Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance
Abstract
The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-) mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms.
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Persistent activation of JNK and/or p38K is positively associated with various liver diseases such as steatohepatitis and I/R injury.
“Furthermore, persistent activation of JNK and/or p38K is positively associated with various liver diseases such as steatohepatitis and I/R injury [122], [123], [124], [125], suggesting the clinical importance of JNK and p38K in human disease states, as reviewed [126].”
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- Authors
- Tuncman, G., Hirosumi, J., Solinas, G., Chang, L., Karin, M., & Hotamisligil, G. S.
- Affiliations
- Harvard University (US)
- University of California San Diego (US)
- *Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115; and
- Corresponding author
- Karin, Michael
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-07-11
- Volume
- 103
- Issue
- 28
- Pages
- 10741-10746
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2003578093
- Cited by
- 350
- References
- 32
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 11 · 2021: 17 · 2020: 17 · 2019: 10 · 2018: 8 · 2017: 16 · 2016: 15 · 2015: 18 · 2014: 16 · 2013: 29 · 2012: 33
- FWCI
- 18.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Iacocca Family Foundation
- National Institutes of Health (ES04151)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK52539, R01DK052539, P30DK040561)
- National Institute of Environmental Health Sciences (ES-04151, R37ES004151)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- JNK1, JNK2, c-Jun N-terminal kinase, obesity, insulin resistance, body weight, glucose metabolism, inflammation, metabolic regulation
- MeSH terms
- Animals, Cell Line, Genetic Markers, Glucose, Humans, Insulin Resistance, Isoenzymes, Male, Obesity, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Lipid Metabolism, Mice
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