Cited by 1,062Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismPeroxisome Proliferator-Activated Receptors

Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects

Open access
Rotter, Victoria, Nagaev, Ivan, Smith, Ulf·2003·Journal of Biological Chemistry

Abstract

Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. We here show that human subcutaneous adipose cells, like 3T3-L1 cells, are target cells for IL-6. To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance.

Integrity signals

Registry

Crossref · 10.1074/jbc.m301977200

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • IL-6 concentrations increased by hypoxia are inferior to those described to inhibit insulin signaling in adipocytes (2 vs. 20 ng/ml).

    “Analysis of conditioned media revealed that IL-6 protein secretion was increased by hypoxia but at concentrations inferior to that described to inhibit the insulin signaling pathway in adipocytes (2 vs. 20 ng/ml) (31).”

    From Hypoxia decreases insulin signaling pathways in adipocytes. (2009) · cites this paper as [31]

  • IL-6, IFN-γ, and CCL2 inhibit insulin signaling in adipocytes.

    “Other factors produced by inflammatory cells have since been shown to inhibit insulin signaling in the adipocyte including IL-6, IFN-γ and CCL2 (72,73).”
  • In vitro studies demonstrate that IL-6 can induce insulin resistance in isolated 3T3-L1 adipocytes and in mice.

    “In vitro studies demonstrate that IL-6 can induce insulin resistance in isolated 3T3-L1 adipocytes [51, 52] and in mice [53].”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Rotter, V., Nagaev, I., & Smith, U.
Affiliations
University of Gothenburg (SE)
Corresponding author
Smith, Ulf
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2003-11
Volume
278
Issue
46
Pages
45777-45784
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2148378054
Cited by
1,062
References
51
Citations by year
2026: 24 · 2025: 27 · 2024: 19 · 2023: 41 · 2022: 43 · 2021: 44 · 2020: 49 · 2019: 37 · 2018: 42 · 2017: 47 · 2016: 54 · 2015: 51 · 2014: 53 · 2013: 67 · 2012: 62
FWCI
24.61
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
interleukin-6, insulin resistance, adipocytes, 3T3-L1 adipocytes, TNF-α, IRS-1, JNK activation, GLUT4, PPARγ, insulin signaling, glucose transport, adipose tissue, cytokines, insulin receptor tyrosine phosphorylation
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Adipose Tissue, Adult, Animals, Biological Transport, Dose-Response Relationship, Drug, Glucose, Humans, Insulin Resistance, Middle Aged, Monosaccharide Transport Proteins, Muscle Proteins, Phosphoproteins, Phosphorylation, Proteins, Repressor Proteins, RNA, RNA, Messenger, Time Factors, Transcription Factors, Transcription, Genetic, Tumor Necrosis Factor-alpha, Tyrosine, Blotting, Northern, Interleukin-6, Up-Regulation, Cytokines, Interleukin-8, Adipocytes, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinase Kinases, 3T3-L1 Cells, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Suppressor of Cytokine Signaling Proteins, Glucose Transporter Type 4, Mice, Insulin Receptor Substrate Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review