Exercise confers metabolic benefits to both normal weight and overweight populations. Responses of the metabolome to acute aerobic exercise may predict cardiovascular fitness and longer-term outcomes, including the development of diabetes and its complications. We applied an LC-MS based untargeted metabolomics platform to evaluate the effect of acute exercise on the serum metabolome of overweight trained (OWT, n = 11, HOMA-IR 1.6 ± 0.1) and normal weight trained (NWT, n = 14, HOMA-IR, 0.9 ± 0.2, p < 0.01) runners. Trained individuals were studied to limit the effects of a deconditioned acute stress response. While NWT and OWT metabolic profiles shared increased circulating acylcarnitines and free fatty acids (FFAs) with exercise, intermediates of adenine metabolism, inosine and hypoxanthine, were strongly correlated with body fat percentage (R = 0.67) and VO2max (R = 0.70) . Untargeted metabolomics-guided follow-up quantitative lipidomic analysis revealed that, as expected, baseline levels of fatty acid esters of hydroxy fatty acids (FAHFAs) were generally diminished in the OWT group. FAHFAs negatively correlated with visceral fat mass and HOMA-IR. Strikingly, a 4-fold decrease in FAHFAs was provoked by acute aerobic running in NWT, an effect that negatively correlated with circulating IL-6 (R ≤ -0.7) . These effects of exercise were not observed in the OWT group. Machine learning models based on a profile including FAHFAs, FFAs, and adenine intermediates predicted 53% of the variation in cardiovascular fitness. Taken together, these findings in relatively insulin resistant overweight human participants and healthy controls have implications for metabolic crosstalk between adipose tissue and skeletal muscle and support the notion that FAHFAs could modulate the inflammatory response, fuel utilization, and insulin resistance.


A.B.Nelson: None. L.S.Chow: Other Relationship; Dexcom, Inc. C.C.Hughey: None. C.Myers: None. X.Han: None. P.A.Crawford: Advisory Panel; Abbott Diabetes, Johnson & Johnson Global Services. P.Puchalska: None.


NIH (DK091538, AG069781, DK098203, TR000114, UL1TR002494)

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