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Updated: Apr 23, 2026
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Mice lacking β-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits
Misbah Rashid1, Lei Wang1, Zhenzhong Cui2
1Molecular Signaling Section, Laboratory of Bioorganic Chemistry.
Abstract:
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.
Insights
Beta-arrestin-2 (barr2) mediates the appetite-suppressing effects of hypothalamic melanocortin 4 receptors (MC4Rs). This finding is crucial for developing new obesity drugs targeting MC4R signaling pathways.
Area of Science:
- Neuroscience
- Endocrinology
- Molecular Biology
Background:
- Hypothalamic melanocortin 4 receptors (MC4Rs) are key regulators of energy homeostasis.
- MC4R dysfunction is linked to monogenic obesity, highlighting the need to understand MC4R signaling.
- MC4Rs interact with G proteins and beta-arrestin-2 (barr2), but barr2's role in MC4R signaling is unclear.
Purpose of the Study:
- To investigate the functional role of beta-arrestin-2 (barr2) in MC4R-mediated regulation of food intake.
- To determine if barr2 is required for the anorectic effects of MC4R agonists like setmelanotide.
Main Methods:
- Utilized mutant mouse models to study MC4R signaling pathways.
- Examined MC4R-mediated activation of barr2/ERK signaling in hypothalamic neurons.
- Assessed the effect of setmelanotide in the presence or absence of barr2.
Main Results:
- MC4R-mediated activation of barr2/ERK signaling in paraventricular nucleus neurons reduces food intake.
- The appetite-suppressing effect of setmelanotide depends on the presence of barr2 in MC4R-expressing neurons.
Conclusions:
- Beta-arrestin-2 (barr2) plays a critical role in mediating the anorectic effects of MC4R signaling.
- MC4R agonists that enhance MC4R/barr2 interactions show potential as novel appetite-suppressing therapeutics for obesity.
