Adiponectin Activation of AMPK Disrupts Leptin-Mediated Hepatic Fibrosis via Suppressors of Cytokine Signaling (SOCS-3)

Adiponectin is an adipocytokine that was recently shown to be anti-fibrogenic in hepatic fibrosis. Leptin, on the other hand, promotes hepatic fibrosis The purpose of the present study was to elucidate a mechanism (or mechanisms) whereby adiponectin dampens leptin signaling in activated hepatic stellate cells (HSCs), and prevents excess extracellular matrix production Activated HSCs, between passages 2 and 5, were cultured and exposed to recombinant human adiponectin and recombinant leptin. Immunoblot analysis for SOCS-3, TIMP-1, and the phosphorylated species of Stat3 and adenosine monophosphate-activated protein kinase (AMPK) were conducted We also examined MMP-1 activity by immunosorbant fluorimetric analysis In HSCs. adiponectin-induced phosphorylation of AMPK, and subsequently suppressed leptin-mediated Stat3 phosphorylation and SOCS-3 induction Adiponectin also blocked leptin-stimulated secretion of TIMP-1, and significantly increased MMP-1 activity, in vitro. To extend this study, we treated adiponectin knockout mice (Ad-/-) daily with 5 mg/kg recombinant leptin and/or carbon tetrachloride (2 ml/kg) for 6 weeks Post-necropsy analysis was performed to examine (or inflammation. and histological changes in the Ad-/- and wild-type mice There was no significant difference in inflammation. or aminotransferases. between mice receiving carbon tetrachloride and leptin versus carbon tetrachloride alone As anticipated, the combination of leptin and CCl4 enhanced hepatic fibrosis in both wild-type and Ad-/- once, as estimated by amount of collagen in injured livers, but wild-type mice had significantly higher levels of SOCS-3 and significantly lower levels of TIMP-1 mRNA and protein than did adiponectin KO mice exposed to both CCl4 and leptin We therefore conclude that the protective effects of adiponectin against liver fibrosis require AMPK activation, and may occur through inhibition of the Jak-Stat signal transduction pathway J Cell. Biochem. 110 1195-1207, 2010 (C) 2010 Wiley-Liss. Inc