Dietary quality indices modifies the effects of melanocortin-4 receptor (MC4R) rs17782313 polymorphism on cardio-metabolic risk factors and hypothalamic hormones in obese adults.
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ABSTRACT:
SUBMITTER: Khodarahmi M
PROVIDER: S-EPMC7001213 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
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Dietary quality indices modifies the effects of melanocortin-4 receptor (MC4R) rs17782313 polymorphism on cardio-metabolic risk factors and hypothalamic hormones in obese adults.
Khodarahmi Mahdieh M Kahroba Houman H Jafarabadi Mohammad Asghari MA Mesgari-Abbasi Mehran M Farhangi Mahdieh Abbasalizad MA
BMC cardiovascular disorders 20200204 1
<h4>Background</h4>Although the Melanocortin-4 Receptor (MC4R) gene rs17782313 C/T has been consistently related to obesity risk, the interaction between MC4R polymorphism and diet quality indices on cardio-metabolic risk factors has not yet investigated. Therefore we aimed to test this hypothesis.<h4>Methods</h4>This cross-sectional study recruited 188 (96 males and 92 females) healthy obese adults aged 20-50 years. Diet quality indices including Healthy Eating Index-2015 (HEI-2015) and Diet Qu ...[more]
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Project description:Background and aimThe association with obesity of a common variant near the melanocortin-4 receptor (MC4R) gene (rs17782313) has been indicated in various studies. Adherence to dietary quality indices also have shown to have potential favorable effects on obesity-related health outcomes. However, no study has examined the interaction between rs17782313 and the Dietary Approach to Stop Hypertension (DASH) score and the Mediterranean Dietary Score (MDS) on cardio-metabolic risk factors and hypothalamic hormones. Therefore, the purpose of the current study was to examine whether adherence to these dietary quality indices modifies the association of the MC4R rs17782313 polymorphism with cardio-metabolic risk factors and hypothalamic hormones among obese adults.MethodTwo hundred eighty-eight healthy obese adults were recruited in this cross-sectional study. Diet quality indices, including DASH score and MDS, were calculated from a validated 147-item food frequency questionnaire (FFQ). MC4R s17782313 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). An ANCOVA multivariate interaction model was used to assess the gene-diet interaction.ResultsSignificant interactions were detected between DASH score and MC4R rs17782313 genotypes on systolic blood pressure (SBP), atherogenic index of plasma (AIP), and serum glucose and triglyceride (TG) among the female group (pInteraction < 0.05). In the male group, there were gene-DASH and gene-MDS interactions in relation to serum glucose concentration and plasma α-melanocyte stimulating hormone (MSH) levels, but these were found only in multi-adjusted interaction models (pInteraction < 0.05). In addition, there was a significant interaction between MC4R rs17782313 polymorphism and DASH score on plasma agouti-related peptide (AgRP) concentrations in the female group in a multivariate interaction model (pInteraction < 0.05). An inverse association between DASH score and chance of having the CC genotype in a multivariate-adjusted model among women was also revealed.ConclusionMC4R rs17782313 interacts with healthy dietary pattern (DASH score and MDS) to influence cardio-metabolic risk factors and hypothalamic hormones in obese individuals. Prospective cohort studies are needed to further assess these findings.
| S-EPMC7403790 | biostudies-literature
Project description:Melanocortins have a crucial role in appetite and weight regulation. Although the melanocortin 4 receptor (MC4R) gene has been repeatedly linked to obesity and antipsychotic-induced weight gain, the mechanism behind how it leads to this effect in still undetermined. The goal of this study was to conduct an in-depth and sophisticated analysis of MC4R polymorphisms, body mass index (BMI), eating behavior and depressed mood.We genotyped 328 individuals of European ancestry on the following MC4R markers based on the relevant literature on obesity and antipsychotic-induced weight gain: rs571312, rs17782313, rs489693, rs11872992, and rs8087522. Height and weight were measured, and information on depressed mood and overeating behaviors was obtained during the in-person assessment.BMI was associated with rs17782313 C allele; however, this finding did not survive correction for multiple testing (P = 0.018). Although rs17782313 was significantly associated with depressed mood and overeating behaviors, tests of indirect effects indicated that emotional eating and food cravings, rather than depressed mood, uniquely accounted for the effect of this marker and BMI (n = 152).To our knowledge, this is the first study to investigate the link between MC4R rs17782313, mood and overeating behavior, as well as to demonstrate possible mechanisms behind MC4R's influence on body weight. If replicated in a larger sample, these results may have important clinical implications, including potential for the use of MC4R agonists in the treatment of obesity and disordered eating.
