Cited by 620Cytokine Signaling Pathways and InteractionsAdipokines, Inflammation, and Metabolic DiseasesGrowth Hormone and Insulin-like Growth Factors

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

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Senn, Joseph J., Klover, Peter J., Nowak, Irena A., Zimmers, Teresa A., Koniaris, Leonidas G., Furlanetto, Richard W., Mooney, Robert A.·2003·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m210689200

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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
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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