6-Gingerol, a Functional Polyphenol of Ginger, Promotes Browning through an AMPK-Dependent Pathway in 3T3-L1...

The main purpose of the present study was to investigate the browning effect of 6-gingerol (6G), one of the main functional compounds in the ethyl acetate extract of ginger (ginger ethyl acetate fraction, GEF), and its underlying mechanisms. In this study, we first discovered that GEF stimulated brown adipocyte differentiation by upregulating the expression levels of browning-specific transcription makers (UCP1, PRDM16, and PGC-1α), thereby reducing lipogenesis transcriptional regulator (C/EBPα) expression in 3T3-L1-differentiated adipocytes. Then, 6G (47.81 ± 0.62 mg/g) was identified as one of the main functional compounds in GEF using high-performance liquid chromatography. 6G promoted adipocyte browning, as evidenced by an increase in some brown/beige fat-specific genes (PGC-1α, Cidea, Prdm16, Cited1, SIRT1, Tmem26, and Ucp1) and proteins (UCP1, CEBP/β, PGC-1α, and PRDM16) expression levels. Moreover, 6G greatly improved mitochondrial respiration and energy metabolism by upregulating the expression levels of some mitochondrial biogenesis markers (Tfam, Nrf1, SIRT1, and p-AMPK/AMPK) and increasing the uncoupled oxygen consumption rate of protons leaked in 3T3-L1 cells. Comparison of the experimental results obtained with an inhibitor (dorsomorphin) and an activator (5-aminoimidazole-4-carboxamide ribonucleotide) suggested that the 6G-associated regulation of the energy metabolism effect was mediated partly through the AMPK signaling pathway. This study provides new insight into the promotion of fat browning and regulation of lipid metabolism by 6G and suggests that 6G likely has potential therapeutic effects on obesity.