Influence of K656N Polymorphism of the Leptin Receptor Gene on Obesity-Related Traits in Nondiabetic Afro-Caribbean Individuals.

Background: Ethnic variations have been reported in allelic frequencies of the leptin receptor gene (LEPR) with population-specific effects. We aimed to explore the association of LEPR polymorphisms with obesity, metabolic syndrome (MetS), and leptin levels in Afro-Caribbean nondiabetic subjects. Methods: Genotypic analysis of three LEPR polymorphisms (K109R, Q223R, and K656N) was performed using TaqMan allelic discrimination assays. Associations were measured with phenotypic variables, including body mass index (BMI), waist circumference (WC), and leptin levels. Linear and logistic regressions were performed to evaluate the effects of single-nucleotide polymorphisms (SNPs). Results: Mean age was 46 ± 12 years. Among the 375 participants, 29.3% were obese, 36.3% had abdominal obesity, and 18.1% had MetS. Significant association between BMI (P < 0.002) and WC (P < 0.005) was observed for K656N, whereas the associations were not statistically significant for the other two SNPs. No association was found with leptin levels for the three SNPs. The variant allele frequencies for LEPR 109R, 223R, and 656N were 0.16, 0.46, and 0.20, respectively. In dominant models, the variant allele 656N (GC/CC vs. GG) was associated with prevalence of obesity [odds ratio (OR) 1.82; P = 0.012] and abdominal obesity (OR 2.00; P = 0.007), but not significantly with prevalence of MetS (OR 1.72; P = 0.029). Individuals carrying four variant alleles of the three SNPs had a significantly higher risk of obesity (OR 2.86; P = 0.032) than those carrying none variant allele. Conclusion: Our results suggest an influence of K656N polymorphism in the LEPR gene on obesity and abdominal obesity in this Afro-Caribbean population.

High Prevalence of Rare Monogenic Forms of Obesity in Obese Guadeloupean Afro-Caribbean Children.

Context: The population of Guadeloupe Island exhibits a high prevalence of obesity. Objective: We aimed to investigate whether rare genetic mutations in genes involved in monogenic obesity (or diabetes) might be causal in this population of Afro-Caribbean ancestry. Design and Setting: This was a secondary analysis of a study on obesity conducted in schoolchildren from Guadeloupe in 2013 that aimed to assess changes in children's profiles after a lifestyle intervention program. Through next-generation sequencing, we sequenced coding regions of 59 genes involved in monogenic obesity or diabetes in participants from this study. Participants and Interventions: A total of 25 obese schoolchildren from Guadeloupe were screened for rare mutations (nonsynonymous, splice-site, or insertion/deletion) in 59 genes. Main Outcome Measures: Correlation between phenotypes and mutations of interest. Results: We detected five rare heterozygous mutations in five different children with obesity: MC4R p.Ile301Thr and SIM1 p.Val326Thrfs*43 mutations that were pathogenic; SIM1 p.Ser343Pro and SH2B1 p.Pro90His mutations that were likely pathogenic; and NTRK2 p.Leu140Phe that was of uncertain significance. In parallel, we identified seven carriers of mutations in ABCC8 (p.Lys1521Asn and p.Ala625Val) or KCNJ11 (p.Val13Met and p.Val151Met) that were of uncertain significance. Conclusions: We were able to detect pathogenic or likely pathogenic mutations linked to severe obesity in >15% of this population, which is much higher than what we observed in Europeans (∼5%).

Homozygous null mutation of the melanocortin-4 receptor and severe early-onset obesity.

OBJECTIVE: To describe the clinical and biological phenotype of a child who is severely obese and is homozygous for a new melanocortin-4 receptor (MC4R) gene mutation leading to a truncated receptor. STUDY DESIGN: Direct sequencing of the MC4R gene was performed in a child who was severely obese and his relatives. Phenotypic characterization included weight evolution, anthropometric parameters, and endocrine and metabolic complications. Growth curves were compared with those of children carrying leptin receptor (LEPR) homozygous mutation, MC4R heterozygous mutations, and MC4R wild type allele. RESULTS: We found a homozygous 2-base pair deletion (del 346-347AG) leading to a stop codon. This new mutation leads to a truncated MC4R after the second transmembrane domain in a 3-year-old boy with severe early-onset obesity. Segregation analysis of the mutation showed that the 2 parents and 2 adult relatives were heterozygous carriers for the mutation. Heterozygous carriers displayed an obese phenotype, but with a variable degree of severity. The homozygous carrier of the mutation was hyperphagic and showed a rapid increase in weight in the very first months of life. His weight evolution closely resembled that of patients who are LEPR deficient, but markedly differed with that of children carrying either heterozygous MC4R mutations or MC4R wild type allele. No other hormonal or metabolic anomaly was found in the child. CONCLUSIONS: This phenotype of a boy carrying a new homozygous MC4R mutation confirms the critical role of MC4R in the early dynamic of weight gain and phenotypic differences with heterozygous carriers.

Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats.

Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD (n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.