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
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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.
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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).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [72]
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].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [51]
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- Authors
- Rotter, V., Nagaev, I., & Smith, U.
- Affiliations
- University of Gothenburg (SE)
- Corresponding author
- Smith, Ulf
- ORCID
- 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
- hybrid
- doi.org
- Licence
- 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
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