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An Obesity Risk SNP (rs17782313) near the MC4R Gene Is Associated with Cerebrocortical Insulin Resistance in Humans.

ABSTRACT: Activation of melanocortin-4 receptor (MC4R) by insulin sensitive neurons is a central mechanism in body weight regulation, and genetic variants in the MC4R gene (e.g., rs17782313) are associated with obesity. By using magnetoencephalography, we addressed whether rs17782313 affects the cerebrocortical insulin response. We measured the cerebrocortical insulin response by using magnetoencephalography in a hyperinsulinemic euglycemic clamp (versus placebo) in 51 nondiabetic humans (26 f/25 m, age 35 ± 3 years, BMI 28 ± 1?kg/m(2)). The C-allele of rs17782313 was minor allele (frequency 23%), and the genotype distribution (TT 30, TC 19, CC 2) was in Hardy-Weinberg-Equilibrium. Insulin-stimulated cerebrocortical theta activity was decreased in the presence of the C-allele (TT 33 ± 16?fT; TC/CC -27 ± 20?fT; P = .023), and this effect remained significant after adjusting for BMI and peripheral insulin sensitivity (P = .047). Cerebrocortical theta activity was impaired in carriers of the obesity risk allele. Therefore, cerebral insulin resistance may contribute to the obesity effect of rs17782313.

SUBMITTER: Tschritter O

PROVIDER: S-EPMC3136179 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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An Obesity Risk SNP (rs17782313) near the MC4R Gene Is Associated with Cerebrocortical Insulin Resistance in Humans.

Tschritter Otto O Haupt Axel A Preissl Hubert H Ketterer Caroline C Hennige Anita M AM Sartorius Tina T Machicao Fausto F Fritsche Andreas A Häring Hans-Ulrich HU

Journal of obesity 20110603

Activation of melanocortin-4 receptor (MC4R) by insulin sensitive neurons is a central mechanism in body weight regulation, and genetic variants in the MC4R gene (e.g., rs17782313) are associated with obesity. By using magnetoencephalography, we addressed whether rs17782313 affects the cerebrocortical insulin response. We measured the cerebrocortical insulin response by using magnetoencephalography in a hyperinsulinemic euglycemic clamp (versus placebo) in 51 nondiabetic humans (26 f/25 m, age 3 ...[more]

PMID: 21773004

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Project description:BACKGROUND:The melanocortin-4 receptor (MC4R) regulates metabolism by modulating eating behavior and MC4R variants (rs17782313 and rs571312) are associated with obesity in Asians and Caucasians. However, the impact of their interactions with nutritional and lifestyle factors on obesity are poorly described. Therefore, we investigated the interaction of MC4R variants and dietary patterns on the risk of obesity in Korean middle-aged adults. METHODS:Data collected included, genetic variations, anthropometric and biochemical measurements, dietary and lifestyle habits, and food intake. Data were obtained from the 8830 adults aged 40-69 years in the Ansung and Ansan cohort of the Korean Genome Epidemiology Study. RESULTS:The MC4R rs18882313 minor allele had a higher frequency in the obese group (P?<?0.01). MC4R genotypes were not associated with differences in daily energy and macronutrient intakes. However, the intakes of processed foods and fat (as percentages of energy) were significantly higher and intake of fruits were significantly lower in subjects with MC4R minor alleles (P?<?0.05). Interestingly, there was a positive interaction between MC4R variants and mental stress levels that were associated with the risk of obesity after adjusting for age, gender, residence area, daily energy intake, smoking status and physical activity (interaction P?=?0.0384). Only in subjects with high stress were MC4R minor alleles associated with higher BMIs after adjusting for confounders. The association was present without modulating energy and nutrient intake. In the group with energy intakes higher than estimated energy requirement (EER), subjects with MC4R minor alleles had higher BMIs than those with the major alleles (P?<?0.001). CONCLUSIONS:The interactions of mental stress and energy intakes with the MC4R minor allele genotype might be associated with increased risk of obesity in Korean adults. This research might identify subjects with a specific MC4R minor alleles as a human subset of people with a low metabolic tolerance for excessive energy intake, especially when under stress.

Project description:BackgroundThe relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory.MethodsElectronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively.ResultsFifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m2, 95% confidence interval [95% CI] = 0.12 to 0.29 kg/m2, p < 0.001), waist circumference (SMD = 0.14 cm, 95% CI = 0.06 to 0.23 cm, p < 0.001) and blood glucose (SMD = 0.09 mg/dL, 95% CI = 0.02 to 0.16 mg/dL, p = 0.01) than the TT homozygotes. Regarding the rs8192678 polymorphism, no significant associations with the indexes of obesity, glucometabolic disorder and dyslipidemia were detected. However, significant correlations between the rs8192678 polymorphism and multiple glucometabolic indexes were observed in subgroup analyses stratified by sex, age, ethnicity and health status.ConclusionThe meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022373543.

Dataset Information

An Obesity Risk SNP (rs17782313) near the MC4R Gene Is Associated with Cerebrocortical Insulin Resistance in Humans.

Publications

An Obesity Risk SNP (rs17782313) near the MC4R Gene Is Associated with Cerebrocortical Insulin Resistance in Humans.

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