Melanocortin 4 receptor mutation in obesity

Abstract

Obesity is increasingly prevalent worldwide, with genetic factors contributing to its development. The hypothalamic leptin-melanocortin pathway is central to the regulation of appetite and weight; leptin activates the proopiomelanocortin neurons, leading to the production of melanocortin peptides; these in turn act on melanocortin 4 receptors (MC4R) which suppress appetite and increase energy expenditure. MC4R mutations are responsible for syndromic and non-syndromic obesity. These mutations are classified based on their impact on the receptor's life cycle: i.e. null mutations, intracellular retention, binding defects, signaling defects, and variants of unknown function. Clinical manifestations of MC4R mutations include early-onset obesity, hyperphagia, and metabolic abnormalities such as hyperinsulinemia and dyslipidemia. Management strategies for obesity due to MC4R mutations have evolved with the development of targeted therapies such as Setmelanotide, an MC4R agonist which can reduce weight and manage symptoms without adverse cardiovascular effects. Future research directions must include expansion of population studies to better understand the epidemiology of MC4R mutations, exploration of the molecular mechanisms underlying MC4R signaling, and development of new therapeutic agents. Understanding the interaction between MC4R and other genetic and environmental factors will be key to advancing both the prevention and treatment of obesity.

Keywords: Leptin-melanocortin pathway; Downstream; G protein; Cyclic AMP; Mutation; Obesity syndromes; Screening; Setmelanotide

Core Tip: The leptin-melanocortin pathway regulates energy balance and body weight. Melanocortin-4 receptor (MC4R) plays a key role in this pathway by reducing hunger, inducing satiety and increasing energy expenditure. Mutations of MC4R result in obesity and hyperphagia in childhood. Setmelanotide is an MC4R agonist approved for use in obesity caused by leptin-melanocortin pathway dysfunction.