weight loss associated with 14 days of treatment with BIM-22511, required functional MC4R but not MC3R. However, while 14 days of treatment with BIM-22511 did not affect body weight and even increased cumulative food intake in MC4RKO, a significant reduction (approximately 50%) in fasting insulin was still observed. Despite lowering insulin, chronic treatment with BIM-22511 did not improve hepatosteatosis in MC4RKO, and did not affect hepatic lipogenic gene expression. Together, these results demonstrate that peripherally administered melanocortin receptor agonists regulate body weight, liver metabolism and glucose homeostasis through independent pathways. MC4R are necessary for melanocortin agonist-induced weight loss and improvements in liver metabolism, but are not required for improvements in hyperinsulinemia. Agonists with activity at MC4R improve glucose homeostasis at least partially by causing weight loss, however other melanocortin receptors may have potential for treating aberrations in glucose homeostasis associated with obesity.
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PMID:Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. 1964 98

Epidemiological studies suggest that obesity increases the risk of developing several cancers, including melanoma. Obesity increases the expression of angiogenic factors, such as leptin, that may contribute to tumor growth. However, a direct cause and effect relationship between obesity and tumor growth has not been clearly established and the role of leptin in accelerating tumor growth is unclear. Our objective in the present study was to examine the rate of melanoma tumor growth in lean and obese mice with leptin deficiency or high levels of plasma leptin. We injected 1 x 10(6) B16F10 melanoma cells subcutaneously into lean wild type (WT), obese melanocortin receptor 4 knockout (MC4R(-/-)), which have high leptin levels, obese leptin-deficient (ob(-/-)), pair fed lean ob(-/-), and lean ob(+/-) mice. Mean body weights were 29.7 +/- 0.3 g (WT), 46.3 +/- 1.9 g (MC4R(-/-)), 63.7 +/- 0.9 g (ob(-/-)), 30.5 +/- 1.0 g (pair fed ob(-/-)) and 31.6 +/- 1.7 g (ob(+/-)). Tumors were much larger in the obese leptin deficient ob(-/-) (5.1 +/- 0.9 g) and obese MC4R(-/-) (5.1 +/- 0.7 g) than in lean WT (1.9 +/- 0.3 g) and ob(+/-) (2.8 +/- 0.7 g) mice. Prevention of obesity by pair feeding ob(-/-) mice dramatically reduced tumor weight (0.95 +/- 0.2 g) to a level that was significantly lower than in WT mice of the same weight. Tumor VEGF levels were the highest in the obese mouse tumors (p < 0.05), regardless of the host leptin levels. Except for the lean ob(+/-), MC4R(-/-) and ob(-/-) melanomas had the highest VEGF receptor 1 and VEGF receptor 2 protein expression (p < 0.01 and p < 0.05), respectively. These results indicate that obesity markedly increases melanoma tumor growth rate by mechanisms that may involve upregulation of VEGF pathways. Although tumor growth does not require host leptin, melanoma tumor growth may be accelerated by leptin.
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PMID:Obesity promotes melanoma tumor growth: role of leptin. 1971 40

MC4R belongs to a seven-transmembrane G-protein-coupled receptor which may regulate body composition and insulin action. Many mutations in the MC4R gene are associated with obesity, energy expenditure and serum triglyceride levels in human and animals. Six mutations in the MC4R gene were identified in our study (-293C>G, -193A>T, -192T>G, -129A>G, -84T>C and 1,069C>G). The -129A>G was significantly associated with live weight (LW) (P < 0.05), Cattle with the genotypes AG and GG had higher LW than genotype AA. The 1,069C>G was significantly associated with LW, carcass weight (CW), backfat thickness and marbling score (MS). Cattle with the genotype GG had higher LW, CW and MS than genotype CC; Cattle with the genotypes GG and CG had higher MS than CC. The results suggested that -129A>G and 1,069C>G SNP of the MC4R gene may be useful as a genetic marker for carcass and meat quality traits in Qinchuan cattle.
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PMID:Mutations of MC4R gene and its association with economic traits in Qinchuan cattle. 1971 85

