RGD Reference Report - Adiponectin activation of AMPK disrupts leptin-mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS-3). - Rat Genome Database

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Adiponectin activation of AMPK disrupts leptin-mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS-3).

Authors: Handy, JA  Saxena, NK  Fu, P  Lin, S  Mells, JE  Gupta, NA  Anania, FA 
Citation: Handy JA, etal., J Cell Biochem. 2010 Aug 1;110(5):1195-207. doi: 10.1002/jcb.22634.
RGD ID: 7207371
Pubmed: PMID:20564215   (View Abstract at PubMed)
PMCID: PMC2907429   (View Article at PubMed Central)
DOI: DOI:10.1002/jcb.22634   (Journal Full-text)

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 for 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 CCl(4) enhanced hepatic fibrosis in both wild-type and Ad-/- mice, 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 CCl(4) 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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to peptide hormone stimulus  IEP 7207371adiponectinRGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp1  (matrix metallopeptidase 1)


Additional Information