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Eating Behaviour in Obese Patients with Melanocortin-4 Receptor Mutations: a Literature Review

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Eating Behaviour in Obese Patients with Melanocortin-4 Receptor Mutations: a Literature Review International Journal of Obesity (2013) 37, 1027–1035 & 2013 Macmillan Publishers Limited All rights reserved 0307-0565/13 www.nature.com/ijo REVIEW Eating behaviour in obese patients with melanocortin-4 receptor mutations: a literature review M Valette1, F Bellisle1, C Carette2,3, C Poitou4,5, B Dubern5,6, G Paradis7,8, S Hercberg1,9, L Muzard2, K Cle´ ment4,5 and S Czernichow2,10 Melanocortin-4 receptor (MC4R) mutations are the most common known cause of monogenic obesity and an important contributor to polygenic obesity. MC4R mutations with partial or total loss of function, as well as the variant rs17782313 mapped near MC4R, are positively associated with obesity. MC4R is involved in the leptin–melanocortin signalling system, located in hypothalamic nuclei, that controls food intake via both anorexigenic or orexigenic signals. Impairment in this receptor might affect eating behaviours. Thus, in the case of MC4R mutation carriers, obesity could be related, at least partly, to inadequate control over eating behaviours. Many published studies address eating behaviours in MC4R mutation carriers. Most studies focus on binge eating disorder, whereas others examine various aspects of intake and motivation. Up to now, no evaluation of this literature has been performed. In this review, we examine the available literature on eating behaviours in carriers of MC4R mutations and variant rs17782313 near MC4R gene. We address binge eating disorder, bulimia nervosa, mealtime hyperphagia, snacking, psychological factors, satiety responsiveness and intake of energy and macro/micronutrient. In a small number of studies, MC4R mutations seem to impair eating behaviours or motivation, but no clear causal effects can be found in the balance of the evidence presented. Improvements in methodologies will be necessary to clarify the behavioural effects of MC4R mutations. International Journal of Obesity (2013) 37, 1027–1035; doi:10.1038/ijo.2012.169; published online 13 November 2012 Keywords: melanocortin-4 receptor; variant rs17782313; MC4R mutations; eating behaviours; eating disorders INTRODUCTION participating in MC4R expression and translation regulation. It is Obesity is a rapidly growing global public health challenge with associated with an increased body mass index (BMI) and has 400 million obese adults in 2005 worldwide and 700 million recently been shown to induce childhood-onset obesity.18 forecasted for 2015.1 Obesity is a complex disorder caused most MC4R is expressed in the brain in the regions of the thalamus, often by the interaction of environmental and genetic factors. hypothalamus, hippocampus and probably in human epidermal However, rare cases of monogenic obesity due to single gene melanocytes.19,20 MC4R mRNA is also present in the dentate gyros, mutations have been described. cortex and amygdala.21 It is largely expressed in several brain sites Melanocortin-4 receptor (MC4R) deficiency is the most common involved in autonomic and endocrine functions. MC4R expressed known cause of monogenic obesity and an important contributor on the surface of target neurons of the paraventricular nucleus has to polygenic obesity.2 About 150 naturally occurring MC4R gene a role in the mechanisms of appetite.22 It affects the leptin– mutations have been identified among patient cohorts,3 in which melanocortin signalling system, an important neuronal circuitry different gene function impairments occur, such as null mutation, involved in the regulation of sympathetic neural function.23 The intracellular-retained mutants, binding-defective mutants and leptin–melanocortin signalling system is activated by leptin signalling-defective mutants. In some cases, an apparently produced in the adipose tissue, which crosses the blood–brain normal function is kept in spite of a mutation.4 The prevalence barrier, binds to its receptors in two subsets of first-order neurons of MC4R mutations with impaired function ranges from 0.5 to and stimulates proopiomelanocortin expression. In the arcuate 5.8%5–9 in childhood-onset obesity and is around 2.3% in obese nucleus, proopiomelanocortin is cleaved to produce alpha- adults.7 melanocyte-stimulating hormone.24 The binding of these In contrast, two single-nucleotide polymorphisms (SNPs) of the peptides to MC4R inhibits food intake. The binding of leptin also MC4R gene, Ile251Leu and Val103Ile, are negatively correlated inhibits the expression of agouti-related peptide, an orexigenic with obesity.10–13 These SNPs occur with a frequency of 0.8–6%, protein that acts as an antagonist for MC4R.25 MC4R activates both both in obese and normal weight subjects