Exercise plasma metabolomics and xenometabolomics in obese, sedentary, insulin-resistant women: Impact of a fitness and weight loss intervention

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 - University Of California; KEIM, NANCY - University Of California, Davis; NEWMAN, JOHN - University Of California, Davis; HUNTER, GARY - University Of Alabama; FERNANDEZ, JOSE - University Of Alabama; GARVEY, W.TIMOTHY - University Of Alabama; HOPPEL, CHARLES - University Of Ottawa; HARPER, MARY-ELLEN - University Of Ottawa; Ferruzzi, Mario

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/17/2019
Publication Date: 9/17/2019
Citation: Grapov, D., Fiehn, O., Campbell, C., Chandler, C.J., Burnett, D.J., Souza, E.C., Casazza, G.A., Keim, N.L., Newman, J.W., Hunter, G.R., Fernandez, J.R., Garvey, W., Hoppel, C.L., Harper, M., Adams, S.H. 2019. Exercise plasma metabolomics and xenometabolomics in obese, sedentary, insulin-resistant women: Impact of a fitness and weight loss intervention. American Journal of Physiology - Endocrinology and Metabolism. 317(6):E999-E1014. https://doi.org/10.1152/ajpendo.00091.2019.
DOI: https://doi.org/10.1152/ajpendo.00091.2019

Interpretive Summary: Certain metabolites that build up in blood and tissues may contribute to cell stress and inflammation associated with obesity and sedentary lifestyle, and appear to negatively impact the ability of the hormone insulin to control blood sugar. It is well-established that weight loss and exercise improve metabolic health in muscle and other tissues, but the metabolites and related signals that drive this healthy profile remain to be identified. To address this question, a comprehensive analysis of hundreds of blood metabolites was conducted during exercise, both pre- and post- a ~14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. Metabolite pattern analysis over the first 15 min of exercise—regardless of pre- vs. post-intervention status—highlighted anticipated increases in fatty acid tissue uptake and oxidation (e.g., reduced long-chain fatty acids), lowering of non-oxidative fates of glucose (e.g., lowered sorbitol-pathway metabolites and glycerolipid synthesis metabolites), and enhanced tissue amino acid use (e.g., drops in amino acids; modest increase in urea). A novel observation was that exercise significantly increased several xenometabolites ("non-self" molecules, from microbes or foods), including benzoic acid/salicylic acid/salicylaldehyde, hexadecanol/octadecanol/dodecanol, and chlorogenic acid. In addition, many non-annotated metabolites changed with exercise. Although exercise itself strongly impacted the global metabolome, there were surprisingly few intervention-associated differences despite marked improvements in insulin sensitivity, fitness, and body fat. It is concluded that when there is a fixed workload on the muscle, most exercise-responsive biochemical pathways in the human body remain closely tethered to energy needs regardless of weight loss or better blood glucose control. Another important aspect of the work is that the catalog of metabolites provide a framework to test which of these molecules participate in fatigue and performance, and contribute to the shorter-term positive effects of exercise on blood glucose control and fat combustion that are well-known to accompany even single exercise bouts. Finally, the study illustrates, for the first time, that exercise can modify circulating blood levels of factors derived from the normal gut bacteria, which may in turn influence how the bacteria signal to the host tissues during periods of physical exertion.

Technical Abstract: Insulin resistance has wide-ranging effects on metabolism but there are knowledge gaps regarding the tissue origins of systemic metabolite patterns, and how patterns are altered by fitness and metabolic health. To address these questions, plasma metabolite patterns were determined every 5 min during exercise (30 min, ~45% of VO2peak, ~63 W) and recovery in overnight-fasted sedentary, obese, insulin resistant women under controlled conditions of diet and physical activity. We hypothesized that improved fitness and insulin sensitivity following a ~14 wk training and weight loss intervention would lead to fixed workload plasma metabolomics signatures reflective of metabolic health and muscle metabolism. Pattern analysis over the first 15 min of exercise—regardless of pre- vs. post-intervention status—highlighted anticipated increases in fatty acid tissue uptake and oxidation (e.g., reduced long12 chain fatty acids), diminution of non-oxidative fates of glucose (e.g., lowered sorbitol-pathway metabolites and glycerol-3-galactoside [possible glycerolipid synthesis metabolite]), and enhanced tissue amino acid use (e.g., drops in amino acids; modest increase in urea). A novel observation was that exercise significantly increased several xenometabolites ("non-self" molecules, from microbes or foods), including benzoic acid/salicylic acid/salicylaldehyde hexadecanol/octadecanol/dodecanol, and chlorogenic acid. In addition, many non-annotated metabolites changed with exercise. Although exercise itself strongly impacted the global metabolome, there were surprisingly few intervention19 associated differences despite marked improvements in insulin sensitivity, fitness, and adiposity. These results, and previously-reported plasma acylcarnitine profiles, support the principle that most metabolic changes during sub-maximal aerobic exercise are closely tethered to absolute ATP turnover rate (workload), regardless of fitness or metabolic health status.