Abstract Background Mitochondria dysfunction is one of the major causes of insulin resistance, and other countless complications of obesity. PGC-1α, and UCP-2 play key roles in energy expenditure regulation in the mitochondrial thermogenesis. However, the effects of bariatric surgery on the level of PGC-1α and UCP-2 and their relationships are unclear. Objective This study aimed to investigate the effect of bariatric surgery on key pathways in energy, and to assess the potential predictive role of body composition and metabolic parameters in this regard. Settings Hazrat-e Rasool General Hospital, Center of Excellence of International Federation for Surgery of Obesity. Methods This prospective cohort study was carried out on 45 patients with morbid obesity who underwent Roux-en-Y gastric bypass surgery. The patients have evaluated three-time points at baseline, three, and six months after the surgery. Body composition components, the levels of PGC-1α, UCP-2, and metabolic parameters were measured three times during this study. Results Significant changes in TWL%, EBMIL%, and metabolic lab tests were observed at three- and six months post-surgery (P