Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes*

By Joseph J. Senn, P. Klover, I. Nowak, T. Zimmers, L. Koniaris, R. Furlanetto, R. Mooney. Journal of Biological Chemistry, 2003

660 citations recorded by the source corpus.

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes51, 3391–3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60–90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.

Subfields: Immunology, Oncology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/5de1b9c9a97c45c0cb6b0d61414c41f11d5b7348

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In Immunology

1. M. Febbraio
2. B. K. Pedersen
3. H. Fang
4. R. L. Judd

In Oncology

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1. K. Walsh
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Citations in the corpus

• Adipose tissue as an endocrine organ. (2010, background): “In adipocytes nd hepatocytes IL-6 has been demonstrated to inhibit the insulin ignaling pathway by up-regulating SOCS3 expression, which in urn is known to impair insulin-induced insulin receptor and IRS- phosphorylation (Senn et al., 2002, 2003; Rotter et al., 2003). owever, studies demonstrating t”
• Adipokines in inflammation and metabolic disease (2011, background): “IL-6 has been shown to suppress insulin-stimulated metabolic actions in hepatocytes through a mechanism that is mediated by the induction of SOCS3 expressio”
• Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis (2010, background): “The liver might be a key target organ for adipose tissue–derived IL-6 and TNFa, because continuous IL-6/TNFa exposure affects hepatic insulin resistance, e.g., via up-regulation of SOCS3.”
• Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase (2006, background): “IL-6 has been shown to activate SOCS proteins in liver (41), and hepatic overexpression of SOCS1 and -3 in mice leads to liver insulin resistance (42).”
• Mitochondrial dynamics in mammalian health and disease. (2009, background): “Interleukin-6 is produced by several cell types including macrophages, adipose cells, and skeletal muscle, and circulating levels are increased in type 2 diabetes (237, 242), thereby interfering with insulin signaling in muscle and hepatic cells (171, 250) and causing hepatic and muscle insulin resi”
• Muscles and their myokines (2011, background): “The IL-6-induced insulin resistance appears to be due to an increase in suppressor of cytokine signalling 3 (SOCS3) expression (Senn et al., 2003), as SOCS-3 may directly inhibit the insulin receptor (Ueki et al.”
• Adipose Tissue in Obesity-Related Inflammation and Insulin Resistance: Cells, Cytokines, and Chemokines (2013, positive): “In adipose tissue and liver, however, IL-6 will exert proinflammatory activities, increasing insulin resistance by upregulating SOCS3 (suppressor of cytokine signaling 3) which, in turn, impairs insulin-induced insulin receptor and IRS1 phosphorylation [36].”
• Visfatin, an Adipocytokine with Proinflammatory and Immunomodulating Properties1 (2007, background): “IL-6 has been demonstrated to promote insulin resistance via induction of suppressor of cytokine signaling proteins (57).”
• Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies (2015, background): “IL-6 causes hepatic insulin resistance by the inhibition of IRS phosphorylation mediated by activating the SOCS-3 protein.(271,330) Adipokines and renal dysfunction.”