Requirement of JIP1-mediated c-Jun N-terminal kinase activation for obesity-induced insulin resistance
Open accessAbstract
The c-Jun NH(2)-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr(103) replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat diet. The loss of JIP1-mediated JNK activation protected the mutant mice against obesity-induced insulin resistance. We conclude that JIP1-mediated JNK activation plays a critical role in metabolic stress regulation of the JNK signaling pathway.
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More physiological studies show that JIP1 is required for JNK activation and is inhibitory only when overexpressed.
“However, it is now clear from more physiologically relevant studies that JIP1 is required for activation of JNK (Jaeschke et al., 2004; Morel et al., 2010; Whitmarsh et al., 2001), and is only inhibitory when overexpressed.”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Morel et al., 2010
JIP1 is a cytoplasmic scaffold that interacts with JNK-activating kinases and is needed for JNK activity in several settings, including obesity-induced insulin resistance.
“JIP1 is a cytoplasmic scaffold protein that interacts with the upstream activating kinases for JNK, and is required for activity in a number of different contexts, including regulation of obesity-induced insulin resistance (Jaeschke et al., 2004; Morel et al., 2010; Weston and Davis, 2007; Whitmarsh et al., 2001).”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Morel et al., 2010
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References 45 · Cited by 30
- Authors
- Morel, C., Standen, C. L., Jung, D. Y., Gray, S., Ong, H., Flavell, R. A., Kim, J. K., & Davis, R. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Program in Molecular Medicine
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Davis, Roger J.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-10-01
- Volume
- 30
- Issue
- 19
- Pages
- 4616-4625
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2950523
- OpenAlex
- W2035246535
- Cited by
- 30
- References
- 45
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 1 · 2014: 1 · 2012: 2
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Diabetes Association
- National Institutes of Health (DK032520)
- National Cancer Institute (CA-65861, R01CA065861)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK80756, R01DK080742, R01DK080756, DK032520, DK080742, P30DK032520)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- JIP1, c-Jun N-terminal kinase, JNK activation, insulin resistance, obesity, high-fat diet, scaffold proteins, metabolic stress, MAPK signaling
- MeSH terms
- Animals, Blood Glucose, Dietary Fats, Energy Metabolism, Enzyme Activation, Fatty Liver, Female, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Obesity, Immunoblotting, Signal Transduction, Cytokines, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, JNK Mitogen-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Mice, Adipokines
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