MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R
Adelaide Bernard, … , Jeremy F. Reiter, Christian Vaisse
Adelaide Bernard, … , Jeremy F. Reiter, Christian Vaisse
Published January 24, 2023
Citation Information: JCI Insight. 2023;8(2):e155900. https://doi.org/10.1172/jci.insight.155900.
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Research Article Endocrinology Metabolism

MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R

Abstract

The G protein–coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor–associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.

Authors

Adelaide Bernard, Irene Ojeda Naharros, Xinyu Yue, Francois Mifsud, Abbey Blake, Florence Bourgain-Guglielmetti, Jordi Ciprin, Sumei Zhang, Erin McDaid, Kellan Kim, Maxence V. Nachury, Jeremy F. Reiter, Christian Vaisse

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Figure 1

MRAP2 functions in MC4R-expressing cells to regulate food intake and restrain body weight.

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MRAP2 functions in MC4R-expressing cells to regulate food intake and res...
(A and B) Body weight curve of Mc4rt2aCre/t2aCre Mrap2fl/fl versus Mc4rt2aCre/t2aCre Mrap2+/+ female (A) and male (B) littermates. (C–R) Respective body composition at 4 and 12 weeks of Mc4rt2aCre/t2aCre Mrap2fl/fl versus Mc4rt2aCre/t2aCre Mrap2+/+ females (body weight [C and D], lean mass [G and H], fat mass [K and L], percent fat mass [O and P]) and males (body weight [E and F], lean mass [I and J], fat mass [M and N], percent fat mass [Q and R]). (S–V) Twenty-four–hour food intake at 4 and 12 weeks of Mc4rt2aCre/t2aCre Mrap2fl/fl versus Mc4rt2aCre/t2aCre Mrap2+/+ females (S and T) and males (U and V). n = 11–24 mice per group were used, individual values are displayed, and exact number of mice per panel is detailed in the methods. Data are represented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 2-tailed Student’s unpaired t test (column analysis; C–V), mixed-effects model (REML), and Sidak’s multiple-comparison tests (weight curves; A and B). The exact number of mice displayed in each panel is as follows, with WT indicating Mc4rt2aCre/t2aCre Mrap2+/+ and mut indicating Mc4rt2aCre/t2aCre Mrap2fl/fl. Body weight: n = 19 WT females (F); 24 mut F; 20 WT males (M); 17mut M. EchoMRI at 4 weeks old: n = 13 WT F; 18 mut F; 17 WT M; 11 mut M. EchoMRI at 12 weeks old: n = 18 WT F; 20 mut F; 17 WT M; 14 mut M. Food intake at 4 weeks old: n = 13 WT F; 18 mut F; 17 WT M; 11 mut M. Food intake at 12 weeks old: n = 18 WT F; 20 mut F; 17 WT M; 14 mut M.