Long-term supplementation of esculetin ameliorates hepatosteatosis and insulin resistance partly by activating AdipoR2–AMPK pathway in diet-induced obese mice

• Esculetin effectively improved hepatosteatosis and insulin resistance in obese mice.
• Esculetin elevated plasma adiponectin level and hepatic AdipoR2–AMPK pathway.
• Esculetin up-regulated expression of hepatic fatty acid oxidation genes.
• Esculetin down-regulated expression of hepatic lipid synthesis genes.
• Esculetin modulated expression of hepatic GLUT2 and glucose metabolic genes.

The effects of esculetin on hepatosteatosis and insulin resistance in high-fat diet (HFD)-induced obese mice were investigated. Esculetin (0.02%, w/w) provided to mice fed a HFD (40% kcal from fat) for 12 weeks reduced body weight gain, visceral adiposity, hepatosteatosis, hyperlipidemia and hyperglycemia, whereas it increased plasma adiponectin level and the protein and mRNA expression of hepatic AdipoR2, which led to the activation of AMPK. The protein and mRNA expression of hepatic PPARα were up-regulated by esculetin and those of SREBP-1c were down-regulated. Esculetin elevated expression of hepatic fatty acid oxidation genes (PGC-1α, PPARα, Acsl1 and CPT), while suppressing expression of fatty acid synthesis gene. Anti-insulin resistant effects of esculetin were mediated by increased hepatic GLUT2 and glucokinase mRNA levels and decreased glucose-6-phosphatase mRNA level. These findings suggest that esculetin supplementation has beneficial effects on hepatosteatosis and insulin resistance in HFD-induced obese mice, partly via activation of the AdiopR2–AMPK pathway.