In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice.

Abstract

Consuming a high-fat diet (HFD) induces insulin resistance in white adipose tissue (WAT) within 1week. However, little is known about the initiating events. One potential mechanism that has remained largely unexplored is excessive mitochondrial emission of reactive oxygen species (ROS). To determine the role of mitochondrial ROS emissions at the onset of insulin resistance, wild-type (WT) mice were placed on an HFD for 1week. WAT insulin sensitivity and inflammation were assessed by western blot. In addition, we optimised/validated a method to determine ROS emissions in permeabilised WAT. An HFD for 1week resulted in impaired insulin signalling, increased c-Jun NH2-terminal kinase (JNK) phosphorylation and an increase in oxidative stress. These changes were associated with an increase in fatty-acid-mediated mitochondrial ROS emissions without any change in mitochondrial respiration/content. To determine that mitochondrial ROS causes insulin resistance, we used transgenic mice that express human catalase in mitochondria (MCAT) as a model of upregulated mitochondrial antioxidant enzyme capacity. MCAT mice displayed attenuated mitochondrial ROS emission, preserved insulin signalling and no inflammatory response following an HFD. Findings from this study suggest that elevated mitochondrial ROS emission contributes to HFD-induced WAT insulin resistance.