Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes
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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) Diabetes 51, 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.
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Interleukin-6 causes hepatic and muscle insulin resistance in humans and in mice.
“and causes hepatic and muscle insulin resistance in humans and in mice (39,55-60).”
From Expression of <i>Mfn2</i>, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [58]
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Physiological and pathophysiological actions of insulin in the liver
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- Authors
- Senn, J. J., Klover, P. J., Nowak, I. A., Zimmers, T. A., Koniaris, L. G., Furlanetto, R. W., & Mooney, R. A.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Mooney, Robert A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 278
- Issue
- 16
- Pages
- 13740-13746
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2080999576
- Cited by
- 620
- References
- 54
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 7 · 2023: 22 · 2022: 15 · 2021: 19 · 2020: 15 · 2019: 19 · 2018: 20 · 2017: 29 · 2016: 24 · 2015: 20 · 2014: 38 · 2013: 48 · 2012: 36
- FWCI
- 14.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (R01-38138)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- SOCS3, interleukin-6, insulin resistance, insulin receptor signaling, hepatocytes, IRS-1 tyrosine phosphorylation, insulin receptor autophosphorylation, PI3K/Akt signaling, suppressor of cytokine signaling, hepatic insulin signaling, inflammation
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cell Line, Dose-Response Relationship, Drug, Humans, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Phosphorylation, Precipitin Tests, Protein Binding, Proteins, Proto-Oncogene Proteins, Receptor, Insulin, Repressor Proteins, RNA, Messenger, Time Factors, Transcription Factors, Transfection, Tumor Cells, Cultured, Blotting, Northern, Signal Transduction, Interleukin-6, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Hepatocytes, Suppressor of Cytokine Signaling Proteins, Proto-Oncogene Proteins c-akt, Mice
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