The timing of associations between common genetic variants for weight or body mass index (BMI) across the life course may provide insights into the aetiology of obesity. We genotyped variants in FTO (rs9939609) and near MC4R (rs17782313) in 1240 men and 1239 women born in 1946 and participating in the MRC National Survey of Health and Development. Birth weight was recorded and height and weight were measured or self-reported repeatedly at 11 time-points between ages 2 and 53 years. Hierarchical mixed models were used to test whether genetic associations with weight or BMI standard deviation scores (SDS) changed with age during childhood and adolescence (2-20 years) or adulthood (20-53 years). The association between FTO rs9939609 and BMI SDS strengthened during childhood and adolescence (rate of change: 0.007 SDS/A-allele/year; 95% CI: 0.003-0.010, P < 0.001), reached a peak strength at age 20 years (0.13 SDS/A-allele, 0.08-0.19), and then weakened during adulthood (-0.003 SDS/A-allele/year, -0.005 to -0.001, P = 0.001). MC4R rs17782313 showed stronger associations with weight than BMI; its association with weight strengthened during childhood and adolescence (0.005 SDS/C-allele/year; 0.001-0.008, P = 0.006), peaked at age 20 years (0.13 SDS/C-allele, 0.07-0.18), and weakened during adulthood (-0.002 SDS/C-allele/year, -0.004 to 0.000, P = 0.05). In conclusion, genetic variants in FTO and MC4R showed similar biphasic changes in their associations with BMI and weight, respectively, strengthening during childhood up to age 20 years and then weakening with increasing adult age. Studies of the aetiology of obesity spanning different age groups may identify age-specific determinants of weight gain.
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PMID:Life course variations in the associations between FTO and MC4R gene variants and body size. 1988 Aug 56

Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity, the so-called hypothalamic obesity (HyOb). HyOb complicates disorders related to the hypothalamus, including those that cause structural damage to the hypothalamus, pituitary macroadenoma with suprasellar extension, glioma, meningioma, teratoma, germ cell tumors, radiotherapy, Prader-Willi syndrome, and mutations in leptin, leptin receptor, POMC, MC4R and CART genes. It is conceivable that a subgroup of patients with 'simple obesity' also have HyOb. The hypothalamus regulates body weight by precisely balancing the intake of food, energy expenditure and body fat tissue. Orexigenic and anorexigenic hypothalamic centers (hyperphagia when impaired) play a central role, connecting to adipose tissue by means of an intricate efferent and afferent signals circuit. Other mechanisms by which the brain regulates adipose tissue and beta cells of the pancreas include the sympathetic nervous system, vagally mediated hyperinsulinemia and the endocrine system, namely growth hormone, thyroid-stimulating hormone and the hypothalamo-pituitary-adrenal axis. Corticotropin-releasing hormone, adrenocorticotropic hormone glucocorticoids and the 11beta-HSD-1 shuttle regulate lipolysis both directly and indirectly. All the above mechanisms may be impaired in HyOb. Management of HyOb targets the major manifestations: hyperphagia, autonomic dysfunction, hyperinsulinemia and impaired energy expenditure. Individual variation is considerable. Satisfactory therapy is currently unavailable.
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PMID:Hypothalamic obesity. 1995 67

Obesity is a global and growing problem. The detrimental health consequences of obesity are significant and include co-morbidities such as diabetes, cancer and coronary heart disease. The marked rise in obesity observed over the last three decades suggests that behavioural and environmental factors underpin the chronic mismatch between energy intake and energy expenditure. However, not all individuals become obese, suggesting that there is considerable variation in responsiveness to 'obesogenic' environments. Some individuals defend easily against a propensity to accumulate fat mass and become overweight whilst others are predisposed to gain weight, possibly as a function of genotype. The genetic contribution to obesity is well established. Common obesity is polygenic, involving complex gene-gene and gene-environment interactions, and it is these interactions that produce the multi-factorial obese phenotypes. Candidate gene variants for polygenic obesity appear to disrupt pathways involved in the regulation of energy intake and expenditure and include adrenergic receptors, uncoupling proteins, PPARG, POMC, MC4R and a set of single nucleotide polymorphisms in the FTO locus. Notably, the FTO gene is the most robust gene for common obesity characterised to date, and recent data shows that the FTO locus seems to confer risk of obesity through increasing energy intake and reduced satiety. Gene variants involved in pathways regulating addiction and reward behaviours may also play a role in predisposition to obesity. Understanding the routes through which the genotype is expressed will ultimately provide opportunities for developing strategies to intervene, as the interaction between genotype and environment is potentially modifiable through behaviour change.
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PMID:Gene-environment interactions in obesity. 1995 87

