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Alterations in the Expression and Cellular Localization of Protein Kinase C Isozymes ε and θ Are Associated With Insulin Resistance in Skeletal Muscle of the High-Fat–Fed Rat
Abstract
We have tested the hypothesis that changes in the levels and cellular location of protein kinase C (PKC) isozymes might be associated with the development of insulin resistance in skeletal muscles from the highfat–fed rat. Lipid measurements showed that triglyceride and diacylglycerol, an activator of PKC, were elevated four- and twofold, respectively. PKC activity assays indicated that the proportion of membraneassociated calcium-independent PKC was also increased. As determined by immunoblotting, total (particulate plus cytosolic) PKC α, ε, and ζ levels were not different between control and fat-fed rats. However, the ratio of particulate to cytosolic PKC ε in red muscles from fat-fed rats was increased nearly sixfold, suggesting chronic activation. In contrast, the amount of cytosolic PKC θ was downregulated to 45% of control, while the ratio of particulate to cytosolic levels increased, suggesting a combination of chronic activation and downregulation. Interestingly, while insulin infusion in glucose-clamped rats increased the proportion of PKC θ in the particulate fraction of red muscle, this was potentiated by fat-feeding, suggesting that the translocation is a consequence of altered lipid flux rather than a proximal event in insulin signaling. PKC ε and θ measurements from individual rats correlated with triglyceride content of red gastrocnemius muscle; they did not correlate with plasma glucose, which was not elevated in fat-fed rats, suggesting that they were not simply a consequence of hyperglycemia. Our results suggest that these specific alterations in PKC ε and PKC θ might contribute to the link between increased lipid availability and muscle insulin resistance previously described using high-fat–fed rats.
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“Increased activity of protein kinase C (PKC-β and δ has been reported in insulin resistant states and can be induced during lipid infusion [174, 175].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [174]
In the citing paper
“GLUT4, the insulin regulatable transporter, is found in skeletal muscle, has a Km of approximately 5 mmol/L, which is close to that of the plasma glucose concentration, and is associated with HK-II [173, 174].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [174]
In the citing paper
“In rodents, a high-fat diet increased the concentration of diacylglycerol in muscles and activated novel PKCs.36”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [36]
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Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
Cellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714
Carr, A., Samaras, K., Burton, S., Law, M. G., Freund, J., Chisholm, D. J., & Cooper, D. A. (1998) · AIDS · doi:10.1097/00002030-199807000-00003 · Cited by 2,364
Self-citationAdipocytes as regulators of energy balance and glucose homeostasis
Rosen, E. D., & Spiegelman, B. M. (2006) · Nature · doi:10.1038/nature05483 · Cited by 2,170
Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561
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Metadata
- Authors
- Schmitz-Peiffer, C., Browne, C. L., Oakes, N. D., Watkinson, A., Chisholm, D. J., Kraegen, E. W., & Biden, T. J.
- Affiliations
- Garvan Institute of Medical Research Sydney, Australia
- Garvan Institute of Medical Research (AU)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1997-02-01
- Volume
- 46
- Issue
- 2
- Pages
- 169-178
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2146243104
- Cited by
- 314
- References
- 0
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 13 · 2014: 3 · 2013: 12 · 2012: 11
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- protein kinase C, protein kinase C epsilon, PKC theta, insulin resistance, skeletal muscle, high-fat diet, diacylglycerol, triglycerides, PKC translocation, red muscle, lipid availability, insulin signaling, gastrocnemius
- MeSH terms
- Animals, Cell Compartmentation, Cytosol, Dietary Fats, Insulin, Insulin Resistance, Isoenzymes, Membranes, Protein Kinase C, Rats, Wistar, Muscle, Skeletal, Rats
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