Mice Lacking Gpr75 are Hypophagic and Thin.

Area of Science:

• Metabolic research
• Genetics
• Endocrinology

Background:

• G protein-coupled receptor 75 (GPR75) is an orphan receptor.
• Human GPR75 haploinsufficiency is associated with a thin phenotype.
• Gpr75 knockout (KO) mice exhibit reduced body weight and improved glucose homeostasis.

Purpose of the Study:

• Confirm findings of thin phenotype and improved glucose homeostasis in Gpr75 KO mice.
• Investigate the contribution of decreased energy intake versus increased energy expenditure to the thin phenotype.
• Evaluate the role of GPR75 in metabolic regulation.

Main Methods:

• Generation of Gpr75 KO mice via homologous recombination.
• Comparative analysis of Gpr75 KO and wild-type (WT) littermates (female and male).
• Assessment of body composition (DXA, QMR), glucose homeostasis (OGTTs), food intake, energy expenditure, and locomotor activity.

Main Results:

• Gpr75 KO mice exhibited significantly reduced body fat (49% less) and lean body mass (4% less) compared to WT littermates.
• KO mice showed reduced body fat at weaning and became hypophagic post-weaning, with comparable energy expenditure and activity levels.
• Improved glucose tolerance and insulin sensitivity were observed in Gpr75 KO mice, with lower glucose and insulin levels during OGTTs.

Conclusions:

• Gpr75 KO mice present as thin, hypophagic, and exhibit enhanced glucose tolerance and insulin sensitivity.
• These findings support the potential of GPR75 inhibition as a therapeutic strategy for obesity and related metabolic disorders in humans.
• Targeting GPR75 may offer a safe approach to reduce body fat and improve metabolic health.