Impaired Peroxisomal Fitness in Obese Mice, a Vicious Cycle Exacerbating Adipocyte Dysfunction via Oxidative Stress.

Abstract

Aims: Peroxisome is a critical organelle for fatty acid oxidation (FAO) and metabolism of reactive oxygen species (ROS). Increased oxidative stress in adipose tissue contributes to the development of insulin resistance and metabolic syndrome in obesity. This study aimed to investigate the role of peroxisomal fitness in maintaining adipocyte function, which has been under-rated in the obesity research area. Results: Reduced peroxisomal gene expressions in white adipose tissue (WAT) of obese mice suggested a close correlation between peroxisomes and obesity. Peroxisomal biogenesis factor 5 siRNA increased cellular ROS and inflammatory mediators in 3T3-L1 adipocytes. On the contrary, hydrogen peroxide or tumor necrosis factor-α treatment significantly decreased biogenesis- and function-related peroxisomal proteins, suggesting a positive feedback loop of ROS/inflammation and peroxisomal dysfunction. Correspondingly, catalase (a major peroxisomal antioxidant)-knockout mice fed with high-fat diet (HFD) exhibited suppressed peroxisomal proteins along with increased oxidative stress and accelerated obesity. In response to fenofibrate (a peroxisomal proliferator) treatment, WAT of HFD-fed wild-type mice showed not only increases in peroxisomal biogenesis and FAO but also attenuated features of adipocyte dysfunction and obesity. However, these results were not observed in peroxisome proliferator-activated receptor-alpha null obese mice. Innovation: Impaired peroxisomal fitness enhanced oxidative stress and inflammation in adipocytes, which exacerbates obesity. Conclusion: Adipose tissue peroxisomal homeostasis plays an important role in attenuating the features of obesity, and it can be a potential therapeutic target of obesity.