Melanocortin 4 Receptor-Mediated Metabolic Effects Require Beta-Arrestin-2 Signaling

Authors

• M Rashid
• L Wang
• O Gavrilova
• Z Cui
• J Wess

Abstract

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that plays a key role in suppressing appetite and stimulating energy expenditure by modulating hypothalamic signaling circuits. Little is known about how neuronal MC4R signaling is regulated at the molecular level. Previous studies have shown that MC4R activation leads to the activation of heterotrimeric G proteins (Gs/Gq) as well as the recruitment of beta-arrestin-2 (barr2). Traditionally, barr2 is known for its role in terminating GPCR signaling via binding to activated receptors. However, more recent studies suggest that barr2, following its recruitment by activated GPCRs, can act as a signaling protein in its own right. To explore the potential role of barr2 in regulating the activity of central MC4Rs, we generated and analyzed mice that lacked barr2 specifically in MC4R-expressing neurons (MC4R-barr2-KO mice). Compared to control littermates, the MC4R-barr2-KO mice showed enhanced food intake, increased adiposity, glucose intolerance, and insulin resistance. To more directly investigate the role of barr2 in MC4R-mediated signaling, we injected MC4R-barr2-KO mice and control mice with melanotan II (MTII), a potent MC4R agonist. While MTII reduced food intake in control mice, these effects were greatly reduced in MC4R-barr2-KO mice. Interestingly, selective re-expression of barr2 in the paraventricular nucleus of MC4R-barr2-KO mice restored control-like MTII effects. These data highlight the key role of barr2 in mediating the beneficial metabolic effects of MC4R signaling. MC4R agonists capable of recruiting barr2 with high efficacy may prove therapeutically useful as novel anti-obesity drugs.

Scientific Focus Area: Molecular Pharmacology

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