GPR75 in glutamatergic neurons regulates body weight

Area of Science:

• Neuroscience
• Metabolic Research
• Genetics

Background:

• G-protein-coupled receptor 75 (GPR75) is a potential therapeutic target for diet-induced obesity (DIO).
• Human loss-of-function mutations in GPR75 correlate with lower body mass index (BMI), and Gpr75-deficient mice are resistant to DIO.

Purpose of the Study:

• To investigate the specific role of GPR75 in glutamatergic and GABAergic neurons in the context of diet-induced obesity.
• To determine if selective deletion or reactivation of GPR75 in specific neuronal populations affects body weight regulation and food intake.

Main Methods:

• Generation of genetically modified mice allowing Cre-dependent deletion or reactivation of Gpr75.
• Selective deletion of Gpr75 in vGlut2+ glutamatergic neurons (Gpr75^vGlut2-KO) and GABAergic neurons.
• Reactivation of Gpr75 in vGlut2-expressing cells of Gpr75 null mice (Gpr75^TB).
• Assessment of body weight, food intake, and energy expenditure in mice fed a high-fat diet (HFD).

Main Results:

• Loss of Gpr75 in glutamatergic neurons (Gpr75^vGlut2-KO) conferred protection against HFD-induced weight gain.
• Deletion of Gpr75 in GABAergic neurons did not protect against DIO.
• Male Gpr75^vGlut2-KO mice exhibited reduced food intake on HFD without altered energy expenditure.
• Reactivation of Gpr75 in vGlut2-expressing cells (Gpr75^TB) fully rescued HFD-induced weight gain, while reactivation in GABAergic cells had no effect.

Conclusions:

• Glutamatergic neurons play a critical role in GPR75-mediated regulation of food intake and protection from obesity.
• GPR75 signaling specifically within glutamatergic pathways is crucial for controlling body weight in response to HFD.