Berberine remodels adipose tissue to attenuate metabolic disorders by activating sirtuin 3

Authors: LI, DAN - Chengdu University; YANG, CHAO - University Of Macau; ZHU, JIAN-ZHONG - University Of Macau; LOPEZ, EDUARDO - Children'S Nutrition Research Center (CNRC); ZHANG, TIAN - University Of Macau; TONG, QIANG - Children'S Nutrition Research Center (CNRC); PENG, CHENG - Chengdu University; LIN, LI-GEN - University Of Macau

Submitted to: Acta Pharmacologica Sinica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/29/2021
Publication Date: 8/20/2021
Citation: Li, D., Yang, C., Zhu, J., Lopez, E., Zhang, T., Tong, Q., Peng, C., Lin, L. 2021. Berberine remodels adipose tissue to attenuate metabolic disorders by activating sirtuin 3. Acta Pharmacologica Sinica. 43:1285-1298. https://doi.org/10.1038/s41401-021-00736-y.
DOI: https://doi.org/10.1038/s41401-021-00736-y

Interpretive Summary: Obesity and related metabolic diseases causes structure changes (remodeling) of adipose tissue. Berberine (BBR), a natural compound, has potent effects on reducing blood lipid and glucose levels. This study explored the role of BBR in modulating adipose tissue remodeling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against obesity, insulin resistance and elevated lipid levels. BBR alleviated adipose tissue inflammation and fibrosis (the thickening and stiffing of a tissue) by inhibiting macrophage accumulation in the adipose tissue and macrophage production of fibrous materials. This effect was mediated by BBR's directly binding to and activating a protein-modifying enzyme Sirtuin 3 (SIRT3) and suppressing the activation of two signaling pathways inside cells. Furthermore, BBR mitigated inflammatory responses in macrophages and adipocytes and suppressed macrophage migration towards adipocytes by activating SIRT3. Collectively, this study revealed that BBR improved adipose tissue structure, and subsequently inhibited the macrophage inflammation, with alleviated obesity, insulin resistance and liver injury in obese mice. Our work uncovered a new role of SIRT3 in the suppression of obesity and metabolic diseases.

Technical Abstract: Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of the mitogen-activated protein kinases and nuclear factor-kB signalling pathways. Furthermore, BBR decreased microRNA-155-5p secretion by macrophages, which in turn ameliorated liver injury. Moreover, BBR mitigated inflammatory responses in both LPS-stimulated macrophages and TNF-a-treated adipocytes and suppressed macrophage migration towards adipocytes by activating SIRT3. Collectively, this study revealed that BBR improved adipose tissue remodelling, and subsequently inhibited the secretion of microRNA-155-5p by macrophages, which alleviated adiposity, insulin resistance and liver injury in obese mice. The modulation of adipose tissue remodelling by activating SIRT3 could contribute to the anti-hyperlipidemic and anti-hyperglycemic effects of BBR.