Center for the Genetics of Host Defense and.
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
J Clin Invest. 2024 Aug 13;134(19):e182121. doi: 10.1172/JCI182121.
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.
G 蛋白偶联受体 75（GPR75）的变体与大规模人类外显子组测序研究中的 BMI 降低有关。然而，GPR75 如何调节体重仍知之甚少。我们使用小鼠随机种系突变，鉴定出 Gpr75 的一个错义等位基因（Thinner），导致瘦表型，并验证了 Gpr75 敲除（Gpr75-/-）小鼠体重和脂肪重量下降。Gpr75-/- 小鼠在高脂肪饮食（HFD）喂养下显示出食物摄入量减少，而配对喂养则使它们的体重正常化。内源性 GPR75 蛋白仅在 3xFlag 标记的 Gpr75 敲入（3xFlag-Gpr75）小鼠的大脑中表达，在不同的大脑区域均有一致的表达。GPR75 与 Gαq 相互作用，在 HFD 喂养后激活各种信号通路。此外，GPR75 定位于下丘脑细胞的初级纤毛中，而 HFD 喂养后瘦表型突变（L144P）和 BMI 较低的个体中的人类 GPR75 变体未能定位于纤毛中。GPR75 的缺失选择性地抑制了 HFD 喂养小鼠的体重增加，但未能抑制瘦素 ob 突变（Lepob-mutant）小鼠和腺苷酸环化酶 3 突变（Adcy3-mutant）小鼠在正常饮食中的肥胖发展。我们的数据表明，GPR75 是一种在大脑中表达的纤毛蛋白，在调节食物摄入方面发挥着重要作用。
