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, 50 (1), e432

Metformin Ameliorates Experimental-Obesity-Associated Autoimmune Arthritis by Inducing FGF21 Expression and Brown Adipocyte Differentiation

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Metformin Ameliorates Experimental-Obesity-Associated Autoimmune Arthritis by Inducing FGF21 Expression and Brown Adipocyte Differentiation

Eun-Kyung Kim et al. Exp Mol Med.

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Treatment with metformin attenuated in obese collagen-induced arthritis (CIA) mice. (a) Reduction in the arthritis score and arthritis incidence in obese CIA mice treated with metformin. (mean±s.e.m. of five mice per group,*P<0.05, **P<0.01, ***P<0.001). (b) Levels of IgG, IgG1 and IgG2a were determined by enzyme-linked immunosorbent assay. (Mean±s.d. of five mice per group,*P<0.05.).
Figure 2
Figure 2
Effects of metformin on proinflammatory molecules in the joints of collagen-induced arthritis (CIA) and obese CIA mice. (a) Histologic features of the joints were stained with hematoxylin and eosin (H&E), and Safranin O. (b) Tissue sections from joints were immunohistochemistry stained with anti-IL-6 and anti-IL-17 antibodies. (Values are the mean ±s.d., *P<0.05, **P<0.01.)
Figure 3
Figure 3
Metformin reduced STAT3 phosphorylation, decreased the frequency of Th17 cells within the population of CD4+ T cells and induced FGF21 expression in collagen-induced arthritis (CIA) and obese CIA mice. (a, b) Spleen tissues from each mouse were examined by immunofluorescence staining. Original magnification × 400. (c) Expression of FGF21 mRNA in isolated splenocytes was measured by real-time polymerase chain reaction, with the results normalized to the expression of β-actin mRNA. (Values are the mean±s.d., *P<0.05, **P<0.01.)
Figure 4
Figure 4
Metformin treatment ameliorated fatty liver and normalized metabolic profiles. (a, d) Obese collagen-induced arthritis (CIA) mice or metformin-treated obese CIA mice had a similar phenotype, but different metabolic profiles. (b) Liver tissues obtained from obese CIA and metformin-treated obese CIA mice were weighed. (c) Sections were stained with hematoxylin and eosin (h&e). Original magnification × 400. (e) Expression of IL-17 and IKBKE mRNA in isolated hepatocytes was measured by real-time polymerase chain reaction, with the results normalized to the expression of β-actin mRNA. (f) Liver tissues from obese CIA and metformin-treated obese CIA mice were examined by immunofluorescence staining. Original magnification × 400. (Values are the mean±s.d., *P<0.05, **P<0.01, ***P<0.001.)
Figure 5
Figure 5
Brown adipose tissue was upregulated by metformin treatment. (a) Weight of brown fat obtained from obese CIA mice or metformin- or Enbrel-treated obese CIA mice. (b) Histologic features of the brown fat tissues stained with hematoxylin and eosin (h&e). Original magnification × 200. (c) Brown fat tissues from each mouse were stained for FGF21+ cells. Original magnification × 400.
Figure 6
Figure 6
BAT reduced the activation of T cells and inhibited Th17 differentiation. (a) Splenocytes were cultured in Th17 conditions and co-cultured with BAT. IL-17 levels in the culture supernatants were measured by ELISA. (b) The differentiation of helper T cells and regulatory T cells obtained from the spleens of mice that received BAT transplants.

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References

    1. Smolen JS, Redlich K, Zwerina J, Aletaha D, Steiner G, Schett G. Pro-inflammatory cytokines in rheumatoid arthritis: pathogenetic and therapeutic aspects. Clin Rev Allergy Immunol 2005; 28: 239–248. - PubMed
    1. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354: 1932–1939. - PubMed
    1. Finckh A, Simard JF, Gabay C, Guerne PA, for the physicians SCQM. Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis. Ann Rheum Dis 2006; 65: 746–752. - PMC - PubMed
    1. Prajapati R, Plant D, Barton A. Genetic and genomic predictors of anti-TNF response. Pharmacogenomics 2011; 12: 1571–1585. - PubMed
    1. Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen IT et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010; 62: 22–32. - PubMed

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