p66Shc-generated oxidative signal promotes fat accumulation

Area of Science:

• Cellular and Molecular Biology
• Metabolism and Endocrinology
• Aging Research

Background:

• Reactive oxygen species (ROS) and insulin signaling in adipose tissue are key factors in aging and related diseases.
• The mechanistic link between ROS and insulin signaling is not fully understood.

Purpose of the Study:

• To investigate the effects of ROS on insulin signaling using p66Shc-null mice as a model system.
• To determine if p66Shc-generated ROS mechanistically link insulin signaling and aging.

Main Methods:

• Utilized p66Shc-null mice, a model lacking the redox enzyme p66Shc which generates mitochondrial ROS.
• Examined insulin signaling pathways, including AKT phosphorylation and Foxo localization, in adipocytes.
• Assessed metabolic parameters such as mitochondrial uncoupling, triglyceride accumulation, metabolic rate, fat mass, and obesity resistance in vivo.

Main Results:

• Insulin activates p66Shc redox activity in adipocytes, with p66Shc-generated ROS regulating insulin signaling.
• p66Shc deletion led to increased mitochondrial uncoupling, reduced adipocyte triglyceride accumulation, and enhanced metabolic rate.
• p66Shc-/- mice exhibited decreased fat mass, resistance to diet-induced obesity, and impaired thermo-insulation.

Conclusions:

• p66Shc-generated ROS modulate insulin's effects on energy metabolism in mice.
• Intracellular oxidative stress, mediated by p66Shc, may accelerate aging by promoting fat deposition and related disorders.