Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates
Open accessAbstract
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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Activation of JNK is positively related to high fat diet-induced insulin resistance and metabolic syndrome.
“In addition, activation of JNK was positively related to high fat diet-induced insulin resistance and metabolic syndrome [119], [121], [122], [123].”
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“In fact, acute exposure to many hepatotoxic agents including alcohol [110,111], APAP [112–116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”
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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
- Publisher
- National Academy of Sciences
- Published
- 2006-10-31
- Volume
- 103
- Issue
- 44
- Pages
- 16454-16459
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1637603
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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