Obesity has become an epidemic in many countries and is one of the major risk conditions for disease including type 2 diabetes, coronary heart disease, stroke, dyslipidemia, and hypertension. Recent genome-wide association studies have identified two genes (FTO and near MC4R) that were unequivocally associated with body mass index (BMI) and obesity. For the Genetic Analysis Workshop 16, data from the Framingham Heart Study were made available, including longitudinal anthropometric and metabolic traits for 7130 Caucasian individuals over three generations, each with follow-up data at up to four time points. We explored the associations between four single-nucleotide polymorphisms (SNPs) on FTO (rs1121980, rs9939609) or near MC4R (rs17782313, rs17700633) with weight and BMI under an additive model. We applied multilevel linear mixed model for continuous outcomes, using the Affymetrix 500k genome-wide genotype data for the four SNPs. The results of the multilevel modeling in the entire sample indicated that the minor alleles of the four SNPs were associated with higher weight and higher BMI. The most significant associations were between rs9939609 and weight (p = 4.7 x 10-6) and BMI (p = 8.9 x 10-8). The results also showed that, for SNPs at FTO, the homozygotes for the minor allele had the most pronounced increase in weight and BMI, while the common allele homozygotes gained less weight and BMI during the follow-up period. Linkage disequilibrium (LD) between the two FTO SNPs was strong (D' = 0.997, r2 = 0.875) but their haplotype was not significantly associated with either weight or BMI. The two SNPs near MC4R were in weak LD (D' = 0.487, r2 = 0.166).
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PMID:A multilevel linear mixed model of the association between candidate genes and weight and body mass index using the Framingham longitudinal family data. 2001 80

Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3(-/Y) (BRS-3 null) mice but was maintained in Npy(-/-)Agrp(-/-), Mc4r(-/-), Cnr1(-/-), and Lepr(db/db) mice. In addition, Brs3(-/Y) mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.
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PMID:Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity. 2009 42

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R-/- mice with wild-type (WT), MC4R-/-, and mice bearing disruption of both genes (double knockout, DKO) on select feeding and neuroanatomical dimensions. DKO mice were significantly more obese than MC4R-/-, whereas MC3R-/- weighed the same as WT. In a food demand protocol, DKO and MC4R-/- were hyperphagic at low unit costs for food, due primarily to increased meal size. However, at higher costs, their intake dropped below that of WT and MC3R-/-, indicating increased elasticity of food demand. To determine whether this higher elasticity was due to either the genotype or to the obese phenotype, the same food demand protocol was conducted in dietary obese C57BL6 mice. They showed similar elasticity to lean mice, suggesting that the effect is of genotypic origin. To assess whether the increased meal size in MC4R-/- and DKO might be due to reduced CCK signaling, we examined the acute anorectic effect of peripherally administered CCK and subsequently the induction of c-Fos immunoreactivity in select brain regions. The anorectic effect of CCK was comparable in MC4R-/-, DKO, and WT, but it was unexpectedly absent in MC3R-/-. CCK-induced c-Fos was lower in the paraventricular nucleus in MC3R-/- than the other genotypes. These data are discussed in terms of demand functions for food intake, MC receptors involved in feeding, and their relation to actions of gut hormones, such as CCK, and to obesity.
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PMID:Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors. 2037 67

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.
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PMID:Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups. 2042 36


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