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

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.

Cytokine Production and Signaling in Stellate Cells

“…Exposure of HSCs to adiponectin activates adenosine monophosphate-activated protein kinase (AMPK), a negative modulator of different characteristics of myofibroblastic HSCs [156,157]. Additionally, adiponectin induces the expression of suppressor of cytokine signaling-3 and protein tyrosine phosphatase 1B, negative regulators of JAK/STAT, a pathway necessary for leptin's fibrogenic signaling [158]. Other mechanisms of the anti-fibrogenic actions of adiponectin include the disassembly of focal adhesion complexes, which may be relevant to resolution of fibrosis [159].…”

Modulation of Cell Death and Survival by Adipokines in the Liver

“…For example, adiponectin induces expression of suppressor of cytokine signaling-3 (SOCS-3) and protein tyrosine phosphatase 1B (PTP1B), which are negative regulators of JAK/STAT signaling. 36,37) This interaction results in the suppression of leptin-induced hepatic fibrosis. Similarly, in hepatic cancer cell lines and HepG2 xenograft model, adiponectin-induced SOCS3 activation suppresses leptin-induced oncogenic effects.…”

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

“…PPARγ ligands inhibit the TGF-β1-induced Erg1 signaling [145]. In mouse, adiponectin prevents fibrosis in liver [146,147]. PPARγ-induced tensin homologue PTEN [131] induces anti-fibrotic effects in lung fibrosis and SSc [129,148].…”