Central regulation of feeding and body weight by ciliary GPR75

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...

Full description

Saved in:
Bibliographic Details
Published inThe Journal of clinical investigation Vol. 134; no. 19
Main Authors Jiang, Yiao, Xun, Yu, Zhang, Zhao
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 13.08.2024
Subjects
Adenylyl Cyclases
Animals
Body Weight
Cilia - genetics
Cilia - metabolism
Diet, High-Fat
Female
Humans
Hypothalamus - metabolism
Male
Mice
Mice, Knockout
Mutation, Missense
Obesity - genetics
Obesity - metabolism
Obesity - pathology
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Cell biology
Obesity
G protein-coupled receptors
Metabolism
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI182121