| S-EPMC4232480 | biostudies-literature
Project description:MC4R represents a key player involved in melanocortin-mediated control of energy balance. Recently identified near MC4R variant rs17782313 (T > C) can serve as a contributing factor for obese phenotype but its association with obesity has never been sought in a sample of the Pakistani population. The role of genetic variants as causal factors varies across populations. Association studies in a specific population can help us to distinguish global from local gene-gene and gene-environment interactions. This is the first study that investigated the association of rs17782313 with obesity and various obesity-linked anthropometric, metabolic, physical, and behavioural traits in Pakistani subjects including 306 OW/OB (overweight and obese) and 300 NW (normal weight) individuals. The comparison of various aforementioned obesity-linked continuous and categorical variables between OW/OB and NW subjects revealed that almost all variables were found significantly aberrant (p < 0.05) in OW/OB subjects as compared to their age- and gender-matched NW controls indicating greater risk of developing various cardio-metabolic disorders. The genotyping of rs17782313 showed significant association of this variant with obesity and obesity-linked anthropometric traits in females suggesting the gender-specific effect of this variant in our population. The minor allele C increased the risk of obesity by 1.55 times (95% CI = 1.1-2.18, p = 0.01) whereas homozygous CC genotype increased the risk by 2.43 times (95% CI = 1.19-4.96, p = 0.015) in females. However, no association of rs17782313 was observed with any of the obesity-linked metabolic, physical, and behavioural traits except random eating timings. In conclusion, the current study significantly contributes to the knowledge of the genetic proneness to obesity in Pakistani females. This could also be helpful for forthcoming meta-analysis studies elucidating which variants are truly associated with the susceptibility to develop an obese phenotype.
| S-EPMC9080305 | biostudies-literature
Project description:BACKGROUND: At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (MC4R) in the development of cancer cachexia. In humans, MC4R mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele. METHODS: BMI (body mass index in kg/m2) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (+/- SD) was 59.0 +/- 14.5 (males: 58.8 +/- 14.0, females 59.2 +/- 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP. RESULTS: Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39). CONCLUSION: Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele; possibly, Ile103 carriers might be more resistant to cancer cachexia in patients with solid tumors. Further studies of the melanocortinergic system in cachexia of patients with solid tumors are warranted.
| S-EPMC2359760 | biostudies-literature
Project description:The dog is considered to be a useful biomedical model for human diseases and disorders, including obesity. One of the numerous genes associated with human polygenic obesity is MC4R, encoding the melanocortin 4 receptor. The aim of our study was to analyze polymorphisms and methylation of the canine MC4R in relation to adiposity. Altogether 270 dogs representing four breeds predisposed to obesity: Labrador Retriever (n = 187), Golden Retriever (n = 38), Beagle (n = 28) and Cocker Spaniel (n = 17), were studied. The dogs were classified into three groups: lean, overweight and obese, according to the 5-point Body Condition Score (BCS) scale. In the cohort of Labradors a complete phenotypic data (age, sex, neutering status, body weight and BCS) were collected for 127 dogs. The entire coding sequence as well as 5' and 3'-flanking regions of the studied gene were sequenced and six polymorphic sites were reported. Genotype frequencies differed considerably between breeds and Labrador Retrievers appeared to be the less polymorphic. Moreover, distribution of some polymorphic variants differed significantly (P < 0.05) between small cohorts with diverse BCS in Golden Retrievers (c.777T>C, c.868C>T and c.*33C>G) and Beagles (c.-435T>C and c.637G>T). On the contrary, in Labradors no association between the studied polymorphisms and BCS or body weight was observed. Methylation analysis, using bisulfite DNA conversion followed by Sanger sequencing, was carried out for 12 dogs with BCS = 3 and 12 dogs with BCS = 5. Two intragenic CpG islands, containing 19 cytosines, were analyzed and the methylation profile did not differ significantly between lean and obese animals. We conclude that an association of the MC4R gene polymorphism with dog obesity or body weight is unlikely, in spite of the fact that some associations were found in small cohorts of Beagles and Golden Retrievers. Also methylation level of this gene is not related with dog adiposity.
| S-EPMC5579139 | biostudies-literature
Project description:Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date.In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting.Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 ± 2.9 kg/m(2) (mean ± SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods.RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs 0.848 ± 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed.Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.
| S-EPMC4399297 | biostudies-literature
Project description:BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine disorder causing infertility in reproductive-age women. The cause of PCOS is not fully understood but it is thought to be influenced by environmental and genetic factors. Obesity is greatly related to PCOS and its reduction is one of the major aims in treating PCOS. Melanocortin 4 receptor (MC4R) gene polymorphisms were detected to be associated with different levels of obesity. Therefore, we aimed to determine the genotype and allele frequency of MC4R variants rs12970134 (A/G) and rs17782313 (C/T) in PCOS and investigate their association with PCOS and its clinical variables.MethodsA case-control study was conducted on 189 women, consisting of 95 PCOS cases and 94 controls. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan™ Genotyping assays. Quantitative data were presented as (median ± interquartile range (IQR) whereas qualitative data were presented as frequencies. The chi-squared test was used to observe the difference between SNPs within the study groups (PCOS and control subjects). Multinomial logistic regression was used to test the risk of obesity and development of PCOS considering p < 0.05 is statistically significant.ResultsRs12970134 and rs17782313 are significantly associated with body mass index (BMI, kg/m2, p < 0.0001) in PCOS women but not associated with PCOS itself. Risk alleles in our population are A in rs12970134 and C in rs17782313 that are associated with high BMI (> 30 kg/m2) in obese women with PCOS (OR = 1.348, p = 0.002 and OR = 1.364, p = 0.002 respectively) in the homozygous state. In addition, we found that the other genotypes for non-obese PCOS group, AG/GG for rs12970134 and CT/TT for rs17782313, are associated with hirsutism, loss of hair, hyperandrogenism and anti-Müllerian hormone in PCOS.ConclusionsThese findings demonstrate that MC4R single nucleotide polymorphisms, rs12970134 and rs17782313, are correlated with elevated BMI in PCOS but are not causative factors for PCOS among women in the western region of Saudi Arabia. Moreover, the reverse genotypes are associated with major clinical variants in non-obese (< 30 kg/m2) PCOS patients may demonstrate a poor prognosis for this group.
