Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity
Patricia René, … , Denis Richard, Michel Bouvier
Patricia René, … , Denis Richard, Michel Bouvier
Published January 12, 2021
Citation Information: JCI Insight. 2021;6(4):e132778. https://doi.org/10.1172/jci.insight.132778.
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Resource and Technical Advance Metabolism Therapeutics

Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity

Abstract

MC4R mutations represent the largest monogenic cause of obesity, resulting mainly from receptor misfolding and intracellular retention by the cellular quality control system. The present study aimed at determining whether pharmacological chaperones (PCs) that restore folding and plasma membrane trafficking by stabilizing near native protein conformation may represent valid therapeutic avenues for the treatment of melanocortin type 4 receptor–linked (MC4R-linked) obesity. To test the therapeutic PC potential, we engineered humanized MC4R (hMC4R) mouse models expressing either the WT human MC4R or a prevalent obesity-causing mutant (R165W). Administration of a PC able to rescue cell surface expression and functional activity of R165W-hMC4R in cells restored the anorexigenic response of the R165W-hMC4R obese mice to melanocortin agonist, providing a proof of principle for the therapeutic potential of MC4R-targeting PCs in vivo. Interestingly, the expression of the WT-hMC4R in mice revealed lower sensitivity of the human receptor to α–melanocyte-stimulating hormone (α-MSH) but not β-MSH or melanotan II, resulting in a lower penetrance obese phenotype in the WT-hMC4R versus R165W-hMC4R mice. In conclusion, we created 2 new obesity models, a hypomorphic highlighting species differences and an amorphic providing a preclinical model to test the therapeutic potential of PCs to treat MC4R-linked obesity.

Authors

Patricia René, Damien Lanfray, Denis Richard, Michel Bouvier

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Figure 2

Body weight gain, food consumption, body length, and blood glucose of WT- and R165W-hMC4R-KI mice and their control littermates.

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Body weight gain, food consumption, body length, and blood glucose of WT...
(A and B) Weight gain of male (A) or female (B) WT-hMC4R-KI mice (left) (male: NTG 7, HET 15, HOMO 10; female: NTG 6, HET 14, HOMO 8) or R165W-hMC4R-KI mice (right) (male: NTG 10, HET 19, HOMO 9; female: NTG 10, HET 12, HOMO 6). (C and D) Food intake during dark cycle of WT-hMC4R (male: NTG 4; HET 13; HOMO 11; female: NTG 5, HET 11, HOMO 7) or R165W-hMC4R (male: NTG 5, HET 11, HOMO 11; female: NTG 8, HET 10, HOMO 13). (E and F) Food intake during light cycle of WT-hMC4R (male: NTG 4; HET 13, HOMO 11; female: NTG 5, HET 11, HOMO 7) or R165W-hMC4R (male: NTG 5; HET 11; HOMO 11; female: NTG 8, HET 10, HOMO 13). The caloric intake was estimated using 3.1 kcal/g as metabolizable energy. (G and H) Total body length of WT-hMC4R (male: NTG 8, HET 15, HOMO 10; female: NTG 7, HET 16, HOMO 8) or R165W-hMC4R (male: NTG 5, HET 11, HOMO 11; female: NTG 7, HET 10, HOMO 13) mice. (I and J) Blood glucose assessment in fasted mice: WT-hMC4R (male: NTG 9, HET 11, HOMO 14; female: NTG 12, HET 12, HOMO 12) or R165W-hMC4R (male: NTG 5, HET 11, HOMO 11; female: NTG 8, HET 10, HOMO 13). Data are shown as the mean ± SEM and were analyzed using 2-way ANOVA test of variance followed by pairwise comparisons using post hoc Bonferroni’s multiple comparisons test (A and B) or 1-way Kruskal-Wallis test of variance followed by pairwise comparisons using post hoc Dunn’s multiple comparisons test (C–J). Asterisks denote significant difference of either HOMO or HET hMC4R-KI mice compared with NTG littermates. *P < 0.05, **P < 0.001.