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Br J Pharmacol. 2017 Aug;174(15):2457-2470. doi: 10.1111/bph.13855. Epub 2017 Jun 21.

Natural alkaloid bouchardatine ameliorates metabolic disorders in high-fat diet-fed mice by stimulating the sirtuin 1/liver kinase B-1/AMPK axis.

Author information

1
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
2
Molecular Pharmacology for Diabetes Group, School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.

Abstract

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 molecular mechanisms of 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 an evaluation of its metabolic effects in mice fed a high-fat diet for 16 weeks with Bou being administered in the last 5 weeks. Further mechanistic investigations were conducted in pertinent organs of the mice and relevant cell models.

KEY RESULTS:

In 3T3-L1 adipocytes, Bou reduced lipid content and increased sirtuin 1 (SIRT1) activity to facilitate liver kinase B1 (LKB1) 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, dyslipidaemia and fatty liver without affecting food intake and no adverse effects were detected. These metabolic effects were associated with activation of the SIRT1-LKB1-AMPK signalling pathway in adipose tissue and liver. Of particular note, UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of Bou-treated mice. Incubation with Bou induced similar changes in primary brown adipocytes isolated from mice.

CONCLUSIONS AND IMPLICATIONS:

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.

PMID:
28493443
PMCID:
PMC5513868
DOI:
10.1111/bph.13855
[Indexed for MEDLINE]
Free PMC Article

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