| S-EPMC6701028 | biostudies-literature
Project description:OBJECTIVE:Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. METHODS:We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants. RESULTS:In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls. CONCLUSIONS:Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.
| S-EPMC5641599 | biostudies-literature
Project description:BACKGROUND:Epidemiologic studies show that cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) gene polymorphism modifies diet-obesity relationships. However, the interaction between CARTPT gene polymorphism and diet quality indices have not been investigated yet. The current study was aimed to evaluate the interaction between major dietary indices including Diet Quality Index-International (DQI-I) and Healthy Eating Index (HEI)-2015 and CARTPT gene rs2239670 variants among apparently healthy obese Iranians. METHODS:This cross-sectional study was carried out by employing 288 apparently healthy obese adults aged 20-50 years with a BMI of 30-40 kg/m2. Diet quality was evaluated by Diet Quality Index-International (DQI-I) and Healthy Eating Index-2015 (HEI-2015) using a 132-items semi-quantitative validated food frequency questionnaire. The CARTPT gene rs2239670 polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Blood concentrations of glycemic markers, lipid profile, ?-melanocyte stimulating hormone (MSH) and agouti-related peptide (AgRP) were also measured. ANCOVA multivariate interaction model was used to analyze gene-diet interactions. RESULTS:The significant interactions were identified between CARTPT gene polymorphism and HEI, affecting BMR (PInteraction?=?0.003), serum glucose (PInteraction?=?0.009) and high density lipoprotein cholesterol HDL concentrations (PInteraction?=?0.03) after adjusting for the effects of sex and age. Also we found gene-diet interaction between CARTPT genotypes and DQI-I in terms of fat mass (FM; PInteraction?=?0.02), waist circumference (WC; PInteraction?<?0.001), body mass index (BMI; PInteraction?<?0.001), basal metabolic rate (BMR, PInteraction?<?0.001), serum fasting glucose (PInteraction?<?0.01) and AgRP (PInteraction?=?0.05) in individuals even after adjusting for potential confounders. CONCLUSION:Current study showed the effects of interaction between CARTPT genotype with adherence to HEI and DQI-I scores on obesity-related anthropometric and metabolic risk-factors.
| S-EPMC6953221 | biostudies-literature
Project description:Background Previous studies have shown that the minor allele (C allele) for melanocortin 4 receptor (MC4R) rs17782313 may be associated with depressed mood. Moreover, dietary patterns have potentially adverse effects on depression. This study investigates the interactions between the MC4R gene variant (rs17782313) and dietary patterns on depression among Iranian obese and overweight women. Methods A total of 289 Iranian overweight and obese women, aged 18–50 years, were enrolled in this cross-sectional study. Biochemical, anthropometric, and body composition indices were assessed in all participants. Moreover, MC4R rs17782313, by the restriction fragment length polymorphism (PCR-RFLP) method, and depression, using the 21-item Depression Anxiety Stress Scales (DASS) questionnaire, were assessed. Food intakes were assessed by completing a 147-item semi-quantitative food frequency questionnaire (FFQ). Results By the use of factor analysis, 2 major dietary patterns were extracted: healthy dietary pattern (HDP) and unhealthy dietary pattern (UDP). Binary logistic analysis showed that individuals with minor allele risk (CC) with high adherence to the unhealthy pattern increased odds for depression (OR: 8.77, 95%CI: -0.86-18.40, P: 0.07), after controlling for confounders. Also, a logical inverse relationship was observed between CT genotype and HDP on depression in the crude and adjusted models (OR: -0.56, 95% CI: -3.69-2.57, P: 0.72) (OR: -4.17, 95% CI: -9.28-0.94, P: 0.11), although this interaction was not statistically significant. Conclusion According to the above findings, adherence to unhealthy food intake pattern increases odds of depression in MC4R risk allele (C allele) carriers. To confirm these findings, more studies are needed in the form of clinical trials and prospective studies with higher sample sizes.
| S-EPMC10111691 | biostudies-literature