Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms

Ueki, Kohjiro; Kondo, Tatsuya; Kahn, C. Ronald

doi:10.1128/mcb.24.12.5434-5446.2004

Cited by 686Adipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and InteractionsMetabolism, Diabetes, and Cancer

Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms

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Ueki, Kohjiro, Kondo, Tatsuya, Kahn, C. Ronald·2004·Molecular and Cellular Biology

DOI 10.1128/mcb.24.12.5434-5446.2004PMC PMC419873

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Abstract

Insulin resistance is a pathophysiological component of type 2 diabetes and obesity and also occurs in states of stress, infection, and inflammation associated with an upregulation of cytokines. Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. In concordance with these increases by LPS, tyrosine phosphorylation of the insulin receptor (IR) is partially impaired and phosphorylation of the insulin receptor substrate (IRS) proteins is almost completely suppressed. Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling.

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Increased concentrations of TNF-a, IL-6, IL-1b, IL-8, resistin and other macrophage-derived factors could contribute to deterioration of insulin sensitivity.
“The increase in the concentrations of TNF-a, IL-6, IL-1b, IL-8, resistin and many other factors produced by macrophage activation could contribute to the deterioration of insulin sensitivity (Fig. 6) (106) .”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [106]

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Authors: Ueki, K., Kondo, T., & Kahn, C. R.
Affiliations: Joslin Diabetes Center (US)
Corresponding author: Kahn, C. Ronald
ORCID: Ueki, Kohjiro
Kondo, Tatsuya
Kahn, C. Ronald
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2004-06
Volume: 24
Issue: 12
Pages: 5434-5446
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.24.12.5434-5446.2004
PMC: PMC419873
OpenAlex: W2126393987
Cited by: 686
References: 59
Citations by year: 2026: 11 · 2025: 15 · 2024: 18 · 2023: 20 · 2022: 20 · 2021: 26 · 2020: 16 · 2019: 17 · 2018: 23 · 2017: 28 · 2016: 37 · 2015: 41 · 2014: 43 · 2013: 44 · 2012: 55
FWCI: 28.62
Type: journal article
Language: en
Update notices: correction (2005-10-01)
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Massachusetts General Hospital
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055545, DK 33201, DK34834, R01DK033201, DK55545)
Topics: Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: SOCS1, SOCS3, insulin resistance, insulin receptor substrate, IRS-1, insulin receptor substrate 2, insulin receptor tyrosine phosphorylation, insulin signaling, lipopolysaccharide, endotoxemia, obesity, type 2 diabetes, TNF-α, glycogen synthesis, glucose uptake, cytokine signaling
MeSH terms: Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, Animals, Base Sequence, Carrier Proteins, Cells, Cultured, Female, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Models, Biological, Phosphoproteins, Phosphorylation, Repressor Proteins, Transcription Factors, Tyrosine, Up-Regulation, Gene Expression, DNA, Complementary, Endotoxemia, Intracellular Signaling Peptides and Proteins, Suppressor of Cytokine Signaling Proteins, Mice, Insulin Receptor Substrate Proteins

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Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms

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