3-Hydroxybutyrate ameliorates insulin resistance 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 (T2D) 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 ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2 (HCAR2). Mechanistically, 3HB increases intracellular calcium ion (Ca2+) levels by activating HCAR2, thereby stimulating adenylate cyclase (AC) to increase cyclic adenosine monophosphate (cAMP) concentration, and then activating protein kinase A (PKA). Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase (Raf1) activity, resulting in a decrease in extracellular signal-regulated kinases 1/2 (ERK1/2) activity and ultimately inhibiting peroxisome proliferator-activated receptor gamma (PPAR gamma) Ser273 phosphorylation in adipocytes. Inhibition of PPAR gamma Ser273 phosphorylation by 3HB altered the expression of PPAR gamma regulated genes and reduced insulin resistance. Collectively, 3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca2+/cAMP/PKA/Raf1/ERK1/2/PPAR gamma.

Automated summary

3-Hydroxybutyrate (3HB), a small ketone body produced in the liver, has been found to reduce blood glucose levels in type 2 diabetic patients. However, the mechanism behind this effect is not well-understood. This study demonstrates that 3HB decreases fasting blood glucose levels and improved insulin resistance in type 2 diabetic mice through the activation of HCAR2. The mechanism involves the activation of intracellular calcium ion levels, followed by the stimulation of AC, the increase in cAMP concentration, activation of PKA, inhibition of Raf1 activity, suppression of ERK1/2 activity, and the reduction of PPARγ Ser273 phosphorylation.