6-Gingerol induces browning of white adipose tissue to improve obesity through PI3K/AKT-RPS6-mediated thermogenesis pathway

The browning of white fat has become a hot topic as it could help to lose weight and improve metabolic health. Therefore, this study aims to explore the in vivo browning or thermogenesis effect of 6-gingerol (6G), a natural bioactive compound of ginger, and to clarify the underlying mechanism. The results showed that 6G limited weight gain, improved cold tolerance, and increased energy expenditure in high-fat diet-induced obese mice. Moreover, histological and immunohistochemical analysis revealed that 6G activated brown adipose tissue (BAT) and induced more beige cells in epididymal adipose tissue (eWAT). Meanwhile, eWAT browning was marked by appearance of multilocular lipid droplets, a higher level of uncoupling protein 1 (UCP1), and increased mitochondrial content. The potential molecular mechanism of eWAT browning was further investigated by RNA-seq, qPCR, and western blot assays. Results indicated that 6G significantly induced the expression of beige and thermogenesis-specific markers in eWAT and triggers thermogenesis mainly through a phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT)-ribosomal protein S6 (RPS6) axis. Consistently, in vitro, data showed that pretreatment of primary white adipocytes with PI3K/AKT pathway inhibitor significantly counteracted the 6G-induced effects. This study reveals, for the first time, that 6G induces browning in adipose tissue by modulating the PI3K/AKT-RPS6 and thermogenesis pathways, thereby alleviating obesity.