Oxidative stress resulting from the removal of endogenous catalase induces obesity by promoting hyperplasia and hypertrophy of white adipocytes

Obesity is regarded as an abnormal expansion and excessive accumulation of fat mass in white adipose tissue. The involvement of oxidative stress in the development of obesity is still unclear. Although mainly present in peroxisomes, catalase scavenges intracellular H(2)O(2) at toxic levels. Therefore, we used catalase-knockout (CKO) mice to elucidate the involvement of excessive H(2)O(2) in the development of obesity. CKO mice with C57BL/6J background gained more weight with higher body fat mass with age than age-matched wild-type (WT) mice fed with either chow or high-fat diets. This phenomenon was attenuated by concomitant treatment with the antioxidants, melatonin or N-acetyl cysteine. Moreover, CKO mouse embryonic fibroblasts (MEFs) appeared to differentiate to adipocytes more easily than WT MEFs, showing increased H(2)O(2) concentrations. Using 3T3-L1-derived adipocytes transfected with catalase-small interfering RNA, we confirmed that a more prominent lipogenesis occurred in catalase-deficient cells than in WT cells. Catalase-deficient adipocytes presented increased nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression but decreased adenosine monophosphate-activated protein kinase (AMPK) expression. Treatment with a NOX4 inhibitor or AMPK activator rescued the propensity for obesity of CKO mice. These findings suggest that excessive H(2)O(2) and related oxidative stress increase body fat mass via both adipogenesis and lipogenesis. Manipulating NOX4 and AMPK in white adipocytes may be a therapeutic tool against obesity augmented by oxidative stress.