title: Adiponectin inhibits leptin signalling via multiple mechanisms to exert protective effects against hepatic fibrosis.
abstract: Adiponectin is protective against hepatic fibrosis, whereas leptin promotes fibrosis. In HSCs (hepatic stellate cells), leptin signals via a JAK2 (Janus kinase 2)/STAT3 (signal transducer and activator of transcription 3) pathway, producing effects that enhance ECM (extracellular matrix) deposition. SOCS-3 (suppressor of cytokine signalling-3) and PTP1B (protein tyrosine phosphatase 1B) are both negative regulators of JAK/STAT signalling, and recent studies have demonstrated a role for adiponectin in regulating SOCS-3 expression. In the present study we investigate mechanisms whereby adiponectin dampens leptin signalling and prevents excess ECM production. We treated culture-activated rat HSCs with recombinant adiponectin, leptin, both or neither, and also treated adiponectin knockout (Ad-/-) and wild-type mice with leptin and/or carbon tetrachloride (CCl4) or saline. We analyse JAK2 and Ob-Rb (long form of the leptin receptor) phosphorylation, and PTP1B expression and activity. We also explore potential mechanisms through which adiponectin regulates SOCS-3-Ob-Rb association. Adiponectin inhibits leptin-stimulated JAK2 activation and Ob-Rb phosphorylation in HSCs, whereas both were increased in Ad-/- mice. Adiponectin stimulates PTP1B expression and activity in vitro, whereas PTP1B expression was lower in Ad-/-mice than in wild-type mice. Adiponectin also promotes SOCS-3-Ob-R association and blocks leptin-stimulated formation of extracellular TIMP-1 (tissue inhibitor of metalloproteinases-1)-MMP-1 (matrix metalloproteinase-1) complexes in vitro. These results suggest two novel mechanisms whereby adiponectin inhibits hepatic fibrosis: (i) by promoting binding of SOCS-3 to Ob-Rb, and (ii) by stimulating PTP1B expression and activity, thus inhibiting JAK2/STAT3 signalling at multiple points.
authors.affiliation: Division of Digestive Diseases, Emory University Department of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Handy
authors.forename: Ping P
authors.initials: PP
authors.lastname: Fu
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Mells
authors.forename: Shvetank
authors.initials: S
authors.lastname: Sharma
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D019610:Cytoprotection; D055786:Gene Knockout Techniques; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D020738:Leptin; D054411:Receptors, Leptin; D011994:Recombinant Proteins; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D002251:Carbon Tetrachloride; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat; D020781:Matrix Metalloproteinase 1