p66Shc-generated Oxidative Signal Promotes Fat Accumulation
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Reactive oxygen species (ROS) and insulin signaling in the adipose tissue are critical determinants of aging and age-associated diseases. It is not clear, however, if they represent independent factors or they are mechanistically linked. We investigated the effects of ROS on insulin signaling using as model system the p66(Shc)-null mice. p66(Shc) is a redox enzyme that generates mitochondrial ROS and promotes aging in mammals. We report that insulin activates the redox enzyme activity of p66(Shc) specifically in adipocytes and that p66(Shc)-generated ROS regulate insulin signaling through multiple mechanisms, including AKT phosphorylation, Foxo localization, and regulation of selected insulin target genes. Deletion of p66(Shc) resulted in increased mitochondrial uncoupling and reduced triglyceride accumulation in adipocytes and in vivo increased metabolic rate and decreased fat mass and resistance to diet-induced obesity. In addition, p66(Shc-/-) mice showed impaired thermo-insulation. These findings demonstrate that p66(Shc)-generated ROS regulate the effect of insulin on the energetic metabolism in mice and suggest that intracellular oxidative stress might accelerate aging by favoring fat deposition and fat-related disorders.
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p66Shc activation is involved in adipogenesis, insulin resistance, and cardiovascular complications associated with diabetes mellitus.
“Additional work has revealed that p66Shc activation is involved in adipogenesis, insulin resistance and cardiovascular complications associated with diabetes mellitus187–189.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [188]
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- Authors
- Berniakovich, I., Trinei, M., Stendardo, M., Migliaccio, E., Minucci, S., Bernardi, P., Pelicci, P. G., & Giorgio, M.
- Affiliations
- IFOM (IT)
- European Institute of Oncology (IT)
- University of Padua (IT)
- University of Milan (IT)
- Corresponding author
- Giorgio, Marco
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 283
- Issue
- 49
- Pages
- 34283-34293
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2590696
- OpenAlex
- W2120992354
- Cited by
- 161
- References
- 41
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 9 · 2020: 9 · 2019: 5 · 2018: 12 · 2017: 12 · 2016: 14 · 2015: 11 · 2014: 11 · 2013: 16 · 2012: 9
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Institute on Aging (P01AG025532)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- p66Shc, reactive oxygen species, insulin signaling, adipocytes, fat deposition, mitochondrial uncoupling, triglyceride accumulation, Akt phosphorylation, FOXO, diet-induced obesity, fat mass, metabolic rate, thermogenesis, aging, oxidative stress
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Adipose Tissue, Animals, Insulin, Mice, Inbred C57BL, Mice, Transgenic, Obesity, Oxidation-Reduction, Oxygen, Phosphorylation, Signal Transduction, Reactive Oxygen Species, Adipocytes, Oxidative Stress, Mice, Shc Signaling Adaptor Proteins
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