Adiponectin inhibits leptin signaling via multiple mechanisms to exert protective effects against hepatic fibrosis

• Authors: Jeffrey A. Handy, Emory University; Ping P. Fu, Emory University; Pradeep Kumar, Emory University; Jamie E. Mells, Emory University; Shvetank Sharma, Emory University; Neeraj K. Saxena, Emory University; Frank A Anania, Emory University
• Journal Title: Biochemical Journal
• Volume: Volume 440, Number 3
• Publisher: Portland Press | 2011-12-15, Pages 385-395
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1042/BJ20102148
• Subjects: Chemistry, Biochemistry
• Keywords: Fibrosis; Adiponectin; Leptin; SOCS-3; PTP1B; Jak2

Abstract

SYNOPSIS Adiponectin is protective against hepatic fibrosis, while leptin promotes fibrosis. In hepatic stellate cells (HSCs), leptin signals via a Janus Kinase 2/Signal Transducers and Activators of Transcription 3 (Jak2/Stat3) pathway, producing effects that enhance extracellular matrix deposition. Suppressors of Cytokine Signaling-3 (SOCS-3) and Protein Tyrosine Phosphatase-1B (PTP1B) are both negative regulators of Jak/Stat signaling, and recent studies demonstrated a role for adiponectin in regulating SOCS-3 expression. In this study we investigated mechanisms whereby adiponectin dampens leptin signaling 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 analyzed Jak2 and Ob-Rb phosphorylation, and PTP1B expression and activity. We also explored potential mechanisms through which adiponectin regulates SOCS-3/Ob-Rb association. Adiponectin inhibited leptin-stimulated Jak2 activation and Ob-Rb phosphorylation in HSCs, while both were increased in Ad−/− mice. Adiponectin stimulated PTP1B expression and activity, in vitro, while PTP1B expression was lower in Ad−/−mice than in wild-type mice. Adiponectin also promoted SOCS-3/Ob-R association, and blocked leptin-stimulated formation of extracellular TIMP-1/MMP-1 complexes, in vitro. These data suggest two novel mechanisms whereby adiponectin inhibits hepatic fibrosis: by promoting binding of SOCS-3 to Ob-Rb, and stimulating PTP1B expression and activity, thus inhibiting Jak2-Stat3 signaling at multiple points.