GPR75 in glutamatergic neurons regulates body weight

Cell Rep. 2026 Mar 24;45(3):117011. doi: 10.1016/j.celrep.2026.117011. Epub 2026 Feb 20.

Abstract

The G-protein-coupled receptor 75 (GPR75) emerged as a promising therapeutic target for treating diet-induced obesity (DIO). Loss-of-function mutations of GPR75 in humans are associated with reduced body mass index (BMI). Also, Gpr75-deficient mice are protected from DIO. Here, we generated genetically modified mice that enable us to selectively delete or reactivate Gpr75 in a Cre-dependent manner. Loss of Gpr75 in vGlut2+ glutamatergic neurons (Gpr75vGlut2-KO) results in protection against high-fat diet (HFD)-induced weight gain, whereas loss of Gpr75 in GABAergic neurons shows no protection against DIO. Furthermore, male Gpr75vGlut2-KO mice have reduced food intake on HFD without a change in energy expenditure. Reactivation of Gpr75 only in vGlut2-expressing cells in a Gpr75 null mouse (Gpr75TB) completely rescues the HFD-induced weight gain, whereas reactivation in GABAergic cells has no effect on body weight or adiposity. These complementary results demonstrate the importance of glutamatergic neurons in GPR75's regulation of food intake and protection from obesity.

Keywords: CP: metabolism; CP: neuroscience; GABAergic; Gpr75; body weight; food intake; glutamatergic neurons; high fat diet; metabolic; obesity.

MeSH terms

  • Animals
  • Body Weight*
  • Diet, High-Fat / adverse effects
  • Eating
  • Energy Metabolism
  • GABAergic Neurons / metabolism
  • Glutamic Acid* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons* / metabolism
  • Obesity / metabolism
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Vesicular Glutamate Transport Protein 2 / metabolism

Substances

  • Receptors, G-Protein-Coupled
  • Glutamic Acid
  • Vesicular Glutamate Transport Protein 2