Impact of a weight loss and fitness intervention on exercise-associated plasma oxylipin patterns in obese, insulin-resistant, sedentary women

Authors: GRAPOV, DMITRY - Cds - Creative Data Solutions; FIEHN, OLIVER - University Of California, Davis; CAMPBELL, CAITLIN - US Department Of Agriculture (USDA); CHANDLER, CAROL - US Department Of Agriculture (USDA); BURNETT, DUSTIN - US Department Of Agriculture (USDA); SOUZA, ELAINE - US Department Of Agriculture (USDA); CASAZZA, GRETCHEN - California State University; Keim, Nancy; HUNTER, GARY - University Of Alabama At Birmingham; FERNANDEZ, JOSE - University Of Alabama At Birmingham; GARVEY, TIMOTHY - University Of Alabama At Birmingham; HOPPEL, CHARLES - Case Western Reserve University (CWRU); HARPER, MARY-ELLEN - University Of Ottawa; Newman, John; Ferruzzi, Mario

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/27/2020
Publication Date: 9/1/2020
Citation: Grapov, D., Fiehn, O., Campbell, C., Chandler, C.J., Burnett, D.J., Souza, E.C., Casazza, G.A., Keim, N.L., Hunter, G.R., Fernandez, J.R., Garvey, T., Hoppel, C.L., Harper, M., Newman, J.W., Adams, S.H. 2020. Impact of a weight loss and fitness intervention on exercise-associated plasma oxylipin patterns in obese, insulin-resistant, sedentary women. Physiological Reports. 8(17). Article e14547. https://doi.org/10.14814/phy2.14547.
DOI: https://doi.org/10.14814/phy2.14547

Interpretive Summary: Specialized bioactive fats (lipids) called endocannabinoids (eCB) and oxylipins (OxL) play important roles in regulating inflammation and blood vessel health. However, little is known about how metabolic health status or metabolic challenges modulate the eCB or OxL lipid classes. To address these questions, plasma eCB and OxL concentrations were determined at rest, 10 and 20 min during an acute sub-maximal exercise bout, and following 20 min recovery in overnight-fasted sedentary, obese, insulin resistant women under controlled diet conditions. We hypothesized that increased fitness and insulin sensitivity following a ~14 wk training and weight loss intervention would lead to significant changes in blood eCB and OxL signatures at rest and during an exercise challenge. In the first 10 min of exercise, blood plasma concentrations of a suite of OxLs (called "diols" and "HETEs") dropped significantly. There was no increase in the OxL "12,13-DiHOME," previously reported to increase with exercise and proposed to activate muscle fatty acid uptake and tissue metabolism. Following weight loss intervention, exercise-associated reductions were more pronounced for several linoleate and alpha-linolenate metabolites including DiHOMEs, DiHODEs, KODEs, and EpODEs, and fasting concentrations of 9,10-DiHODE, 12,13-DiHODE, and 9,10-DiHOME were reduced. These findings suggest that improved metabolic health modifies enzyme systems in the body that can regulate the levels of OxLs. Acute exercise led to reductions for most eCB metabolites, with no evidence for concentration increases even at recovery. It is proposed that during sub-maximal aerobic exercise, the fates of long-chain saturated, monounsaturated, and polyunsaturated fatty acids are directed toward combustion to energy, instead of non-oxidative fates such as eCB and OxL production. This allows for sustained energy during exercise while regulating bioactive fat metabolites that in turn impact inflammation and blood vessel activities. These changes may help explain some of the positive health outcomes associated with regular exercise.

Technical Abstract: Very little is known about how metabolic health status, insulin resistance or metabolic challenges modulate the endocannabinoid (eCB) or polyunsaturated fatty acid-derived oxylipin (OxL) lipid classes. To address these questions, plasma eCB and OxL concentrations were determined at rest, 10 and 20 min during an acute exercise bout (30 min total, ~45% of pre-intervention V'O2peak, ~63 W), and following 20 min recovery in overnight-fasted sedentary, obese, insulin resistant women under controlled diet conditions. We hypothesized that increased fitness and insulin sensitivity following a ~14 wk training and weight loss intervention would lead to significant changes in lipid signatures using an identical acute exercise protocol to pre-intervention. In the first 10 min of exercise, concentrations of a suite of OxL diols and HETE metabolites dropped significantly. There was no increase in 12,13-DiHOME, previously reported to increase with exercise and proposed to activate muscle fatty acid uptake and tissue metabolism. Following weight loss intervention, exercise-associated reductions were more pronounced for several linoleate and alpha-linolenate metabolites including DiHOMEs, DiHODEs, KODEs, and EpODEs, and fasting concentrations of 9,10-DiHODE, 12,13-DiHODE, and 9,10-DiHOME were reduced. These findings suggest that improved metabolic health modifies soluble epoxide hydrolase (sEH), cytochrome P450 epoxygenase (CYP), and lipoxygenase (LOX) systems. Acute exercise led to reductions for most eCB metabolites, with no evidence for concentration increases even at recovery. It is proposed that during sub-maximal aerobic exercise, non-oxidative fates of long-chain saturated, monounsaturated, and polyunsaturated fatty acids are attenuated in tissues that are important contributors to the blood OxL and eCB pools.