Low Aerobic Capacity and High-Fat Diet Contribute to Oxidative Stress and IRS-1 Degradation in the Kidney

Abstract

Background/Aims: Insulin receptor (IR-α and IR-β) is reduced in the kidney of insulin-resistant rodents. It is unknown if there are also reductions in insulin receptor substrate (IRS)-1 or if these effects are due to metabolic injury. Thereby, we hypothesized intrinsically high aerobic fitness would protect against high-fat diet (HFD)-induced reactive oxygen species (ROS) and IRS-1 degradation. Methods: We investigated the effects of HFD on triglyceride content, ROS production and IRS-1 degradation in the kidney of high-capacity (HCR)/low-capacity (LCR) rats, a model of intrinsic high and low aerobic capacity. Eighteen-week-old HCR and LCR rats were placed on a HFD or normal chow diet for 7 weeks. Intraperitoneal glucose tolerance, ROS, IR-β, total IRS-1 and ubiquitination were measured. Results: The HCR displayed greater insulin sensitivity and were resistant to HFD-induced insulin resistance. In the LCR kidney, HFD increased ROS potential, and reduced total IR-β and IRS-1 without altering triacylglycerol content. IRS-1 ubiquitination was higher in the LCR than HCR kidney, increased after HFD. Conclusions: Our data support that HFD-mediated kidney ROS is associated with reductions in IRS-1 and systemic insulin resistance. Further, high intrinsic aerobic capacity protects against IRS-1 degradation in the kidney following exposure to HFD.