Exercise-induced improvement in risk for chronic disease is attributed to changes in body composition, cardiorespiratory fitness, blood pressure and glucose metabolism; however, the underlying mechanism is unclear. Metabolomics offers the technology needed to investigate large numbers of metabolites that may participate in biochemical pathways of exercise-induced improvement in cardiometabolic risk. PURPOSE: To investigate the impact of an exercise intervention on plasma metabolites and whether changes in metabolite levels are related to changes in cardiometabolic risk factors. METHODS: A secondary analysis was performed in 216 middle-aged abdominally obese men and women ([mean (SD)], 52.4 (8.0) years) originally recruited to participate in a 6-month randomized controlled trial examining the effects of exercise amount and intensity on cardiometabolic risk factors. 139 metabolites were profiled by liquid chromatography-mass spectrometry. Cardiorespiratory fitness (CRF) was assessed using standard open-circuit spirometry during a maximal graded exercise test. Waist circumference (WC) was measured at the superior edge of the iliac crest. 2-hour glucose was measured in response to a 2-hour 75-g oral glucose tolerance test. Systolic (SBP) and diastolic blood pressure (DBP) was measured using an automated BP monitor. RESULTS: Seven metabolites significantly changed in the exercise compared to control group (p<0.05). There were no significant associations at the adjusted p-value (p<0.0004) between change in metabolites and change in 2-hour glucose, SBP or DBP. Change in leucine (B=-0.29), isoleucine (B=-0.30) and UDP-N-acetylglucosamine (B=-0.40) were negatively associated and citric acid isocitric acid (B=0.29) was positively associated with change in CRF. Change in UDP-N-acetylglucosamine (B=0.46) was positively associated with change in WC (p<0.0004). CONCLUSION: These findings represent a more global effort to uncover the biochemical pathways in which exercise elicits its cardiometabolic effects. These observations implicate several metabolites that may serve as biomarkers or have a direct regulatory role in pathways related to exercise and improved cardiometabolic status. Supported by Canadian Institute of Health Research Grant