Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans

• Published in: Cell death & disease 2019-06, Vol.10 (6), p.468-18, Article 468
• Main Authors: Wu, Lingyan, Xia, Mingfeng, Duan, Yanan, Zhang, Lina, Jiang, Haowen, Hu, Xiaobei, Yan, Hongmei, Zhang, Yiqiu, Gu, Yushen, Shi, Hongcheng, Li, Jia, Gao, Xin, Li, Jingya
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis; Adipose tissue (brown); Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - metabolism; Adult; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Anti-Obesity Agents - therapeutic use; Antibodies; Berberine; Berberine - administration & dosage; Berberine - pharmacology; Berberine - therapeutic use; Biochemistry; Biomedical and Life Sciences; Body weight; Body Weight - drug effects; Cell Biology; Cell Culture; Cell Differentiation - drug effects; Demethylation; Diarrhea; DNA Methylation - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Energy expenditure; Energy metabolism; Energy Metabolism - drug effects; Fatty liver; Humans; Immunology; Insulin; Insulin Resistance; Ketoglutaric acid; Ketoglutaric Acids - metabolism; Life Sciences; Liver diseases; Male; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - enzymology; Non-alcoholic Fatty Liver Disease - metabolism; Non-shivering; Obesity; Obesity - drug therapy; Obesity - metabolism; Overweight; Preadipocytes; Promoter Regions, Genetic; Thermogenesis; Thermogenesis - drug effects; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tricarboxylic acid cycle
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1706-y

Brown adipose tissue (BAT) dissipates metabolic energy and mediates non-shivering thermogenesis, thereby boosting energy expenditure. Increasing BAT mass and activity is expected to be a promising strategy for combating obesity; however, few medications effectively and safely recruit and activate BAT in humans. Berberine (BBR), a natural compound, is commonly used as a nonprescription drug to treat diarrhea. Here, we reported that 1-month BBR intervention increased BAT mass and activity, reduced body weight, and improved insulin sensitivity in mildly overweight patients with non-alcoholic fatty liver disease. Chronic BBR treatment promoted BAT development by stimulating the expression of brown adipogenic genes, enhanced BAT thermogenesis, and global energy expenditure in diet-induced obese mice and chow-fed lean mice, Consistently, BBR facilitated brown adipocyte differentiation in both mouse and human primary brown preadipocytes. We further found that BBR increased the transcription of PRDM16, a master regulator of brown/beige adipogenesis, by inducing the active DNA demethylation of PRDM16 promoter, which might be driven by the activation of AMPK and production of its downstream tricarboxylic acid cycle intermediate α-Ketoglutarate. Moreover, chronic BBR administration had no impact on the BAT thermogenesis in adipose-specific AMPKa1 and AMPKa2 knockout mice. In summary, we found that BBR intervention promoted recruitment and activation of BAT and AMPK–PRDM16 axis was indispensable for the pro-BAT and pro-energy expenditure properties of BBR. Our findings suggest that BBR may be a promising drug for obesity and related metabolic disorders in humans partially through activating BAT.