Dihydromyricetin delays the onset of hyperglycemia and ameliorates insulin resistance without excessive weight gain in Zucker diabetic fatty rats

•Dihydromyricetin improves insulin sensitivity of Zucker diabetic fatty rats.•Dihydromyricetin does not cause excessive body weight gain in ZDF rats.•The mechanism relies on reduction of PPARγ phosphorylation Ser273 via ERK/CDK5 axis.

Many flavonoids are reported to be partial agonists of PPARγ and exert antidiabetic effects with fewer side effects compared with full agonists. Here, we assessed the effects of flavonoid dihydromyricetin (DHM) on glucose homeostasis in male Zucker diabetic fatty rats. Animals were treated with DHM (50-200  mg kg−1) or rosiglitazone (4  mg kg−1) once a day for 8 weeks. We found that DHM reduced fasting blood glucose and delayed the onset of hyperglycemia by 4 weeks. Furthermore, DHM preserved pancreatic β-cell mass, elevated adiponectin and improved lipid profile more vigorously than rosiglitazone. Notably, DHM decreased body weight gain and fat accumulation in both liver and adipose tissue, while rosiglitazone caused a significant increase of body weight and fat accumulation. DHM inhibited phosphorylation of PPARγ at serine 273 more efficiently than rosiglitazone. These results suggest that DHM exerts antidiabetic effects without causing excessive body weight gain via inhibition of PPARγ phosphorylation.