Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations

Abstract

Recently, Branson and coworkers reported a strong association between binge-eating disorder (BED) and variants in the melanocortin-4 receptor gene (MC4R). In the current study, we compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations and of 35 polymorphism carriers (V103I or I251L) with wild-type carriers. The module for eating disorders of the Composite International Diagnostic Interview was used to identify binge-eating behavior. The Three-Factor Eating Questionnaire and the Leeds Food Frequency Questionnaire were used to assess restrained eating, disinhibition, hunger and percent total energy intake as fat. No significant differences between carriers of MC4R variants and wildtype carriers were detected. In particular, we found no evidence for an increased rate of bingeeating behavior in obese carriers of MC4R variants. Our findings do not support the strong association between BED and MC4R carrier status. Keywords: fat intake; obesity; bulimia nervosa; eating disorders; MC4RThe melanocortinergic system is involved in energy homeostasis and body weight regulation.1-3 The melanocortin-4 receptor gene (MC4R) is expressed in the hypothalamus; both a-and b-melanocyte-stimulating hormone (MSH) can act as agonists and induce satiety and an elevated energy expenditure; 4 agoutirelated peptide (AGRP) also binds to this receptor as an antagonist/inverse agonist and stimulates feeding. 5,6 The importance of the MC4R for body weight regulation was demonstrated in vivo by the occurrence of hyperphagia and obesity in MC4R knockout mice, which additionally show an increased length and hyperinsulinemia.7-9 Heterozygous mice have a body weight intermediate between Mc4rÀ/À and wildtype mice. 7,9 In the first human studies, MC4R mutations were detected in extremely obese individuals only. [10][11][12] Since then, frameshift, nonsense and missense mutations have been identified in several obese study groups of different ethnicity.3 All of these mutations occur infrequently; among extremely obese individuals heterozygosity rates are below 1% for any single mutation, several of which have been observed only once worldwide.3 Functional studies have shown that most of these mutations, over 30 of which have been reported, lead either to total or partial loss of function. [13][14][15][16]3 Between 2 and 4% of extremely obese individuals harbor such mutations. 3 The two missense variants V103I and I251L, which occur in approximately 3 and 1% of the probands investigated as of today, do not predispose to obesity; similar allele frequencies have been detected in both cases and controls. 17 Pedigree analyses revealed that mutations proven to be functionally relevant in vitro underlie co-dominantly inherited obesity. [16][17][18] Similar to the findings in Mc4r À/À mice, the degree of adiposity in homozygotes and compound heterozygotes exceeds that of heterozygous carriers. 19,17,3 Within families ascertained via an obese MC4R mutation carrier, heterozygotes have infrequently been shown to be nonobese ...

Appetite-related gut peptides, ghrelin, PYY, and GLP-1 in obese women with and without binge eating disorder (BED)

“…As is the case for obesity, BED is more prevalent in women than in men (3:2) [3]. There is evidence of a biological basis for BED, including a moderate heritability of 0.50 [4], possible, although controversial, association with melanocortin-4 receptor (MCR4) mutation [5,6,7], an enlarged stomach capacity [8,9], and more brain activation in response to binge-type food stimuli [10].…”

Prevalence of Melanocortin-4 Receptor Deficiency in Europeans and Their Age-Dependent Penetrance in Multigenerational Pedigrees

“…The contribution of MC4R mutations to late-onset obesity is still debated (13,(15)(16)(17)(18). Obesity due to MC4R mutations has been extensively studied, and although heterozygous loss-of-function mutations can clearly cause familial obesity, they can be found in individuals who are not obese (19).…”

Monogene Adipositas

“…Allerdings bessern sich (bei heterozygoten Trägern) diese Verhaltensmuster im späteren Leben [24]. Bei einigen Patienten ist auch eine Binge-Eating-Störung beschrieben worden¸diese Daten konnten jedoch von nachfolgenden Studien nicht bestätigt werden [33,49]. Einige Mutationen scheinen außerdem das Risiko für Depressionen [52], bipolare Stö-rungen [52] oder ADHS [2] zu erhöhen.…”