The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models

A little more than a decade ago, the molecular basis of the lipostat was largely unknown. At that time, many laboratories were at work attempting to clone the genes encoding the obesity, diabetes, fatty, tubby and agouti loci, with the hope that identification of these obesity genes would help shed light on the process of energy homeostasis, appetite and energy expenditure. Characterization of obesity and diabetes elucidated the nature of the adipostatic hormone leptin and its receptor, respectively, while cloning of the agouti gene eventually led to the identification and characterization of one of the key neural systems upon which leptin acts to regulate intake and expenditure. In this review, we describe the neural circuitry known as the central melanocortin system and discuss the current understanding of its role in feeding and other processes involved in energy homeostasis

Cardiac phenotype and tissue sodium content in adolescents with defects in the melanocortin system

CONTEXT: Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. OBJECTIVE: We aimed to characterize cardiac morphology and function as well as tissue Na(+) content in humans with mutations in POMC and MC4R genes. PARTICIPANTS: A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause and 12 normal-weight controls) underwent cardiac magnetic resonance (CMR) imaging and (23)Na-MRI. RESULTS: Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) compared to non-monogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in non-monogenic obese patients. Subcutaneous fat and skin Na(+) content was significantly higher in POMC- and MC4R-deficient patients compared to non-monogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control-groups. CONCLUSIONS: Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA and stored more Na(+) within the subcutaneous fat tissue compared to non-monogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function, tissue Na(+) storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients