TY - JOUR
T1 - p66Shc-generated oxidative signal promotes fat accumulation
AU - Berniakovich, Ina
AU - Trinei, Mirella
AU - Stendardo, Massimo
AU - Migliaccio, Enrica
AU - Minucci, Saverio
AU - Bernardi, Paolo
AU - Pelicci, Pier Giuseppe
AU - Giorgio, Marco
PY - 2008/12/5
Y1 - 2008/12/5
N2 - 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 p66Shc-null mice. p66Shc is a redox enzyme that generates mitochondrial ROS and promotes aging in mammals. We report that insulin activates the redox enzyme activity of p66Shc specifically in adipocytes and that p66Shc-generated ROS regulate insulin signaling through multiple mechanisms, including AKT phosphorylation, Foxo localization, and regulation of selected insulin target genes. Deletion of p66Shc 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 p66Shc-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.
AB - 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 p66Shc-null mice. p66Shc is a redox enzyme that generates mitochondrial ROS and promotes aging in mammals. We report that insulin activates the redox enzyme activity of p66Shc specifically in adipocytes and that p66Shc-generated ROS regulate insulin signaling through multiple mechanisms, including AKT phosphorylation, Foxo localization, and regulation of selected insulin target genes. Deletion of p66Shc 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 p66Shc-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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U2 - 10.1074/jbc.M804362200
DO - 10.1074/jbc.M804362200
M3 - Article
C2 - 18838380
AN - SCOPUS:57749091893
VL - 283
SP - 34283
EP - 34293
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 49
ER -