Regulation of Interleukin-6-induced Hepatic Insulin Resistance by Mammalian Target of Rapamycin through the STAT3-SOCS3 Pathway
Open accessAbstract
The proinflammatory cytokine interleukin (IL)-6 has been proposed to be one of the mediators that link obesity-derived chronic inflammation with insulin resistance. Signaling through the mammalian target of rapamycin (mTOR) has been found to impact insulin sensitivity under various pathological conditions, through serine phosphorylation and inhibition of insulin receptor substrate by the downstream effector of mTOR, ribosomal S6 kinase 1 (S6K1). However, an involvement of mTOR in IL-6-induced insulin resistance has not yet been reported. Here we show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes. IL-6 activates S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1. Interestingly, we find that the phosphorylation of STAT3 on Ser(727) and STAT3 transcriptional activity are regulated by mTOR upon IL-6 stimulation and that STAT3 is required for IL-6 inhibition of insulin signaling. Furthermore, IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6. Taken together, we propose that mTOR plays a key role in IL-6-induced hepatic insulin resistance by regulating STAT3 activation and subsequent SOCS3 expression.
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IL-6 promotes hepatic insulin resistance through IL-6/STAT3-induced inhibition of insulin receptor signaling.
“consistent with previous studies that indicate IL-6 promotes hepatic insulin resistance through IL-6/STAT3induced inhibition of insulin receptor signaling 18,45,46”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [46]
Il6, Spp1, and Igfbp1 are involved in hepatic insulin resistance.
“genes reported to be involved in hepatic insulin resistance, including Il6 45-48 , Spp1 49,50 and Igfbp1 51”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [46]
Mice raised under germ-free conditions fail to develop experimental colitis, suggesting an important modulating role of intestinal microbiota on local inflammatory processes.
“Mice raised under germ-free conditions fail to develop experimental colitis, suggesting an important modulating role of intestinal microbiota on local inflammatory processes (826) .”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [826]
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- Authors
- Kim, J.-H., Kim, J. E., Liu, H.-Y., Cao, W., & Chen, J.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- The Hamner Institutes for Health Sciences (US)
- Corresponding author
- Chen, Jie
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 283
- Issue
- 2
- Pages
- 708-715
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1989472173
- Cited by
- 154
- References
- 53
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 9 · 2016: 5 · 2015: 8 · 2014: 14 · 2013: 12 · 2012: 12
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076039, R01DK76039)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR48914, R01AR048914)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- interleukin-6, hepatic insulin resistance, mTOR signaling, STAT3, SOCS3, S6K1, rapamycin, insulin signaling, glycogen synthesis, obesity-associated inflammation, hepatocytes
- MeSH terms
- Carcinoma, Hepatocellular, Homeostasis, Humans, Insulin, Insulin Resistance, Liver Neoplasms, Luciferases, Protein Kinases, Recombinant Proteins, Signal Transduction, Interleukin-6, Lentivirus, Genes, Reporter, DNA Primers, Ribosomal Protein S6 Kinases, Sirolimus, RNA Interference, Cell Line, Tumor, TOR Serine-Threonine Kinases
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