['To determine the physiologic importance of endocannabinoids and mitochondrial function in the long-term outcome using a rat model of Roux-en-Y gastric bypass (RYGB) surgery.', 'Sixteen million people are morbidly obese and RYGB surgery is the most effective treatment. Endocannabinoids are implicated in appetite stimulation and regulation of peripheral energy metabolism. We hypothesize that down-regulation of endocannabinoids and alterations in mitochondrial function and hormones favoring catabolism contribute to sustained RYGB-induced weight loss.', 'Diet-induced obese Sprague-Dawley rats were randomized to sham-operated obese controls, RYGB, and sham-operated obese pair-fed rats. Body weight and food intake were recorded, and food efficiency was calculated. Endocannabinoid levels in skeletal muscle and liver, muscle mitochondrial respiratory complex I-V content, and hormones concentrations were determined 14 and 28 days postsurgery, reflecting rapid and sustained weight loss periods after RYGB, respectively.', 'Compared with pair-fed controls, RYGB rats had significant reduction in body weight and food efficiency (P < 0.001). Increased cholecystokinin, reduced insulin, leptin, adiponectin, T3, and down-regulation of mitochondrial complex I were evident on day 14 postsurgery. On day 28, leptin, insulin, and T3 remained low, whereas adiponectin and cholecystokinin were normal. Along with complex I, the endocannabinoids anandamide in muscle (P = 0.003) and 2-arachidonoylglycerol in liver were significantly down-regulated (P < 0.001).'] Is sustained weight loss after Roux-en-Y gastric bypass characterized by down regulation of endocannabinoids and mitochondrial function?