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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 fibroblast growth factor 19 (FGF19; a regulator of BA synthesis) and 7-alpha-hydroxy-cholesten-3-one (C4, a marker of CYP7A1 enzymatic activity) also were measured. Using linear mixed-model analyses and the change in V̇O 2peak (mL/min/kg) as a covariate, we observed that 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, whereas 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. postintervention 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. NEW & NOTEWORTHY Exercise and weight loss in previously sedentary, insulin-resistant women facilitates a significant improvement in insulin sensitivity and fitness that may be linked to changes in bile acid metabolism. Diet-induced weight loss plus exercise-induced increases in fitness promote greater postabsorptive bile acid synthesis while also sensitizing the bile acid metabolic system to feedback inhibition during a glucose challenge when glucose and insulin are elevated.

For estimating the oxidation rates (Rox) of glucose and other substrates by use of (13)C-labeled tracers, we obtained correction factors to account for label dilution in endogenous bicarbonate pools and TCA cycle exchange reactions. Fractional recoveries of (13)C label in respiratory gases were determined during 225 min of rest and 90 min of leg cycle ergometry at 45 and 65% peak oxygen uptake (VO(2 peak)) after continuous infusions of [1-(13)C]acetate, [2-(13)C]acetate, or NaH(13)CO(3). In parallel trials, [6,6-(2)H]glucose and [1-(13)C]glucose were given. Experiments were conducted after an overnight fast with exercise commencing 12 h after the last meal. During the transition from rest to exercise, CO(2) production increased (P < 0.05) in an intensity-dependent manner. Significant differences were observed in the fractional recoveries of (13)C label as (13)CO(2) at rest (NaH(13)CO(3), 77.5 +/- 2.8%; [1-(13)C]acetate, 49.8 +/- 2.4%; [2-(13)C]acetate, 26.1 +/- 1.4%). During exercise, fractional recoveries of (13)C label from [1-(13)C]acetate, [2-(13)C]acetate, and NaH(13)CO(3) were increased compared with rest. Magnitudes of label recoveries during both exercise intensities were tracer specific (NaH(13)CO(3), 93%; [1-(13)C]acetate, 80%; [2-(13)C]acetate, 65%). Use of an acetate-derived correction factor for estimating glucose oxidation resulted in Rox values in excess (P < 0.05) of glucose rate of disappearance during hard exercise. We conclude that, after an overnight fast: 1) recovery of (13)C label as (13)CO(2) from [(13)C]acetate is decreased compared with bicarbonate; 2) the position of (13)C acetate label affects carbon dilution estimations; 3) recovery of (13)C label increases in the transition from rest to exercise in an isotope-dependent manner; and 4) application of an acetate correction factor in glucose oxidation measurements results in oxidation rates in excess of glucose disappearance during exercise at 65% of VO(2 peak). Therefore, bicarbonate, not acetate, correction factors are advocated for estimating glucose oxidation from carbon tracers in exercising men.

Related to hepatic autoregulation we evaluated hypotheses that 1) glucose production would be altered as a result of a glycerol load, 2) decreased glucose recycling rate (Rr) would result from increased glycerol uptake, and 3) the absolute rate of gluconeogenesis (GNG) from glycerol would be positively correlated to glycerol rate of disappearance (R(d)) during a glycerol load. For these purposes, glucose and glycerol kinetics were determined in eight men during rest and during 90 min of leg cycle ergometry at 45 and 65% of peak O2 consumption (.VO2 (peak)). Trials were conducted after an overnight fast, with exercise commencing 12 h after the last meal. Subjects received a continuous infusion of [6,6-(2)H(2)]glucose, [1-(13)C]glucose, and [1,1,2,3,3-(2)H(5)]glycerol without (CON) or with an additional 1,000 mg (rest: 20 mg/min; exercise: 40 mg/min) of [2-(13)C]- or unlabeled glycerol added to the infusate (GLY). Infusion of glycerol dampened glucose Rr, calculated as the difference between [6,6-(2)H(2)]- and [1-(13)C]glucose rates of appearance (R(a)), at rest [0.35 +/- 0.12 (CON) vs. 0.12 +/- 0.10 mg. kg(-1). min(-1) (GLY), P < 0.05] and during exercise at both intensities [45%: 0.63 +/- 0.14 (CON) vs. 0.04 +/- 0.12 (GLY); 65%: 0.73 +/- 0.14 (CON) vs. 0.04 +/- 0.17 mg. kg(-1). min(-1) (GLY), P < 0.05]. Glucose R(a) and oxidation were not affected by glycerol infusion at rest or during exercise. Throughout rest and both exercise intensities, glycerol R(d) was greater in GLY vs. CON conditions (rest: 0.30 +/- 0.04 vs. 0.58 +/- 0.04; 45%: 0.57 +/- 0.07 vs. 1.19 +/- 0.04; 65%: 0.73 +/- 0.06 vs. 1.27 +/- 0.05 mg. kg(-1). min(-1), CON vs. GLY, respectively). Differences in glycerol R(d) (DeltaR(d)) between protocols equaled the unlabeled glycerol infusion rate and correlated with plasma glycerol concentration (r = 0.97). We conclude that infusion of a glycerol load during rest and exercise at 45 and 65% of .VO2(peak) 1) does not affect glucose R(a) or R(d), 2) blocks glucose Rr, 3) increases whole body glycerol R(d) in a dose-dependent manner, and 4) results in gluconeogenic rates from glycerol equivalent to CON glucose recycling rates.

