GPR30 Selective Agonist G1 Exhibits Antiobesity Effects and Promotes Insulin Resistance and Gluconeogenesis in Postmenopausal Mice Fed a High-Fat Diet

G1, a specific agonist targeting the G protein-coupled receptor 30 (GPR30), has demonstrated significant involvement in combating obesity and regulating glucose homeostasis. Nevertheless, the beneficial effects of G1 treatment have solely been investigated in animal models under normal feeding conditions, leaving its therapeutic potential in high-fat feeding scenarios unexplored. To address this gap, our study employed an ovariectomized high-fat diet mouse model to assess the therapeutic effects of G1 in combating obesity and metabolic dysfunction. The findings revealed that G1 treatment resulted in weight loss, but concurrently led to increased blood glucose levels and insulin resistance. Treatment with G1 resulted in an amplification of fat mobilization and an enhancement of pyruvate carboxylase activity in mice fed a high-fat diet. Moreover, the combined impact of G1 treatment and a high-fat diet on pyruvate metabolism, as well as the regulation of crucial gluconeogenesis enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), phosphoenolpyruvate carboxykinase (PEPCK), and glucose transporter 2 (GLUT2), expedites the elevation of blood glucose and the progression of insulin resistance. These findings indicate that G1 treatment is influenced by a high-fat diet, potentially disrupting glucolipid metabolism and promoting insulin resistance alongside its antiobesity effects. Consequently, further investigation is imperative to thoroughly explore this potential toxic side effect of G1 therapy.