GPR75

Cilia effects upon perturbation of GPR75

Ciliogenesis screen results (3 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-2.61) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381

Phenotypes

Mouse ciliopathy phenotype:

Gpr75-/- mice: reduced body weight and fat mass; reduced food intake on high-fat diet; pair-feeding normalises body weight. Thinner allele (L144P) missense: lean phenotype; mutant protein fails to localise to primary cilia in hypothalamic neurons. Selectivity: Gpr75-/- protects against HFD-induced obesity but does not protect Lep^ob (leptin-deficient) or Adcy3-mutant mice from obesity on chow diet — indicates a leptin/ADCY3-dependent pathway (PMID 39137039).

Human ciliopathy phenotype:

GPR75 loss-of-function variants associated with reduced BMI in human exome-sequencing studies (lean phenotype); the disease association is inverse — GPR75 loss is protective against obesity rather than causal for it. Ciliary localisation of GPR75 is required for its role in central regulation of feeding (PMID 39137039).

Ciliopathy associations

• Ciliary Monogenic Obesity

Subcellular localization

cilia

Functional category

• Signaling (Hedgehog, GPCRs, ion channels)
• Ciliary membrane
• Metabolism

Function

Orphan G-protein-coupled receptor expressed exclusively in the brain (consistent across regions in 3xFlag-tagged Gpr75 knock-in mice). Interacts with Gαq and localises to primary cilia of hypothalamic cells. Jiang et al. 2024 (PMID 39137039) showed that loss-of-function GPR75 variants in human exome-sequencing studies associate with lower BMI; a missense allele identified by random germline mutagenesis in mice (Thinner, L144P) produces a lean phenotype, mirrored in Gpr75-/- mice (reduced body weight, fat mass, and food intake on high-fat diet; pair-feeding normalises body weight). Both the Thinner allele and human BMI-lowering GPR75 variants fail to localise to cilia, supporting that ciliary localisation is required for GPR75 function in central feeding regulation. GPR75 loss selectively suppresses HFD-induced weight gain but does not protect Lep^ob or Adcy3-mutant mice from obesity on chow.

Model organism evidence