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PKC-δ-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase
Abstract
Oxidative stress is thought to be one of the causative factors contributing to insulin resistance and type 2 diabetes. Previously, we showed that reactive oxygen species (ROS) production is significantly increased in adipocytes from high-fat diet-induced obese and insulin-resistant mice (HF). ROS production was also associated with the increased activity of PKC-δ. In the present studies, we hypothesized that PKC-δ contributes to ROS generation and determined their intracellular source. NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) reduced ROS levels by 50% in HF adipocytes, and inhibitors of NO synthase (l-NAME, 1 mM), xanthine oxidase (allopurinol, 100 μM), AGE formation (aminoguanidine, 10 μM), or the mitochondrial uncoupler (FCCP, 10 μM) had no effect. Rottlerin, a selective PKC-δ inhibitor, suppressed ROS levels by ∼50%. However, neither GÖ-6976 nor LY-333531, effective inhibitors toward conventional PKC or PKC-β, respectively, significantly altered ROS levels in HF adipocytes. Subsequently, adenoviral-mediated expression of wild-type PKC-δ or its dominant negative mutant (DN-PKC-δ) in HF adipocytes resulted in either a twofold increase in ROS levels or their suppression by 20%, respectively. In addition, both ROS levels and PKC-δ activity were sharply reduced by glucose depletion. Taken together, these results suggest that PKC-δ is responsible for elevated intracellular ROS production in HF adipocytes, and this is mediated by high glucose and NADPH oxidase.
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Metadata
- Authors
- Talior, I., Tennenbaum, T., Kuroki, T., & Eldar-Finkelman, H.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2005-02
- Volume
- 288
- Issue
- 2
- Pages
- E405-E411
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W1913740938
- Cited by
- 120
- References
- 51
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 4 · 2014: 9 · 2013: 4 · 2012: 5
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- PKCδ, oxidative stress, adipocytes, insulin resistance, obesity, NADPH oxidase, reactive oxygen species, high-fat diet, diphenyleneiodonium, glucose depletion, type 2 diabetes, adipose tissue
- MeSH terms
- Animals, Cells, Cultured, Dietary Fats, Dose-Response Relationship, Drug, Enzyme Activation, Insulin Resistance, Mice, Inbred C57BL, Obesity, Onium Compounds, Protein Kinase C, Reactive Oxygen Species, Adipocytes, Oxidative Stress, NADPH Oxidases, Mice, Protein Kinase C-delta
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