Mice lacking β-arrestin-2 in melanocortin 4 receptor–expressing neurons show marked metabolic deficits
Misbah Rashid, Lei Wang, Zhenzhong Cui, Oksana Gavrilova, Huiyan Lu, Kozo Kaibuchi, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit, Jürgen Wess
Misbah Rashid, Lei Wang, Zhenzhong Cui, Oksana Gavrilova, Huiyan Lu, Kozo Kaibuchi, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit, Jürgen Wess
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Research Article Endocrinology Metabolism

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

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.

Authors

Misbah Rashid, Lei Wang, Zhenzhong Cui, Oksana Gavrilova, Huiyan Lu, Kozo Kaibuchi, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit, Jürgen Wess

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Figure 5

Metabolic phenotypes of MC4R-Mek1dn mice maintained on an HFD.

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Metabolic phenotypes of MC4R-Mek1dn mice maintained on an HFD. All exper...
All experiments were carried out with male MC4R-Mek1dn mice. These mice express a dominant-negative mutant of MEK1 in MC4R neurons of the PVN. MC4R-Cre mice expressing mCherry in MC4R neurons of the PVN served as control animals (see Figure 4A for details). (A) Body weight gain of mice switched from regular chow (RC) to an HFD (n = 7 or 8). (B) Daily food intake per day of single-housed mice monitored over a 3-week period (mouse age 14–17 weeks) (n = 8). (C) Glucose tolerance test (GTT). After an overnight fast, mice received an i.p. glucose bolus (1 g/kg; mouse age 19–20 weeks) (n = 8). (D) Insulin tolerance test (ITT). After a 4-hour fast, mice were injected i.p. with insulin (1 U/kg) (mouse age 18–19 weeks; n = 7 or 8). (E and F) Blood glucose (E) and plasma insulin levels (F) under fed and fasted conditions (control, n = 8; MC4R-Mek1dn, n = 6) (mouse age 20–21 weeks). (G) MTII-induced inhibition of food intake. After a 24-hour fast, single-housed mice were injected i.p. with either saline or MTII (200 μg) 30 minutes before lights out (6 pm). Food intake was recorded during the first 3.5 hours of the dark phase (mouse age 17–18 weeks, n = 8). Data are presented as mean ± SEM. Statistical significance was assessed using *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (2-way ANOVA followed by Šidák’s multiple-comparison test in A and C–G or unpaired 2-tailed Student’s t test B and bars in C and D. dn, dominant negative; AOC, area of the curve.