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Open Access Highly Accessed Research article

The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy

Feng Fang1, Lei Liu2, Yang Yang2, Zenshiro Tamaki1, Jun Wei1, Roberta G Marangoni1, Swati Bhattacharyya1, Ross S Summer3, Boping Ye2 and John Varga1*

Author Affiliations

1 Division of Rheumatology, Northwestern University Feinberg School of Medicine, McGaw M230, 240 E Huron Street, Chicago, IL, 60611 USA

2 School of Life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, Jiangsu, 210009 China

3 Pulmonary Center, Boston University School of Medicine, 850 Harrison Avenue, Boston, MA, 02118 USA

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Arthritis Research & Therapy 2012, 14:R229  doi:10.1186/ar4070

Published: 23 October 2012

Abstract

Introduction

Fibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-ß (TGF-β), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-γ regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-γ are unknown.

Methods

Regulation of fibrotic gene expression and TGF-ß signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR.

Results

Adiponectin, an adipokine directly regulated by PPAR-γ, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-γ.

Conclusions

These findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis.