Metformin enhances mitochondrial biogenesis and thermogenesis in brown adipocytes of mice

Biomed Pharmacother. 2019 Mar;111:1156-1165. doi: 10.1016/j.biopha.2019.01.021. Epub 2019 Jan 12.

Abstract

Aims: We studied the effect of metformin on the brown adipose tissue (BAT) in a fructose-rich-fed model, focusing on BAT proliferation, differentiation, and thermogenic markers.

Main methods: C57Bl/6 mice received isoenergetic diets for ten weeks: control (C) or high-fructose (F). For additional eight weeks, animals received metformin hydrochloride (M, 250 mg/kg/day) or saline. After sacrifice, BAT and white fat pads were prepared for light microscopy and molecular analyses.

Key findings: Body mass gain, white fat pads, and adiposity index were not different among the groups. There was a reduction in energy intake in the F group and energy expenditure in the F and FM groups. Metformin led to a more massive BAT in both groups CM and FM, associated with a higher adipocyte proliferation (β1-adrenergic receptor, proliferating cell nuclear antigen, and vascular endothelial growth factor), and differentiation (PR domain containing 16, bone morphogenetic protein 7), in part by activating 5' adenosine monophosphate-activated protein kinase. Metformin also enhanced thermogenic markers in the BAT (uncoupling protein type 1, peroxisome proliferator-activated receptor gamma coactivator-1 alpha) through adrenergic stimuli and fibroblast growth factor 21. Metformin might improve mitochondrial biogenesis in the BAT (nuclear respiratory factor 1, mitochondrial transcription factor A), lipolysis (perilipin, adipose triglyceride lipase, hormone-sensitive lipase), and fatty acid uptake (lipoprotein lipase, cluster of differentiation 36, adipocyte protein 2).

Significance: Metformin effects are not linked to body mass changes, but affect BAT thermogenesis, mitochondrial biogenesis, and fatty acid uptake. Therefore, BAT may be a metformin adjuvant target for the treatment of metabolic disorders.

Keywords: Brown adipose tissue; Fructose; Metformin; Mouse; Thermogenesis.

MeSH terms

  • Adipocytes, Brown / drug effects*
  • Adipocytes, Brown / metabolism
  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Biomarkers / metabolism
  • Body Mass Index
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Energy Metabolism / drug effects
  • Fibroblast Growth Factors / metabolism
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Organelle Biogenesis
  • Thermogenesis / drug effects*

Substances

  • Biomarkers
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Metformin