The hypothesis that endurance training increases gluconeogenesis (GNG) during rest and exercise was evaluated. We determined glucose turnover with [6,6-(2)H]glucose and lactate incorporation into glucose by use of [3-(13)C]lactate during 1 h of cycle ergometry at two intensities [45 and 65% peak O(2) consumption (VO(2 peak))] before and after training [65% pretraining VO(2 peak)], same absolute workload (ABT), and 65% posttraining VO(2 peak), same relative intensity (RLT). Nine males (178.1 +/- 2.5 cm, 81.8 +/- 3.3 kg, 27.4 +/- 2.0 yr) trained for 9 wk on a cycle ergometer 5 times/wk for 1 h at 75% VO(2 peak). The power output that elicited 66.0 +/- 1.1% of VO(2 peak) pretraining elicited 54.0 +/- 1.7% posttraining. Rest and exercise arterial glucose concentrations were similar before and after training, regardless of exercise intensity. Arterial lactate concentration during exercise was significantly greater than at rest before and after training. Compared with 65% pretraining, arterial lactate concentration decreased at ABT (4.75 +/- 0.4 mM, 65% pretraining; 2.78 +/- 0.3 mM, ABT) and RLT (3.76 +/- 0.46 mM) (P < 0.05). At rest after training, the percentage of glucose rate of appearance (R(a)) from GNG more than doubled (1.98 +/- 0.5% pretraining; 5.45 +/- 1.3% posttraining), as did the rate of GNG (0.11 +/- 0.03 mg x kg(-1) x min(-1) pretraining, 0.24 +/- 0.06 mg x kg(-1) x min(-1) posttraining). During exercise after training, %glucose R(a) from GNG increased significantly at ABT (2.3 +/- 0.8% at 65% pre- vs. 7.6 +/- 2.1% posttraining) and RLT (6.1 +/- 1.5%), whereas GNG increased almost threefold (P < 0.05) at ABT (0.24 +/- 0.08 mg x kg(-1) x min(-1) 65% pre-, and 0.71 +/- 0.18 mg x kg(-1) x min(-1) posttraining) and RLT (0.75 +/- 0.26 mg x kg(-1) x min(-1)). We conclude that endurance training increases gluconeogenesis twofold at rest and threefold during exercise at given absolute and relative exercise intensities.

We evaluated the hypotheses that endurance training decreases arterial lactate concentration ([lactate](a)) during continuous exercise by decreasing net lactate release () and appearance rates (R(a)) and increasing metabolic clearance rate (MCR). Measurements were made at two intensities before [45 and 65% peak O(2) consumption (VO(2 peak))] and after training [65% pretraining VO(2 peak), same absolute workload (ABT), and 65% posttraining VO(2 peak), same relative intensity (RLT)]. Nine men (27.4 +/- 2.0 yr) trained for 9 wk on a cycle ergometer, 5 times/wk at 75% VO(2 peak). Compared with the 65% VO(2 peak) pretraining condition (4.75 +/- 0.4 mM), [lactate](a) decreased at ABT (41%) and RLT (21%) (P < 0.05). decreased at ABT but not at RLT. Leg lactate uptake and oxidation were unchanged at ABT but increased at RLT. MCR was unchanged at ABT but increased at RLT. We conclude that 1) active skeletal muscle is not solely responsible for elevated [lactate](a); and 2) training increases leg lactate clearance, decreases whole body and leg lactate production at a given moderate-intensity power output, and increases both whole body and leg lactate clearance at a high relative power output.

We examined the effects of exercise intensity and a 10-wk cycle ergometer training program [5 days/wk, 1 h, 75% peak oxygen consumption (VO2 peak)] on plasma free fatty acid (FFA) flux, total fat oxidation, and whole body lipolysis in healthy male subjects (n = 10; age = 25.6 +/- 1.0 yr). Two pretraining trials (45 and 65% of VO2 peak) and two posttraining trials (same absolute workload, 65% of old VO2 peak; and same relative workload, 65% of new VO2 peak) were performed by using an infusion of [1-13C]palmitate and [1,1,2,3, 3-2H]glycerol. An additional nine subjects (age 25.4 +/- 0.8 yr) were treated similarly but were infused with [1,1,2,3,3-2H]glycerol and not [1-13C]palmitate. Subjects were studied postabsorptive for 90 min of rest and 1 h of cycling exercise. After training, subjects increased VO2 peak by 9.4 +/- 1.4%. Pretraining, plasma FFA kinetics were inversely related to exercise intensity with rates of appearance (Ra) and disappearance (Rd) being significantly higher at 45 than at 65% VO2 peak (Ra: 8.14 +/- 1.28 vs. 6.64 +/- 0.46, Rd: 8. 03 +/- 1.28 vs. 6.42 +/- 0.41 mol. kg-1. min-1) (P

