Cited by 284Pancreatic function and diabetesAdipokines, Inflammation, and Metabolic DiseasesMetabolism, Diabetes, and Cancer

Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates

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Solinas, Giovanni, Naugler, Willscott, Galimi, Francesco, Lee, Myung-Shik, Karin, Michael·2006·Proceedings of the National Academy of Sciences

Abstract

JNKs are attractive targets for treatment of obesity and type-2 diabetes. A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic beta-cells. In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. This mechanism may account for the induction of central insulin resistance by free fatty acids.

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Crossref · 10.1073/pnas.0607626103

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Authors
Solinas, G., Naugler, W., Galimi, F., Lee, M.-S., & Karin, M.
Affiliations
  • University of California San Diego (US)
  • University of Sassari (IT)
  • Samsung Medical Center (KR)
Venue
Proceedings of the National Academy of Sciences
Published
2006-10-31
Volume
103
Issue
44
Pages
16454-16459
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2073959976
Cited by
284
References
43
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 13 · 2021: 6 · 2020: 13 · 2019: 8 · 2018: 13 · 2017: 7 · 2016: 18 · 2015: 23 · 2014: 22 · 2013: 19 · 2012: 18
FWCI
19.66
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UnissResearch (Università degli Studi di Sassari) (submittedVersion, other-oa)
Funders
  • National Science Foundation
  • American Diabetes Association
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007202)
  • National Institute of Environmental Health Sciences (ES 06376, R01ES006376)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
saturated fatty acids, palmitic acid, JNK, insulin gene transcription, IRS-1, insulin receptor substrate 2, insulin resistance, insulin signaling, pancreatic beta cells, hepatocytes, obesity, type 2 diabetes, free fatty acids
MeSH terms
Amino Acid Sequence, Animals, Blood Glucose, Cells, Cultured, Enzyme Activation, Fatty Acids, Gene Expression Regulation, Humans, Insulin, Insulin Resistance, Male, Obesity, Phosphoproteins, Phosphorylation, Substrate Specificity, Transcription, Genetic, Palmitic Acid, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 8, Mice, Rats, Insulin Receptor Substrate Proteins

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