Natural alkaloid bouchardatine ameliorates metabolic disorders in high-fat diet fed mice via stimulating the SIRT1-LKB1-AMPK axis

Background and purpose Promoting energy metabolism is known to provide therapeutic effects for obesity and associated metabolic disorders. The present study evaluated the therapeutic effects of the newly-identified bouchardatine (Bou) on obesity associated metabolic disorders and the molechular mechanisms for these effects. Experimental approach The molecular mode of action of Bou for its effects on lipid metabolism was first examined in 3T3-L1 adipocytes and HepG2 cells. This was followed by the evaluation of its metabolic effects in mice fed a high-fat diet for 16 weeks with the administration of Bou in last 5 weeks. Further mechanistic investigations were conducted in implicated organs of the mice and relevant cell models. Key results In 3T3-L1 adipocytes, Bou reduced lipid content and increased SIRT1 activity to facilitate LKB1's activation of AMPK. Chronic administration of Bou (50 mg kg-1 every other day) in mice significantly attenuated high-fat diet induced increases in body weight gain, dyslipidemia and fatty liver without affecting food intake and detectable signs of adverse effects. These metabolic effects were associated with activation of the SIRT1-LKB1-AMPK signaling pathway in adipose tissue and liver. Of particular note were increases in UCP1 expression and mitochondrial biogenesis in both white and brown adipose tissues of Bou-treated mice. Similar changes were induced in primary brown adipocytes isolated from mice after incubation with Bou. Conclusions Bou may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues and liver through a mechanism involving the SIRT1-LKB1-AMPK axis.