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Absence of the ROS Scavenger DJ-1 Paradoxically Protects Mice from Obesity and Insulin Resistance

      While excessive reactive oxygen species (ROS) have been implicated in the development of insulin resistance and type 2 diabetes, ROS generated at physiological levels play essential biological functions. DJ-1 is an evolutionarily conserved protein originally identified in the context of neuronal survival in Parkinson’s disease. It is thought to participate in the oxidative stress response by acting as a ROS scavenger or redox sensor. To investigate its role in metabolism, we employed a mouse model of chronic metabolic stress by feeding mice with a high-fat diet (HFD) for 3 months starting at 8 weeks of age. Of all the metabolic tissues examined, prolonged HFD feeding induced a 2-fold increase in DJ-1 expression in mouse skeletal muscle, particularly in females. This increase occurred in association with an expected elevation in muscle ROS levels. Consistent with its antioxidant role, whole-body DJ-1 deficiency further raised HFD-induced ROS accumulation in muscle, accompanied by enhanced activation of ROS-activated pathways including AMP-activated protein kinase (AMPK) and autophagy. In line with the implication of AMPK in cellular energy metabolism, DJ-1 knockout (KO) mice exhibited increased energy expenditure and reduced adiposity. Accordingly, DJ-1 KO mice, especially females, were protected from HFD-induced obesity, glucose intolerance and insulin resistance. This metabolically favourable phenotype was attributed to elevated muscle ROS and was abolished by the antioxidant N-acetyl-L-cysteine. Altogether, our study demonstrates a key role of DJ-1 in metabolism and identifies fine-tuning of ROS as a potential therapeutic strategy for type 2 diabetes.