We examined the effects of exercise intensity and training [12 wk, 5 days/wk, 1 h, 75% peak oxygen consumption (VO2 peak)] on lipolysis and plasma free fatty acid (FFA) flux in women (n = 8; 24.3 +/- 1.6 yr). Two pretraining trials (45 and 65% of VO2 peak) and two posttraining trials [same absolute workload (65% of old VO2 peak; ABT) and same relative workload (65% of new VO2 peak; RLT)] were performed using infusions of [1,1,2,3,3-2H]glycerol and [1-13C]palmitate. Pretraining rates of FFA appearance (Ra), disappearance (Rd), and oxidation (Rox p) were similar between the 65% (6.8 +/- 0.6, 6.2 +/- 0.7, 3.1 +/- 0.3 micromol. kg-1. min-1, respectively) and the 45% of VO2 peak trials. At ABT and RLT training increased FFA Ra to 8.4 +/- 1.0 and 9.7 +/- 1.1 micromol. kg-1. min-1, Rd to 8.3 +/- 1.0 and 9.5 +/- 1.1 micromol. kg-1. min-1, and Rox p to 4.8 +/- 0.4 and 6.7 +/- 0.7 micromol. kg-1. min-1, respectively (P

We examined the hypothesis that glucose flux was directly related to relative exercise intensity both before and after a 12-wk cycle ergometer training program [5 days/wk, 1-h duration, 75% peak O2 consumption (VO2 peak)] in healthy female subjects (n = 17; age 23.8 +/- 2.0 yr). Two pretraining trials (45 and 65% of VO2 peak) and two posttraining trials [same absolute workload (65% of old VO2 peak) and same relative workload (65% of new VO2 peak)] were performed on nine subjects by using a primed-continuous infusion of [1-13C]- and [6,6-2H]glucose. Eight additional subjects were studied by using [6, 6-2H]glucose. Subjects were studied postabsorption for 90 min of rest and 1 h of cycling exercise. After training, subjects increased VO2 peak by 25.2 +/- 2.4%. Pretraining, the intensity effect on glucose kinetics was evident between 45 and 65% of VO2 peak with rates of appearance (Ra: 4.52 +/- 0.25 vs. 5.53 +/- 0.33 mg . kg-1 . min-1), disappearance (Rd: 4.46 +/- 0.25 vs. 5.54 +/- 0.33 mg . kg-1 . min-1), and oxidation (Rox: 2.45 +/- 0.16 vs. 4.35 +/- 0.26 mg . kg-1 . min-1) of glucose being significantly greater (P

We examined the hypothesis that glucose flux was directly related to relative exercise intensity both before and after a 10-wk cycle ergometer training program in 19 healthy male subjects. Two pretraining trials [45 and 65% of peak O2 consumption (VO2peak)] and two posttraining trials (same absolute and relative intensities as 65% pretraining) were performed for 90 min of rest and 1 h of cycling exercise. After training, subjects increased VO2peak by 9.4 +/- 1.4%. Pretraining, the intensity effect on glucose kinetics was evident with rates of appearance (R(a); 5.84 +/- 0.23 vs. 4.73 +/- 0.19 mg x kg(-1) x min(-1)), disappearance (R(d); 5.78 +/- 0.19 vs. 4.73 +/- 0.19 mg x kg(-1) x min(-1) x min(-1)), oxidation (R(ox); 5.36 +/- 0.15 vs. 3.41 +/- 0.23 mg x kg(-1) x min(-1)), and metabolic clearance (7.03 +/- 0.56 vs. 5.20 +/- 0.28 ml x kg(-1) x min(-1)) of glucose being significantly greater (P < or = 0.05) in the 65% than the 45% VO2peak trial. When R(d) was expressed as a percentage of total energy expended per minute (R(dE)), there was no difference between the 45 and 65% intensities. Training did reduce R(a) (4.63 +/- 0.25), R(d) (4.65 +/- 0.24), R(ox) (3.77 +/- 0.43), and R(dE) (15.30 +/- 0.40 to 12.85 +/- 0.81) when subjects were tested at the same absolute workload (P < or = 0.05). However, when they were tested at the same relative workload, R(a), R(d), and R(dE) were not different, although R(ox) was lower posttraining (5.36 +/- 0.15 vs. 4.41 +/- 0.42, P < or = 0.05). These results show 1) glucose use is directly related to exercise intensity; 2) training decreases glucose flux for a given power output; 3) when expressed as relative exercise intensity, training does not affect the magnitude of blood glucose use during exercise; 4) training alters the pathways of glucose disposal.