摘要
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(Ca^(2+))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 receptorγ(PPARγ)Ser273 phosphorylation in adipocytes.Inhibition of PPARγSer273 phosphorylation by 3HB altered the expression of PPARγregulated genes and reduced insulin resistance.Collectively,3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca^(2+)/cAMP/PKA/Raf1/ERK1/2/PPARγ.
基金
supported by the National Natural Science Foundation of China(Grant No.31870859)and Tsinghua Chunfeng Foundation.
