To establish the Fat ROS–eliminated mice, we generated aP2- Cat/ SOD1 double-transgenic mice (aP2-dTg), which expressed rat Cat and human SOD1 under control of the aP2 promoter. However, the causal role of Fat ROS in obesity in vivo still remains unclear because no mouse model has been available in which oxidative stress targeting adipocytes is manipulated. Systemic or skeletal muscle-specific manipulation of oxidative stress in vivo, including administration of apocynin ( 8) or manganese–5,10,15,20-tetrakis (4-benzoic acid) porphyrin (MnTBAP) ( 19), overexpression of Sod ( 19, 20) or Cat ( 21, 22), and glutathione depletion ( 23– 25), showed various effects on insulin sensitivity. Many studies have suggested that Fat ROS are involved in various pathways in metabolic syndrome, including adipocyte insulin signaling ( 12), adipose inflammation ( 8), endoplasmic reticulum stress ( 13), mitochondrial function ( 14), cellular senescence ( 15), gut microbiota ( 16), adiponectin ( Adipoq) ( 8), adiponectin receptor ( AdipoR) ( 17), and angiotensin II signaling ( 18). We reported that the presence of high levels of pro-oxidants, such as NADPH oxidases, and low levels of antioxidant enzymes, such as Cat and Sod, in obese WAT resulted in high oxidative stress, conceptualized as adipose oxidative stress (Fat reactive oxygen species ), in mice ( 8) and humans ( 9– 11). 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. In vitro approaches identified KDM1A-mediated attenuation of sterol-regulatory element-binding transcription factor 1 (SREBF1) transcriptional activities as the underlying mechanism for the suppression of de novo lipogenesis by oxidative stress. In the white adipose tissues of these mice, macrophage polarization, tissue fibrosis, and de novo lipogenesis were significantly changed. 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. 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.
In this research, we generated two models of Fat ROS–manipulated mice and evaluated the metabolic features in diet-induced obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivo remain unclear because no mouse model has been available in which oxidative stress is manipulated by targeting adipocytes. Recent studies have emphasized the association of adipose oxidative stress (Fat reactive oxygen species ) with the pathogenesis of metabolic disorders in obesity.
0 kommentar(er)
