Central regulation of feeding and body weight by ciliary GPR75
Yiao Jiang, … , Yu Xun, Zhao Zhang
Yiao Jiang, … , Yu Xun, Zhao Zhang
Published August 13, 2024
Citation Information: J Clin Invest. 2024;134(19):e182121. https://doi.org/10.1172/JCI182121.
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Research Article Cell biology Metabolism

Central regulation of feeding and body weight by ciliary GPR75

Abstract

Variants of the G protein–coupled receptor 75 (GPR75) are associated with a lower BMI in large-scale human exome-sequencing studies. However, how GPR75 regulates body weight remains poorly understood. Using random germline mutagenesis in mice, we identified a missense allele (Thinner) of Gpr75 that resulted in a lean phenotype and verified the decreased body weight and fat weight in Gpr75-knockout (Gpr75–/–) mice. Gpr75–/– mice displayed reduced food intake under high-fat diet (HFD) feeding, and pair-feeding normalized their body weight. The endogenous GPR75 protein was exclusively expressed in the brains of 3xFlag-tagged Gpr75-knockin (3xFlag-Gpr75) mice, with consistent expression across different brain regions. GPR75 interacted with Gαq to activate various signaling pathways after HFD feeding. Additionally, GPR75 was localized in the primary cilia of hypothalamic cells, whereas the Thinner mutation (L144P) and human GPR75 variants in individuals with a lower BMI failed to localize in the cilia. Loss of GPR75 selectively inhibited weight gain in HFD-fed mice but failed to suppress the development of obesity in leptin ob–mutant (Lepob-mutant) mice and adenylate cyclase 3–mutant (Adcy3-mutant) mice on a chow diet. Our data reveal that GPR75 is a ciliary protein expressed in the brain and plays an important role in regulating food intake.

Authors

Yiao Jiang, Yu Xun, Zhao Zhang

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Figure 1

Identification and mapping of the Thinner allele.

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Identification and mapping of the Thinner allele. (A–C) Relative body we...
(A–C) Relative body weight (A), fat weight (B), and lean weight (C) phenotypic data plotted versus genotype at the Gpr75 mutation site. Mean (μ) and SD (σ) are indicated. Ref, homozygous for the reference allele; Het, heterozygous for the reference allele and for the Thinner allele; Var, homozygous for the Thinner allele. Raw weight data were compared with the predicted weight of mice based on age and sex to calculate the relative values, minimizing the effects of age and sex differences in G3 mice. (D–F) Manhattan plots showing P values calculated using an additive model of inheritance about relative body weight (D), fat weight (E), and lean weight (F). The −log10 P values (y axis) are plotted versus the chromosomal positions of 53 mutations (x axis) identified in the G1 founder of the pedigree. Horizontal dark red and pink lines represent thresholds of P = 0.05 with and without Bonferroni’s correction, respectively.