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BACKGROUND The present study aimed to uncover the potential effects of zingerone (ZIN), one of the bioactive compounds in ginger, on the development of obesity as well as the mechanisms in C57BL/6J mice fed with a high-fat diet (HFD). RESULTS Supplementation with 0.2% (wt/wt) zingerone for 16 weeks significantly reduced the final body weight, liver weight and epididymal white adipose tissue (eWAT) weight without changing their food intake when compared with HFD group. The hyperlipidemia of HFD-fed mice was ameliorated after zingerone administration, including decreased plasma triacylglycerol (TG) and total cholesterol (TC) level. The lipids content in liver was lower and the adipocyte size in eWAT and inguinal white adipose tissue (iWAT) was smaller in HFD+ZIN-fed mice compared with HFD group. Furthermore, zingerone binds with nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα) with an optimal docking energy of -7.31kJ/mol. Uncoupling protein 1 (UCP1), PPAR-γ coactivator-1α (PGC-1α) and PR domain containing 16 (PRDM16), the downstream genes of PPAR which are related to thermogenic function of adipocytes, were significantly increased in both brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) after zingerone administration, compared to HFD fed mice. In addition, zingerone intake restructured the community composition of gut microbiota. In detail, the ratio of Firmicutes to Bacteroidetes was decreased, and the relative abundance of Akkermansia_mucinphila was increased. CONCLUSION Zingerone can attenuate obesity and related symptoms in HFD-fed mice probably via the modulation of PPARα-thermogenesis-gut microbiota interactions. This article is protected by copyright. All rights reserved.