Dietary Flavonoid Hyperoside Ameliorates High‐Fat Diet‐Induced Type 2 Diabetes Mellitus by Enhancing Brown Adipose Tissue Thermogenesis, White Adipose Tissue Browning, and Gut Microbiota Remodeling

ABSTRACT Hyperoside, a natural dietary flavonoid widely found in a variety of fruits, vegetables, and medicinal plants, exhibits hypoglycemic as well as hepatorenal protective activities. However, its effects on type 2 diabetes mellitus (T2DM) and the underlying mechanisms remain poorly understood. In this study, T2DM mice were established after 8 weeks of high‐fat diet (HFD) feeding and were subsequently treated with hyperoside for 6 weeks. Then, indices of glucose and lipid metabolism, energy expenditure, hepatic histopathology, brown adipose tissue (BAT) thermogenesis, inguinal white adipose tissue (iWAT) browning, macrophage polarization in iWAT, and gut microbiota composition were evaluated. Hyperoside significantly reduced HFD‐induced body weight gain in T2DM mice without suppressing appetite. HFD‐induced insulin resistance, dyslipidemia, hepatic steatosis, and fibrosis were markedly ameliorated by hyperoside. Hyperoside also increased oxygen consumption, carbon dioxide production, and energy expenditure, and decreased the respiratory exchange ratio. In addition, hyperoside treatment was accompanied by increased UCP1 and PGC‐1α protein expression and upregulated mRNA expression of PGC‐1α, UCP1, PRDM16, and Cidea in BAT and iWAT, consistent with enhanced BAT thermogenic activity and an iWAT browning‐related phenotype. Flow cytometry analysis further revealed that hyperoside inhibited M1 macrophage polarization and reduced the M1/M2 ratio in iWAT. Moreover, hyperoside partially modulated gut microbial diversity and taxonomic composition in T2DM mice, increased the relative abundance of Bacteroidetes and the Bacteroidetes/Firmicutes ratio, and partially restored the relative abundance of Muribaculaceae and Lachnospiraceae _NK4A136_group. In conclusion, hyperoside ameliorated metabolic dysfunction in HFD‐induced T2DM mice, accompanied by enhanced BAT thermogenic activity, iWAT browning‐related changes, modulation of macrophage polarization in iWAT, and remodeling of the gut microbiota. These findings suggest that hyperoside may represent a potential natural product candidate with metabolic benefits, although further pharmacokinetic, safety, long‐term, and clinical validation is required.