Melanocortin‐4 receptor complexity in energy homeostasis, obesity and drug development strategies

The melanocortin‐4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signaling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease‐causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain‐of‐function variants seem to rescue obesity and related complications via specific pathways such as beta‐arrestin (ß‐arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia...