Endurance training has little effect on active muscle free fatty acid, lipoprotein cholesterol, or triglyceride net balances

We evaluated the hypothesis that net leg total FFA, LDL-C, and TG uptake and HDL-C release during moderate-intensity cycling exercise would be increased following endurance training. Eight sedentary men (26 +/- 1 yr, 77.4 +/- 3.7 kg) were studied in the postprandial state during 90 min of rest and 60 min of exercise twice before (45% and 65% V(O2 peak)) and twice after 9 wk of endurance training (55% and 65% posttraining V(O2 peak)). Measurements across an exercising leg were taken to be a surrogate for active skeletal muscle. To determine limb lipid exchange, femoral arterial and venous blood samples drawn simultaneously at rest and during exercise were analyzed for total and individual FFA (e.g., palmitate, oleate), LDL-C, HDL-C, and TG concentrations, and limb blood flow was determined by thermodilution. The transition from rest to exercise resulted in a shift from net leg total FFA release (-44 +/- 16 micromol/min) to uptake (193 +/- 49 micromol/min) that was unaffected by either exercise intensity or endurance training. The relative net leg release and uptake of individual FFA closely resembled their relative abundances in the plasma with approximately 21 and 41% of net leg total FFA uptake during exercise accounted for by palmitate and oleate, respectively. Endurance training resulted in significant changes in arterial concentrations of HDL-C (49 +/- 5 vs. 52 +/- 5 mg/dl, pre vs. post) and LDL-C (82 +/- 9 vs. 76 +/- 9 mg/dl, pre vs. post), but there was no net TG or LDL-C uptake or HDL-C release across the resting or active leg before or after endurance training. In conclusion, endurance training favorably affects blood lipoprotein profiles, even in young, healthy normolipidemic men, but muscle contractions per se have little effect on net leg LDL-C, or TG uptake or HDL-C release during moderate-intensity cycling exercise. Therefore, the favorable effects of physical activity on the lipid profiles of young, healthy normolipidemic men in the postprandial state are not attributable to changes in HDL-C or LDL-C exchange across active skeletal muscle.     

Lipid metabolism during fasting

These studies were conducted to understand the relationship between measures of systemic free fatty acid (FFA) reesterification and regional FFA, glycerol, and triglyceride metabolism during fasting. Indirect calorimetry was used to measure fatty acid oxidation in six men after a 60-h fast. Systemic and regional (splanchnic, renal, and leg) FFA ([(3)H]palmitate) and glycerol ([(3)H]glycerol) kinetics, as well as splanchnic triglyceride release, were measured. The rate of systemic FFA reesterification was 366 +/- 93 micromol/min, which was greater (P < 0.05) than splanchnic triglyceride fatty acid output (64 +/- 6 micromol/min), a measure of VLDL triglyceride fatty acid export. The majority of glycerol uptake occurred in the splanchnic and renal beds, although some leg glycerol uptake was detected. Systemic FFA release was approximately double that usually present in overnight postabsorptive men, yet the regional FFA release rates were of the same proportions previously observed in overnight postabsorptive men. In conclusion, FFA reesterification at rest during fasting far exceeds splanchnic triglyceride fatty acid output. This indicates that nonhepatic sites of FFA reesterification are important, and that peripheral reesterification of FFA exceeds the rate of simultaneous intracellular triglyceride fatty acid oxidation.     

Fatty acid kinetics and carbohydrate metabolism during electrical exercise in spinal cord-injured humans

Motor center activity and reflexes from contracting muscle have been shown to be important for mobilization of free fatty acids (FFA) during exercise. We studied FFA metabolism in the absence of these mechanisms: during involuntary, electrically induced leg cycling in individuals with complete spinal cord injury (SCI). Healthy subjects performing voluntary cycling served as controls (C). Ten SCI (level of injury: C5-T7) and six C exercised for 30 min at comparable oxygen uptake rates (approximately 1 l/min), and [1-14C]palmitate was infused continuously to estimate FFA turnover. From femoral arteriovenous differences, blood flow, muscle biopsies, and indirect calorimetry, leg substrate balances as well as concentrations of intramuscular substrates were determined. Leg oxygen uptake was similar in the two groups during exercise. In SCI, but not in C, plasma FFA and FFA appearance rate fell during exercise, and plasma glycerol increased less than in C (P < 0.05). Fractional uptake of FFA across the working legs decreased from rest to exercise in all individuals (P < 0.05) but was always lower in SCI than in C (P < 0.05). From rest to exercise, leg FFA uptake increased less in SCI than in C subjects (14 +/- 3 to 57 +/- 20 vs. 41 +/- 13 to 170 +/- 57 micromol x min(-1) x leg(-1); P < 0.05). Muscle glycogen breakdown, leg glucose uptake, carbohydrate oxidation, and lactate release were higher (P < 0.05) in SCI than in C during exercise. Counterregulatory hormonal changes were more pronounced in SCI vs. C, whereas insulin decreased only in C. In conclusion, FFA mobilization, delivery, and fractional uptake are lower and muscle glycogen breakdown and glucose uptake are higher in SCI patients during electrically induced leg exercise compared with healthy subjects performing voluntary exercise. Apparently, blood-borne mechanisms are not sufficient to elicit a normal increase in fatty acid mobilization during exercise. Furthermore, in exercising muscle, FFA delivery enhances FFA uptake and inhibits carbohydrate metabolism, while carbohydrate metabolism inhibits FFA uptake.     

Acute exposure to GH during exercise stimulates the turnover of free fatty acids in GH-deficient men.

The secretion of growth hormone (GH) increases acutely during exercise, but whether this is associated with the concomitant alterations in substrate metabolism has not previously been studied. We examined the effects of acute GH administration on palmitate, glucose, and protein metabolism before, during, and after 45 min of moderate-intensity aerobic exercise in eight GH-deficient men (mean age = 40.8 +/- 2.9 yr) on two occasions, with (+GH; 0.4 IU GH) and without GH administered (-GH). A group of healthy controls (n = 8, mean age = 40.4 +/- 4.2 yr) were studied without GH. The GH replacement during exercise on the +GH study mimicked the endogenous GH profile seen in healthy controls. No significant difference in resting free fatty acid (FFA) flux was found between study days, but during exercise a greater FFA flux was found when GH was administered (211 +/- 26 vs. 168 +/- 28 micromol/min, P < 0.05) and remained elevated throughout recovery (P < 0.05). With GH administered, the exercise FFA flux was not significantly different from that observed in control subjects (188 +/- 14 micromol/min), but the recovery flux was greater on the +GH day than in the controls (169 +/- 17 vs. 119 +/- 11 micromol/min, respectively, P < 0.01). A significant time effect (P < 0.01) for glucose rate of appearance from rest to exercise and recovery occurred in the GH-deficient adults and the controls, whereas there were no differences in glucose rate of disappearance. No significant effect across time was found for protein muscle balance. In conclusion, 1) acute exposure to GH during exercise stimulates the FFA release and turnover in GH-deficient adults, 2) GH does not significantly impact glucose or protein metabolism during exercise, and 3) the exercise-induced secretion of GH plays a significant role in the regulation of fatty acid metabolism.     

Contributions of working muscle to whole body lipid metabolism are altered by exercise intensity and training

To evaluate the contribution of working muscle to whole body lipid oxidation, we examined the effects of exercise intensity and endurance training (9 wk, 5 days/wk, 1 h, 75% Vo(2 peak)) on whole body and leg free fatty acid (FFA) kinetics in eight male subjects (26 +/- 1 yr, means +/- SE). Two pretraining trials [45 and 65% Vo(2 max) (45UT, 65UT)] and two posttraining trials [65% of pretraining Vo(2 peak) (ABT), and 65% of posttraining Vo(2 peak) (RLT)] were performed using [1-(13)C]palmitate infusion and femoral arteriovenous sampling. Training increased Vo(2 peak) by 15% (45.2 +/- 1.2 to 52.0 +/- 1.8 ml.kg(-1).min(-1), P < 0.05). Muscle FFA fractional extraction was lower during exercise (EX) compared with rest regardless of workload or training status ( approximately 20 vs. 48%, P < 0.05). Two-leg net FFA balance increased from net release at rest ( approximately -36 micromol/min) to net uptake during EX for 45UT (179 +/- 75), ABT (236 +/- 63), and RLT (136 +/- 110) (P < 0.05), but not 65UT (51 +/- 127). Leg FFA tracer measured uptake was higher during EX than rest for all trials and greater during posttraining in RLT (716 +/- 173 micromol/min) compared with pretraining (45UT 450 +/- 80, 65UT 461 +/- 72, P < 0.05). Leg muscle lipid oxidation increased with training in ABT (730 +/- 163 micromol/min) vs. 65UT (187 +/- 94, P < 0.05). Leg muscle lipid oxidation represented approximately 62 and 30% of whole body lipid oxidation at lower and higher relative intensities, respectively. In summary, training can increase working muscle tracer measured FFA uptake and lipid oxidation for a given power output, but both before and after training the association between whole body and leg lipid metabolism is reduced as exercise intensity increases.     

Effect of gender on lipid kinetics during endurance exercise of moderate intensity in untrained subjects

We evaluated lipid metabolism during 90 min of moderate-intensity (50% VO(2) peak) cycle ergometer exercise in five men and five women who were matched on adiposity (24 +/- 2 and 25 +/- 1% body fat, respectively) and aerobic fitness (VO(2) peak: 49 +/- 2 and 47 +/- 1 ml x kg fat-free mass(-1) x min(-1), respectively). Substrate oxidation and lipid kinetics were measured by using indirect calorimetry and [(13)C]palmitate and [(2)H(5)]glycerol tracer infusion. The total increase in glycerol and free fatty acid (FFA) rate of appearance (R(a)) in plasma during exercise (area under the curve above baseline) was approximately 65% greater in women than in men (glycerol R(a): 317 +/- 40 and 195 +/- 33 micromol/kg, respectively; FFA R(a): 652 +/- 46 and 453 +/- 70 micromol/kg, respectively; both P < 0.05). Total fatty acid oxidation was similar in men and women, but the relative contribution of plasma FFA to total fatty acid oxidation was higher in women (76 +/- 5%) than in men (46 +/- 5%; P < 0.05). We conclude that lipolysis of adipose tissue triglycerides during moderate-intensity exercise is greater in women than in men, who are matched on adiposity and fitness. The increase in plasma fatty acid availability leads to a greater rate of plasma FFA tissue uptake and oxidation in women than in men. However, total fat oxidation is the same in both groups because of a reciprocal decrease in the oxidation rate of fatty acids derived from nonplasma sources, presumably intramuscular and possibly plasma triglycerides, in women.     

Kinetics of intramuscular triglyceride fatty acids in exercising humans.

A pulse ([(14)C]palmitate)-chase ([(3)H]palmitate) approach was used to study intramuscular triglyceride (imTG) fatty acid and plasma free fatty acid (FFA) kinetics during exercise at approximately 45% peak O(2) consumption in 12 adults. Vastus lateralis muscle was biopsied before and after 90 min of bicycle exercise; (3)H(2)O production, breath (14)CO(2) excretion and lipid oxidation (indirect calorimetry) rates were measured during exercise. Results: during exercise, 8.2+/-1.2 and 8.4+/-0.7 micromol x kg(-1) x min(-1) of imTG fatty acids and plasma FFA, respectively, were oxidized according to isotopic measurements. The sum of these two values was not different (P = 0.6) from lipid oxidation by indirect calorimetry (15.4 +/-1.6 micromol x kg(-1) x min(-1)); the isotopic and indirect calorimetry values were correlated (r = 0.79, P<0.005). During exercise, imTG turnover rate was 0.32+/-0.07%/min (6.0+/-2.0 micromol of imTG x kg wet muscle(-1) x min(-1)) and plasma FFA were incorporated into imTG at a rate of 0.7+/-0.1 micromol x kg wet muscle(-1) x min(-1). The imTG pool size did not change during exercise. This pulse-chase, dual tracer appears to be a reasonable approach to measure oxidation and synthesis kinetics of imTG.     

Substantial working muscle glycerol turnover during two-legged cycle ergometry

We combined tracer and arteriovenous (a-v) balance techniques to evaluate the effects of exercise and endurance training on leg triacylglyceride turnover as assessed by glycerol exchange. Measurements on an exercising leg were taken to be a surrogate for working skeletal muscle. Eight men completed 9 wk of endurance training [5 days/wk, 1 h/day, 75% peak oxygen consumption (Vo(2peak))], with leg glycerol turnover determined during two pretraining trials [45 and 65% Vo(2peak) (45% Pre and 65% Pre, respectively)] and two posttraining trials [65% of pretraining Vo(2peak) (ABT) and 65% of posttraining Vo(2peak) (RLT)] using [(2)H(5)]glycerol infusion, femoral a-v sampling, and measurement of leg blood flow. Endurance training increased Vo(2peak) by 15% (45.2 +/- 1.2 to 52.0 +/- 1.8 mlxkg(-1)xmin(-1), P < 0.05). At rest, there was tracer-measured leg glycerol uptake (41 +/- 8 and 52 +/- 15 micromol/min for pre- and posttraining, respectively) even in the presence of small, but significant, net leg glycerol release (-68 +/- 19 and -50 +/- 13 micromol/min, respectively; P < 0.05 vs. zero). Furthermore, while there was no significant net leg glycerol exchange during any of the exercise bouts, there was substantial tracer-measured leg glycerol turnover during exercise (i.e., simultaneous leg muscle uptake and leg release) (uptake, release: 45% Pre, 194 +/- 41, 214 +/- 33; 65% Pre, 217 +/- 79, 201 +/- 84; ABT, 275 +/- 76, 312 +/- 87; RLT, 282 +/- 83, 424 +/- 75 micromol/min; all P < 0.05 vs. corresponding rest). Leg glycerol turnover was unaffected by exercise intensity or endurance training. In summary, simultaneous leg glycerol uptake and release (indicative of leg triacylglyceride turnover) occurs despite small or negligible net leg glycerol exchange, and furthermore, leg glycerol turnover can be substantially augmented during exercise.     

Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity.

We evaluated plasma fatty acid availability and plasma and whole body fatty acid oxidation during exercise in five lean and five abdominally obese women (body mass index = 21 +/- 1 vs. 38 +/- 1 kg/m(2)), who were matched on aerobic fitness, to test the hypothesis that obesity alters the relative contribution of plasma and nonplasma fatty acids to total energy production during exercise. Subjects exercised on a recumbent cycle ergometer for 90 min at 54% of their peak oxygen consumption. Stable isotope tracer methods ([(13)C]palmitate) were used to measure fatty acid rate of appearance in plasma and the rate of plasma fatty acid oxidation, and indirect calorimetry was used to measure whole body substrate oxidation. During exercise, palmitate rate of appearance increased progressively and was similar in obese and lean groups between 60 and 90 min of exercise [3.9 +/- 0.4 vs. 4.0 +/- 0.3 micromol. kg fat free mass (FFM)(-1). min(-1)]. The rate of plasma fatty acid oxidation was also similar in obese and lean subjects (12.8 +/- 1.7 vs. 14.5 +/- 1.8 micromol. kg FFM(-1). min(-1); P = not significant). However, whole body fatty acid oxidation during exercise was 25% greater in obese than in lean subjects (21.9 +/- 1.2 vs. 17.5 +/- 1.6 micromol. kg FFM(-1). min(-1); P < 0.05). These results demonstrate that, although plasma fatty acid availability and oxidation are similar during exercise in lean and obese women, women with abdominal obesity use more fat as a fuel by oxidizing more nonplasma fatty acids.     

Effects of high fat provision on muscle PDH activation and malonyl-CoA content in moderate exercise.

This study examined the effects of elevated free fatty acid (FFA) provision on the regulation of pyruvate dehydrogenase (PDH) activity and malonyl-CoA (M-CoA) content in human skeletal muscle during moderate-intensity exercise. Seven men rested for 30 min and cycled for 10 min at 40% and 10 min at 65% of maximal O(2) uptake while being infused with either Intralipid and heparin (Int) or saline (control). Muscle biopsies were taken at 0, 1 (rest-to-exercise transition), 10, and 20 min. Exercise plasma FFA were elevated (0.99 +/- 0.11 vs. 0.33 +/- 0.03 mM), and the respiratory exchange ratio was reduced during Int (0.87 +/- 0.02) vs. control (0.91 +/- 0.01). PDH activation was lower during Int at 1 min (1.33 +/- 0.19 vs. 2.07 +/- 0.14 mmol. min(-1). kg(-1) wet muscle) and throughout exercise. Muscle pyruvate was reduced during Int at rest [0.17 +/- 0.03 vs. 0.25 +/- 0.03 mmol/kg dry muscle (dm)] but increased above control during exercise. NADH was higher during Int vs. control at rest and 1 min of exercise (0.122 +/- 0.016 vs. 0.102 +/- 0.005 and 0.182 +/- 0.016 vs. 0.150 +/- 0.016 mmol/kg dm), but not at 10 and 20 min. M-CoA was lower during Int vs. control at rest and 20 min of exercise (1.12 +/- 0.22 vs. 1.43 +/- 0.17 and 1.33 +/- 0.16 vs. 1.84 +/- 0.17 micromol/kg dm). The reduced PDH activation with elevated FFA during the rest-to-exercise transition was related to higher mitochondrial NADH at rest and 1 min of exercise and lower muscle pyruvate at rest. The decreased M-CoA may have increased fat oxidation during exercise with elevated FFA by reducing carnitine palmitoyltransferase I inhibition and increasing mitochondrial FFA transport.     

