Endocrine Abstracts

The leptin-melanocortin signaling pathway plays a pivotal role in the regulation of body weight within the hypothalamus. Leptin, secreted by the adipose tissue, activates the leptin receptor at the arcuate nucleus, which in turn leads to the production of proopiomelanocortin (POMC) derived peptides as melanocyte stimulating hormone (MSH). MSH activates the melanocortin 4 receptor (MC4R), regulating thereby satiety and energy expenditure. Mutations within this pathway are leading to severe early onset obesity based on severe hyperphagia. After the discovery of MSH, different approaches have been made to generate MC4R agonists. Unfortunately, most of the studies were not successful either due to ineffectiveness of the drug to reduce body-weight or due to severe side-effects as e.g. increased blood pressure. However, recently the development of new MC4R agonists as setmelanotide (RM-493), which is leading to severe weight loss in POMC deficient patients, has open new perspectives for the treatment of monogenic obesity forms. Future studies will elucidate whether this new compounds will be of advantage and a new treatment option for obesity in these rare diseases.