Cited by 92Cytokine Signaling Pathways and InteractionsMetabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic Diseases

Signal transducer and activator of transcription 3 (STAT3) mediates amino acid inhibition of insulin signaling through serine 727 phosphorylation

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Kim, Jeong-Ho, Yoon, Mee-Sup, Chen, Jie·2009·Journal of Biological Chemistry

Abstract

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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  1. Tremblay, F., Bru ˆle ´, S., Um, S. H., Li, Y., Masuda, K., Roden, M., Sun, X. J., Krebs, M., Polakiewicz, R. D., Thomas, G., and Marette, A. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 14056 -14061

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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)
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
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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