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Experiments in rodents with trained exercise have shown that exercise improves vascular function and reduces vascular inflammation by modulating the balance between nitric oxide (NO) and oxidative stress. However, the upstream regulator of exercise-induced vascular benefits is unclear. We aimed to investigate the involvement of peroxisome proliferator\u2013activated receptor \u03b4 (PPAR\u03b4) in exercise-induced vascular functional improvement. We show that PPAR\u03b4 is a crucial mediator for exercise to exert a beneficial effect on the vascular endothelium in diabetic mice. In db\/db mice and high-fat diet\u2013induced obese mice, 4 weeks of treadmill exercise restored endothelium-dependent vasodilation of aortas and flow-mediated vasodilation in mesenteric resistance arteries, whereas genetic ablation of Ppard abolished such improvements. Exercise induces AMPK activation and subsequent PPAR\u03b4 activation, which help to reduce endoplasmic reticulum (ER) and oxidative stress, thus increasing NO bioavailability in endothelial cells and vascular tissues. Chemical chaperones 4-phenylbutyric acid and tauroursodeoxycholic acid decrease ER stress and protect against endothelial dysfunction in diabetic mice. The results demonstrate that PPAR\u03b4-mediated inhibition of ER stress contributes to the vascular benefits of exercise and provides potentially effective targets for treating diabetic vasculopathy.<\/jats:p>","DOI":"10.2337\/db15-1657","type":"journal-article","created":{"date-parts":[[2016,11,17]],"date-time":"2016-11-17T22:40:15Z","timestamp":1479422415000},"page":"519-528","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":85,"title":["PPAR\u03b4 Is Required for Exercise to Attenuate Endoplasmic Reticulum Stress and Endothelial Dysfunction in Diabetic Mice"],"prefix":"10.2337","volume":"66","author":[{"given":"Wai San","family":"Cheang","sequence":"first","affiliation":[{"name":"Institute of Vascular Medicine, Shenzhen Research Institute, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong"},{"name":"Institute of Chinese Medical Sciences, State Key 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