Acteoside prevents high-fat diet-induced obesity by regulating brown adipose tissue production, lipid metabolism, and the gut microbiota.

Acteoside, a phenylethanol glycoside, possesses various pharmacological properties. The aim of this study was to investigate the mechanism of its anti-obesity effects on high-fat diet (HFD)-induced obese mice, as well as to evaluate the anti-obesity effects of its two active metabolites, caffeic acid and hydroxytyrosol. Mice were randomly divided into six groups in the first part experiment and five groups in the second part experiment as follows: control diet group; control diet + acteoside at 150 mg/kg/day group; HFD group; HFD + orlistat at 20 mg/kg/day group; HFD + caffeic acid at 45 mg/kg/day group; HFD + hydroxytyrosol at 40 mg/kg/day group; HFD + acteoside at 75 mg/kg/day group; and HFD + acteoside at 150 mg/kg/day group. The results showed that acteoside exhibited more pronounced anti-obesity effects compared with its two active metabolites. Acteoside supplementation reduced body weight and white adipose tissue (WAT) weight and improved glucose tolerance and insulin sensitivity in obese mice, as well as partially reverse hepatic damage and fat accumulation. In addition, acteoside induced the production of brown adipose tissue (BAT) when compared with caffeic acid and hydroxytyrosol, as well as promote a thermogenesis program in BAT and activate AMPK and HSL signaling in both WAT and BAT. Furthermore, high-dose acteoside supplementation altered the gut microbiota by increasing the abundance of Akkermansia muciniphila in obese mice. In summary, our results indicate that long-term acteoside supplementation may partially reverse obesity by stimulating adipose thermogenesis, modulating lipid metabolism, and altering the gut microbiota.