OR18-5 Absence of the ROS Scavenger DJ-1 Paradoxically Protects Mice from Obesity and Insulin Resistance

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR18-Diabetes-Associated Genes & Pathways
Basic/Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 304 (Moscone Center)
Sally Yu Shi*1, Shun-Yan Lu2, Tharini Sivasubramaniyam1, Stephanie A. Schroer2, Tak W Mak3 and Minna Woo4
1University of Toronto, Toronto, ON, Canada, 2Toronto General Research Institute, Toronto, ON, Canada, 3Ontario Cancer Institute, Toronto, ON, Canada, 4University Health Network/University of Toronto, Toronto, ON, Canada
While excessive reactive oxygen species (ROS) have been implicated in the development of insulin resistance and type 2 diabetes, ROS generated at physiological levels are critical components of cellular signalling, emphasizing the importance of redox balance in energy homeostasis. DJ-1 is a ubiquitously expressed 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 a redox sensor. To investigate its role in glucose homeostasis and energy balance, we employed a mouse model of chronic metabolic stress by feeding mice with a high fat diet (HFD; 60% of calories from fat) for 3 months starting at 6-8 weeks of age. We utilized whole-body DJ-1 knockout (KO) mice generated by homologous recombination to examine the physiological role of DJ-1 in vivo. 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, deficiency of DJ-1 further raised HFD-induced accumulation of ROS in the skeletal muscle without causing overt oxidative stress. Biochemical analysis revealed enhanced activation of ROS-activated pathways including AMP-activated protein kinase (AMPK) and autophagy in the skeletal muscle of DJ-1 KO mice. In line with the implication of AMPK in cellular energy metabolism, DJ-1 KO mice exhibited increased energy expenditure and reduced adiposity. Accordingly, despite higher muscle ROS levels, DJ-1 KO mice, especially of the female gender, were remarkably protected from HFD-induced obesity, glucose intolerance and insulin resistance. Administration of the antioxidant N-acetyl-L-cysteine (NAC) at the end of the HFD feeding period abolished the beneficial findings including increased insulin sensitivity, AMPK activation and autophagy in DJ-1 KO mice, providing a causal mechanistic link between increased muscle ROS levels and the metabolically favorable phenotype observed in the setting of DJ-1 deficiency. Taken together, our work uncovers a novel and important role of the antioxidant protein DJ-1 in metabolism. Our results suggest that increased skeletal muscle ROS levels as a result of DJ-1 deficiency activate several cellular homeostatic mechanisms including AMPK and autophagy that together enhance energy expenditure and improve insulin sensitivity. Consequently, mice deficient in DJ-1 are protected from HFD-induced obesity and glucose intolerance. In summary, our study highlights the importance of redox balance in glucose and energy homeostasis and suggests fine-tuning of ROS levels as a potential therapeutic strategy for type 2 diabetes.

Nothing to Disclose: SYS, SYL, TS, SAS, TWM, MW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: CIHR operating grants MOP-201188 and MOP-191501; Canadian Diabetes Association (CDA) Grant-in-Aid; Canadian Liver Foundation Graduate Studentship; CDA Doctoral Student Research Award; Banting and Best Diabetes Centre