Ciliary localization of GPR75 promotes fat accumulation in mice

Abstract

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.

Figure 1. Mice with the Gpr75 allele Thinner are resistant to weight gain when exposed to a HFD.

(A) 3xFlag-GPR75 is expressed in primary cilia of hypothalamic neurons, and wild-type mice become obese when fed a HFD. (B) The 3xFlag-GPR75-L144P mutant fails to localize to primary cilia, and mice carrying this mutation show resistance to weight gain.