Submitted to: Experimental Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2016
Publication Date: 1/1/2017
Citation: Zhang, J., Light, A.R., Hoppel, C.L., Campbell, C., Chandler, C.J., Burnett, D.J., Souza, E.C., Casazza, G.A., Hughen, R.W., Keim, N.L., Newman, J.W., Hunter, G.R., Fernandez, J.R., Garvey, W.T., Harper, M., Fiehn, O., Adams, S.H. 2017. Acylcarnitines as markers of exercise-associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons. Experimental Physiology. 102(1):48-69. doi:10.1113/EP086019.

Interpretive Summary: Certain metabolites that build up in blood and tissues may contribute to cell stress and inflammation associated with obesity and sedentary lifestyle. With insulin-resistance or pre-diabetes, mismatches between tissue fatty fuel delivery and fat combustion results leads to excessive accumulation of metabolite markers of incomplete fatty acid oxidation. These metabolites include a class known as short- or medium-chain acylcarnitines, thought to contribute to muscle cell stress and inflammation that may exacerbate resistance to the blood sugar-regulating hormone insulin. It was reasoned that incomplete FAO and the associated metabolite markers in muscle would be normalized concurrent with improved insulin sensitivity and fitness following a ~14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced blood plasma acylcarnitine markers of incomplete fat combustion did not differ between pre-intervention and post-intervention phases. These metabolites all increased robustly with modest exercise and decreased during a 20 min cool-down, highlighting that ramped-up muscle work accelerates fat delivery to the tissue that exceeds capacity to fully burn the fuel. This supports the idea that, regardless of insulin sensitivity and fitness, incomplete FAO is closely tethered to absolute ATP turnover rate. Finally, we considered the question of how muscle communicates to the brain during exercise, by asking if acylcarnitine metabolites signal to muscle-innervating circuits. Consistent with this idea, the 16-carbon metabolites palmitoylcarnitine activated a sub-set (~2.5-5%) of these neurons in cell culture. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as exertion signals to short-loop somatosensory-motor circuits or to the brain. Understanding how fatigue and exertion signals change in the pre-diabetic state, obesity, and among individuals may hold the key in designing context-specific physical activity interventions to improve metabolic health.

Technical Abstract: With insulin-resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives (markers of incomplete long-chain fatty acid oxidation [FAO]). We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ~14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced plasma C4-C14 acylcarnitines did not differ between pre-intervention and post-intervention phases. These metabolites all increased robustly with exercise (~45% of pre-intervention VO2peak) and decreased during a 20 min cool-down. This supports the idea that, regardless of insulin sensitivity and fitness, intramitochondrial muscle B-oxidation and attendant incomplete FAO are closely tethered to absolute ATP turnover rate. Acute exercise also led to branched-chain amino acid (BCAA) acylcarnitine derivative patterns suggestive of rapid diminution of BCAA flux through mitochondrial branched-chain ketoacid dehydrogenase complex. We confirmed our prior novel observation that weight loss/fitness intervention alters plasma xenometabolites (i.e., cis-3,4-methylene-heptanoylcarnitine, and y-butyrobetaine [a co-metabolite possibly derived in part from gut bacteria]), suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered if acylcarnitine metabolites signal to muscle-innervating afferents: palmitoylcarnitine at concentrations as low as 1-10 uM activated a sub-set (~2.5-5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as exertion signals to short-loop somatosensory-motor circuits or to the brain.