Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.

Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs not only interact with heterotrimeric G proteins but also can recruit β-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found the appetite-suppressing effect of setmelanotide, an MC4R agonist FDA approved for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs.