Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation

Exp Mol Med. 2018 Jan 26;50(1):e432. doi: 10.1038/emm.2017.245.

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformin's action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / drug effects*
  • Adipocytes, Brown / pathology
  • Adipocytes, Brown / transplantation
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / genetics
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / etiology
  • Arthritis, Rheumatoid / pathology
  • Cell Differentiation / drug effects
  • Fibroblast Growth Factors / genetics*
  • Gene Expression Regulation / drug effects
  • Male
  • Metformin / pharmacology*
  • Mice, Inbred DBA
  • Obesity / complications*
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes, Regulatory / drug effects
  • Th17 Cells / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Metformin