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Mice Lacking Gpr75 are Hypophagic and Thin.

David R Powell1, Deon D Doree1, Christopher M DaCosta1

  • 1Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc, The Woodlands, TX, USA.

Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy
|January 13, 2022
PubMed
Summary

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Mice lacking GPR75 (Gpr75 knockout) are thin and have improved glucose control. This suggests GPR75 inhibition may reduce body fat and enhance insulin sensitivity in humans.

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).
Keywords:
diabetesdruggablehealthy thinnessinsulin sensitivityobesity

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  • 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.