Hydrangenol exerts anti-obesity effects by disturbing adipogenesis via mitotic clonal expansion and gut microbiota dysbiosis.

Obesity is a metabolic disorder influenced by genetic and environmental factors. Developing therapeutic strategies that maintain energy metabolism and gut microbiota balance is essential for addressing obesity. This study investigated the anti-obesity potential of hydrangenol (HG), a bioactive compound found in the leaves of Hydrangea serrata (Thunb.) Ser., in 3T3-L1 preadipocytes as well as high-fat diet (HFD)-induced and db/db obese mice. HG inhibited lipid accumulation in differentiated 3T3-L1 cells by disrupting mitotic clonal expansion through modulation of cell cycle-related proteins (cyclin D1, cyclin E, cyclin B1, CDK2, and p21). It also enhanced AMP-activated protein kinase α (AMPKα) phosphorylation while suppressing Akt and mTOR phosphorylation. In line with these in vitro results, HG also suppressed lipid deposition in obese mice by regulating key adipogenesis-related proteins such as C/EBPα, PPAR-γ, and AMPKα in white adipose and liver tissues, resulting in reduced fat mass. Furthermore, HG lowered plasma cholesterol, low-density lipoprotein, leptin, and insulin levels in HFD-fed mice resulting in the improvement of plasma profiles. 16S rRNA sequencing revealed that HG altered the composition of the gut microbiota, increasing the relative abundance of Bacteroidetes and decreasing Firmicutes and Proteobacteria in obese mice. Overall, these results highlight HG's potential as a promising candidate for reducing lipid accumulation and correcting gut microbiota dysbiosis, offering a strategy for obesity prevention.