Exercise training and diet-induced weight loss increase markers of hepatic bile acid (BA) synthesis and reduce serum total BA concentrations in obese women

Authors: MERCER, KELLY - Arkansas Children'S Nutrition Research Center (ACNC); MAURER, ADRIANNA - Children'S Mercy Hospital; PACK, LINDSAY - Arkansas Children'S Nutrition Research Center (ACNC); ONO-MOORE, KIKUMI - Arkansas Children'S Nutrition Research Center (ACNC); SPRAY, BEVERLY - Arkansas Children'S Nutrition Research Center (ACNC); 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 - US Department Of Agriculture (USDA); NEWMAN, JOHN - US Department Of Agriculture (USDA); HUNTER, GARY - University Of Alabama At Birmingham; FERNADEZ, JOSE - University Of Alabama At Birmingham; GARVEY, TIMOTHY - University Of Alabama At Birmingham; HARPER, MARY-ELLEN - University Of Ottawa; HOPPEL, CHARLES - Case Western Reserve University (CWRU); Ferruzzi, Mario; THYFAULT, JOHN - Children'S Mercy Hospital

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/23/2021
Publication Date: 3/1/2021
Citation: Mercer, K.E., Maurer, A., Pack, L.M., Ono-Moore, K., Spray, B.J., Campbell, C., Chandler, C., Burnett, D., Souza, E., Casazza, G., Keim, N., Newman, J., Hunter, G., Fernadez, J., Garvey, T.W., Harper, M., Hoppel, C., Adams, S.H., Thyfault, J. 2021. Exercise training and diet-induced weight loss increase markers of hepatic bile acid (BA) synthesis and reduce serum total BA concentrations in obese women. American Journal of Physiology - Endocrinology and Metabolism. 320(5):E864-E873. https://doi.org/10.1152/ajpendo.00644.2020.
DOI: https://doi.org/10.1152/ajpendo.00644.2020

Interpretive Summary: Regular exercise has profound influence on promoting health and preventing disease, but the specific mechanisms remain to be fully understood. Bile acids (BAs) help break down fats in the gut, but also are now appreciated to serve as signaling molecules in the body and are responsive to exercise and fitness. Circulating BAs increase with obesity and insulin resistance, but effects following exercise and diet induced weight loss are unknown. BAs are synthesized exclusively in the liver from cholesterol via the rate-limiting enzyme cholesterol 7 alpha-hydroxylase (CYP7A1). To test if improvements in fitness and weight loss as a result of exercise training enhance BA metabolism, we measured serum concentrations of total BAs (conjugated and unconjugated primary and secondary BAs) in sedentary, obese, insulin-resistant women (N=11) before (PRE) and after (POST) a ~14 wk exercise and diet-induced weight loss intervention. BAs were measured in serum collected after an overnight fast and during an oral glucose tolerance test (OGTT). Serum FGF19 (a regulator of BA synthesis) and 7-alpha-hydroxy-cholesten-3-one (C4, a marker of CYP7A1 enzymatic acitivity) were also measured. Exercise and weight loss intervention decreased total fasting serum BA by ~30% and increased fasting serum C4 concentrations by 55%. C4 was significantly correlated with serum total BAs only in the POST condition while serum FGF19 was unchanged. These data indicate that a fitness and weight loss intervention modifies BA metabolism in obese women, and suggest that improved metabolic health associates with higher postabsorptive (fasting) BA synthesis. Furthermore, pre- vs. post-intervention patterns of serum C4 following an OGTT support the hypothesis that improved metabolic health leads to a more robust response of BA synthesis to its typical regulation following a meal. These studies highlight new mechanisms by which regular exercise signals body-wide and in the gut in support of health, and suggests that nutritional or physical activity interventions that modify BAs can in turn improve health and prevent disease.

Technical Abstract: Regular exercise has profound metabolic influence on the liver, but effects on bile acid (BA) metabolism are less well known. BAs are synthesized exclusively in the liver from cholesterol via the rate-limiting enzyme cholesterol 7 alpha-hydroxylase (CYP7A1). BAs contribute to the solubilization and absorption of lipids and serve as important signaling molecules, capable of systemic endocrine function. Circulating BAs increase with obesity and insulin resistance, but effects following exercise and diet induced weight loss are unknown. To test if improvements in fitness and weight loss as a result of exercise training enhance BA metabolism, we measured serum concentrations of total BAs (conjugated and unconjugated primary and secondary BAs) in sedentary, obese, insulin-resistant women (N=11) before (PRE) and after (POST) a ~14 wk exercise and diet-induced weight loss intervention. BAs were measured in serum collected after an overnight fast and during an oral glucose tolerance test (OGTT). Serum FGF19 (a regulator of BA synthesis) and 7-alpha-hydroxy-cholesten-3-one (C4, a marker of CYP7A1 enzymatic acitivity) were also measured. Using linear mixed-model analyses and the change in VO2peak (mL/min/kg) as a covariate, we observed that the exercise and weight loss intervention decreased total fasting serum BA by ~30% (P =0.001) and increased fasting serum C4 concentrations by 55% (P =0.004). C4 was significantly correlated with serum total BAs only in the POST condition while serum FGF19 was unchanged. These data indicate that a fitness and weight loss intervention modifies BA metabolism in obese women, and suggest that improved metabolic health associates with higher postabsorptive (fasting) BA synthesis. Furthermore, pre- vs. post-intervention patterns of serum C4 following an OGTT support the hypothesis that responsiveness of BA synthesis to postprandial inhibition is improved after exercise and weight loss.