Ketone Body 3-Hydroxybutyrate Enhances Insulin Sensitivity by Inhibiting PPARγ Ser273 Phosphorylation in Type 2 Diabetic Mice

3-Hydroxybutyrate (3HB) is a small ketone body molecule produced endogenously by the body in the liver. Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic patients. However, there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of 3HB. Here we demonstrate that 3HB reduces fasting blood glucose level, improves glucose tolerance, and enhances insulin sensitivity in type 2 diabetic mice through GPR109a receptor. Mechanistically, 3HB increases intracellular Ca2+ levels by activating GPR109a, thereby stimulating adenylate cyclase to increase cAMP concentration, and then activating PKA. Activated PKA inhibits Raf1 activity, resulting in a decrease in ERK1/2 activity and ultimately inhibiting PPARγ Ser273 phosphorylation in adipocytes. Inhibition of PPARγ Ser273 phosphorylation by 3HB altered the expression of PPARγ regulated genes and enhanced insulin sensitivity. Collectively, 3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of GPR109a/Ca2+/cAMP/PKA/Raf1/ERK1/2/PPARγ.