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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\u20103, TIMP\u20101, and the phosphorylated species of Stat3 and adenosine monophosphate\u2010activated protein kinase (AMPK) were conducted. We also examined MMP\u20101 activity by immunosorbant fluorimetric analysis. In HSCs, adiponectin\u2010induced phosphorylation of AMPK, and subsequently suppressed leptin\u2010mediated Stat3 phosphorylation and SOCS\u20103 induction. Adiponectin also blocked leptin\u2010stimulated secretion of TIMP\u20101, and significantly increased MMP\u20101 activity, in vitro. To extend this study, we treated adiponectin knockout mice (Ad\u2212\/\u2212) daily with 5\u2009mg\/kg recombinant leptin and\/or carbon tetrachloride (2\u2009ml\/kg) for 6 weeks. Post\u2010necropsy analysis was performed to examine for inflammation, and histological changes in the Ad\u2212\/\u2212 and wild\u2010type 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 CCl<jats:sub>4<\/jats:sub> enhanced hepatic fibrosis in both wild\u2010type and Ad\u2212\/\u2212 mice, as estimated by amount of collagen in injured livers, but wild\u2010type mice had significantly higher levels of SOCS\u20103 and significantly lower levels of TIMP\u20101 mRNA and protein than did adiponectin KO mice exposed to both CCl<jats:sub>4<\/jats:sub> 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\u2010Stat signal transduction pathway. J. Cell. Biochem. 110: 1195\u20131207, 2010. 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