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

Cell Death Dis. 2019 Jun 13;10(6):468. doi: 10.1038/s41419-019-1706-y.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue, Brown / drug effects*
  • Adipose Tissue, Brown / metabolism
  • Adult
  • Animals
  • Anti-Obesity Agents / therapeutic use
  • Berberine / administration & dosage
  • Berberine / pharmacology
  • Berberine / therapeutic use*
  • Body Weight / drug effects
  • Cell Differentiation / drug effects
  • DNA Methylation / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Energy Metabolism / drug effects
  • Humans
  • Insulin Resistance
  • Ketoglutaric Acids / metabolism
  • Male
  • 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*
  • Obesity / drug therapy
  • Obesity / metabolism*
  • Promoter Regions, Genetic
  • Thermogenesis / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Anti-Obesity Agents
  • DNA-Binding Proteins
  • Ketoglutaric Acids
  • Prdm16 protein, mouse
  • Transcription Factors
  • Berberine
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • AMP-Activated Protein Kinases