from different satiety and hunger signals by integrating an anorexigenic (satiety) ethnic backgrounds.14–17 Moreover, a variant mapped 188 kb signal provided by the alpha-melanocyte-stimulating hormone downstream MC4R gene (rs17782313) may affect gene function by and an orexigenic signal provided by the agouti-related peptide.26 1Nutritional Epidemiology Research Unit-UMR U557 INSERM, U1125 INRA, CNAM, Paris 13 University, CRNH-IdF, Bobigny, France; 2Department of Nutrition, Ambroise Pare´ Hospital (AP-HP), Boulogne-Billancourt, France; 3INSERM U1016, CNRS UMR 8104, University of Paris-Descartes, Cochin Institute, Paris, France; 4Department of Nutrition, Pitie´ Salpetrie`re Hospital (AP-HP), Paris, France; 5Institut National de la Sante´ et de la Recherche Me´dicale, U872 team7, Nutriomique, Cordelier Research Center, Paris, France; 6Department of Gastroenterology and Pediatric Nutrition, Armand-Trousseau Hospital, Paris, France; 7Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; 8McGill University Health Center Research Institute, Montreal, Quebec, Canada; 9Department of Public Health, Avicenne Hospital (AP-HP), Bobigny, France and 10University of Versailles Saint Quentin en Yvelines, Boulogne-Billancourt, France. Correspondence: Professor S Czernichow, Unite´ de Nutrition – Hoˆ pital Ambroise Pare´, 9 avenue Charles de Gaulles, 92100 Boulogne-Billancourt, France. E-mail: [email protected] Received 2 April 2012; revised 7 September 2012; accepted 9 September 2012; published online 13 November 2012 Eating behaviour and MC4R mutations M Valette et al 1028 By affecting the leptin–melanocortin signalling system, functional Snacking OR Satiety OR Energy Intake OR Nutrient Intake. This generated MC4R mutations, variants near MC4R gene, and SNPs may have a 222 articles, which were then limited to human works published in English. key role in central appetite control and affect eating behaviours.27 Reference lists of full-length articles were hand searched to identify Among the other four known melanocortin receptors, significant additional studies relevant for inclusion. Sixteen observational studies on linkages with adiposity-related variables were found for MC5R28 MC4R mutation carriers’ eating behaviour were identified and reviewed. The studies were classified according to the type of behaviour studied. and a potential association with obesity has been suggested for MC3R, but data are available only in rats.25,29 Eating behaviours can be considered in numerous qualitative EATING DISORDERS: BN AND BED and quantitative aspects. They fulfil nutritional as well as hedonic Two reference manuals, the International Classification Disease and social functions. Energy intake and amounts of food ingested (ICD-10)35 and the DSM-IV-Text Revised33 define several eating are under the control of the physiological mechanisms of disorders, such as anorexia nervosa, BN, BED and eating disorders hunger, appetite and satiety, whereas food likes and dislikes orient not otherwise specified. Two of them, BN and BED, were reported food choices.30 Altered brain mechanisms of appetite control might in studies of MC4R mutations and variant rs17782313 effects. induce eating disorders and/or nutrition-related pathologies.31 In the case of MC4R mutation carriers, obesity could be related, at least partly, to inadequate control over eating behaviours.32 In the Bulimia nervosa (BN) published literature about MC4R mutations, eating disorders Hebebrand et al. hypothesized that genetic factors predisposing classified in the Diagnostic and Statistical Manual of Mental to obesity, such as MC4R mutations, might be commonly detected Disorders – Fourth edition (DSM-IV)33 as well as many other in patient with BN. However, in a population of 81 patients with aspects of eating behaviours have been examined. Up to now, no clinically assessed BN, only 1 extremely obese woman, with a systematic evaluation of the literature has been performed. current BMI of 48 kg m À 2, aged 32 years, had a functionally In this review, we address eating behaviours and eating-related relevant mutation in the MC4R gene.36 Stutzmann et al.37 cited the psychological aspects observed in subjects with MC4R mutations DESIR (Data from an Epidemiological Study on the Insulin and variant rs17782313. First, we examine the reports of eating Resistance Syndrome) study38 of French adults in whom the disorders, including the binge eating disorder (BED) and bulimia variant rs17782313, near MC4R, was not associated with self- nervosa (BN). According to the DSM-IV-Text Revised, BED is defined reported ‘bulimia’. No validated method was used in this study to as episodes of rapid consumption of an unusually large amount of confirm the presence of clinical BN. The studied population had food in the absence of hunger, without purging behaviour, 4877 obese and non-obese subjects, with
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