Recent studies have emphasized the association of adipose oxidative stress (Fat ROS) with the pathogenesis of metabolic disorders in obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivoremain unclear because no mouse model has been available in which oxidative stress is manipulated targeting adipocytes.
In this research, we generated two models of Fat ROS-manipulated mice and evaluated the metabolic features in diet-induced obesity. Fat ROS-eliminated mice in which Cat and Sod1 were overexpressed in adipocytes exhibited adipose expansion with decreased ectopic lipid accumulation and improved insulin sensitivity.
Conversely, Fat ROS-augmented mice, in which glutathione was depleted specifically in adipocytes, exhibited restricted adipose expansion associated with increased ectopic lipid accumulation and deteriorated insulin sensitivity. In the white adipose tissues of these mice, macrophage polarization, tissue fibrosis and de novo lipogenesis were significantly changed. In vitro approaches identified KDM1A-mediated attenuation of SREBF1 transcriptional activities as the underlying mechanism for the suppression of de novo lipogenesis by oxidative stress.
Thus, our study uncovered the novel roles of Fat ROS in healthy adipose expansion, ectopic lipid accumulation and insulin resistance, providing the possibility for the adipocyte-targeting antioxidant therapy.