An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis

Takashi Yamashita, Katja Lakota, Takashi Taniguchi, Ayumi Yoshizaki, Shinichi Sato, Wen Hong, Xingchun Zhou, Snezn Sodin-Semrl, Feng Fang, Yoshihide Asano*, John Varga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-β in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

Original languageEnglish (US)
Article number11843
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis'. Together they form a unique fingerprint.

Cite this