title: Berberine inhibits palmitate-induced NLRP3 inflammasome activation by triggering autophagy in macrophages: A new mechanism linking berberine to insulin resistance improvement.
abstract: NLRP3 (Nod-like receptor family pyrin domain containing 3) inflammasome has been reported to contribute to obesity-induced inflammation and insulin resistance. However, there are few drugs targeting NLRP3 inflammasome for the treatment of insulin resistance. In the present study, we showed that berberine (BBR) significantly suppressed saturated fatty acid palmitate (PA)-induced NLRP3 inflammasome activation and interleukin-1β (IL-1β) release in macrophages, which was one of the most important mediators in the insulin sensitivity of adipose tissue. BBR treatment dramatically upregulated macrophage autophagic level while knockdown beclin1 and autophagy inhibitor reversed BBR's suppression on inflammasome. Furthermore, AMPK (adenosine monophosphate-activated protein kinase) inhibitor Adenine 9-β-d-arabinofuranoside (Ara-A) blocked most effects of BBR, suggesting that AMPK signals may be involved in BBR-induced macrophage autophagy. Importantly, BBR also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced insulin resistance model. Adoptive transfer of BBR-treated bone marrow-derived macrophages (BMDMs), which was induced by lipopolysaccharide (LPS) plus palmitate-bovine serum albumin (PA-BSA), significantly ameliorated insulin resistance of ob/ob mice as compared with control mice. However, the co-treatment of the BMDMs with autophagy inhibitor 3-Methyladenine (3-MA) reversed the effect of BBR almost completely. Taken together, BBR exerted its anti-inflammatory effects through activation of AMPK-dependent autophagy in adipose tissue macrophages (ATMs). This study amplified the mechanisms of BBR and its potential in attenuating insulin resistance.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China. Electronic address: xudongwu@nju.edu.cn.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Road, Nanjing 210023, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001599:Berberine / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D001599:Berberine
keywords: Adipose tissue macrophages; Autophagy; Berberine; Insulin resistance; NLRP3 inflammasome