Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation
Open accessAbstract
Nutrient overload is associated with the development of obesity, insulin resistance, and type II diabetes. High plasma concentrations of amino acids have been found to correlate with insulin resistance. At the cellular level, excess amino acids impair insulin signaling, the mechanisms of which are not fully understood. Here, we report that STAT3 plays a key role in amino acid dampening of insulin signaling in hepatic cells. Excess amino acids inhibited insulin-stimulated Akt phosphorylation and glycogen synthesis in mouse primary hepatocytes as well as in human hepatocarcinoma HepG2 cells. STAT3 knockdown protected insulin sensitivity from inhibition by amino acids. Amino acids stimulated the phosphorylation of STAT3 at Ser(727), but not Tyr(705). Replacement of the endogenous STAT3 with wild-type, but not S727A, recombinant STAT3 restored the ability of amino acids to inhibit insulin signaling, suggesting that Ser(727) phosphorylation was critical for STAT3-mediated amino acid effect. Furthermore, overexpression of STAT3-S727D was sufficient to inhibit insulin signaling in the absence of excess amino acids. Our results also indicated that mammalian target of rapamycin was likely responsible for the phosphorylation of STAT3 at Ser(727) in response to excess amino acids. Finally, we found that STAT3 activity and the expression of its target gene socs3, known to be involved in insulin resistance, were both stimulated by excess amino acids and inhibited by rapamycin. In conclusion, our study reveals STAT3 as a novel mediator of nutrient signals and identifies a Ser(727) phosphorylation-dependent and Tyr(705) phosphorylation-independent STAT3 activation mechanism in the modulation of insulin signaling.
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STAT3 plays a key role in amino acid-mediated dampening of insulin signaling in hepatic cells, primarily through a mTOR-mediated pS-STAT3 pathway that is independent of pY-STAT3.
“STAT3 also plays a key role in amino acid–mediated dampening of insulin signaling in hepatic cells, primarily through a mTOR-mediated pS-STAT3 pathway that is independent of pY-STAT3 (Kim et al., 2009).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Kim et al., 2009
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- Authors
- Kim, J.-H., Yoon, M.-S., & Chen, J.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Chen, Jie
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 284
- Issue
- 51
- Pages
- 35425-35432
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2790971
- OpenAlex
- W2161272864
- Cited by
- 92
- References
- 47
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 10 · 2015: 3 · 2014: 13 · 2013: 5 · 2012: 6
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R56AR048914, AR 48914, R01AR048914)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- STAT3, amino acids, insulin signaling, insulin resistance, mTOR, hepatic insulin sensitivity, glycogen synthesis, Akt phosphorylation, SOCS3, nutrient overload, type 2 diabetes
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Amino Acids, Animals, Diabetes Mellitus, Type 2, Gene Expression Regulation, Humans, Insulin, Insulin Resistance, Phosphorylation, Signal Transduction, Amino Acid Substitution, Mutation, Missense, Hepatocytes, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Gene Knockdown Techniques, Hep G2 Cells
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