Alterations in lipid kinetics in men with HIV-dyslipidemia

Hypertriglyceridemia is common in individuals with human immunodeficiency (HIV) infection, but the mechanisms responsible for increased plasma triglyceride (TG) concentrations are not clear. We evaluated fatty acid and VLDL-TG kinetics during basal conditions and during a glucose infusion that resulted in typical postprandial plasma glucose and insulin concentrations in six men with HIV-dyslipidemia [body mass index (BMI): 28 +/- 2 kg/m2] and six healthy men (BMI: 26 +/- 2 kg/m2). VLDL-TG secretion and palmitate rate of appearance (Ra) in plasma were measured by using stable-isotope-labeled tracer techniques. Basal palmitate Ra and VLDL-TG secretion rates were greater (P < 0.01 for both) in men with HIV-dyslipidemia (1.04 +/- 0.07 micromol palmitate x kg-1 x min-1 and 5.7 +/- 0.6 micromol VLDL-TG x l plasma-1 x min-1) than in healthy men (0.67 +/- 0.08 micromol palmitate. kg-1 x min-1 and 3.0 +/- 0.5 micromol VLDL-TG x l plasma-1 x min-1). Basal VLDL-TG plasma clearance was lower in men with HIV-dyslipidemia (13 +/- 1 ml/min) than in healthy men (19 +/- 2 ml/min; P < 0.05). Glucose infusion decreased palmitate Ra (by approximately 50%) and the VLDL-TG secretion rate (by approximately 30%) in both groups, but the VLDL-TG secretion rate remained higher (P < 0.05) in subjects with HIV-dyslipidemia. These findings demonstrate that increased secretion of VLDL-TG and decreased plasma VLDL-TG clearance, during both fasting and fed conditions, contribute to hypertriglyceridemia in men with HIV-dyslipidemia. Although it is likely that increased free fatty acid release from adipose tissue contributes to the increase in basal VLDL-TG concentration, other factors must be involved, because insulin-induced suppression of lipolysis and systemic fatty acid availability did not normalize the VLDL-TG secretion rate.     

Regional disposal of intravenously infused glucose during prolonged hyperglycemia-hyperinsulinemia

We measured splanchnic and leg glucose uptake during prolonged (i.e., 15 hours), moderate hyperglycemia-hyperinsulinemia (clamp). Plasma free fatty acid (FFA) concentration was maintained at basal concentration during the clamp via infusion of exogenous lipids and heparin in healthy volunteers to create a metabolic profile similar to glucose intolerance (i.e., hyperglycemia-hyperinsulinemia with elevated FFA concentration). During the clamp, glucose was infused at an average rate of 49 +/- 4 micromol/kg/min, which resulted in a plasma glucose concentration of 8.8 +/- 0.5 mmol/L compared with a concentration of 4.4 +/- 0.2 mmol/L in the basal state (P < 0.05). Insulin concentration increased from 5.5 +/- 1.1 microU/mL (basal) to 31.3 +/- 12.7 microU/mL (clamp; P < 0.05), whereas plasma FFA concentration was similar in the two conditions (3.9 +/- 0.5 mmol/L and 4.1 +/- 0.5 mmol/L, basal and clamp, respectively). Glucose balance across the splanchnic region switched from net release (-5.8 +/- 0.7 micromol/kg/min) in the basal state to net uptake in the clamp (19.8 +/- 3.7 micromol/kg/min; P < 0.05) and accounted for approximately 40% of the infused glucose. Glucose uptake across the leg was 0.7 +/- 0.2 micromol/kg/min (basal) and 5.5 +/- 2.2 micromol/kg/min (clamp; P < 0.05). In summary, tissues in the splanchnic region (i.e., liver) are important for disposal of intravenously infused glucose during prolonged, moderate hyperglycemia-hyperinsulinemia. Accelerated hepatic glucose uptake may disrupt normal liver metabolism, with potentially dangerous consequences for the patient. Measures to control systemic glucose concentration may be necessary to prevent excessive glucose disposal in the liver.     

Sex-specific influence of aging on exercising leg blood flow.

Our previous work suggests that healthy human aging is associated with sex-specific differences in leg vascular responses during large muscle mass exercise (2-legged cycling) (Proctor DN, Parker BA. Microcirculation 13: 315-327, 2006). The present study determined whether age x sex interactions in exercising leg hemodynamics persist during small muscle mass exercise that is not limited by cardiac output. Thirty-one young (20-30 yr; 15 men/16 women) and 31 older (60-79 yr; 13 men/18 women) healthy, normally active adults performed graded single-leg knee extensions to maximal exertion. Femoral artery blood velocity and diameter (Doppler ultrasound), heart rate (ECG), and beat-to-beat arterial blood pressure (mean arterial pressure, radial artery tonometry) were measured during each 3-min work rate (4.8 and 8 W/stage for women and men, respectively). The results (means +/- SE) were as follows. Despite reduced resting leg blood flow and vascular conductance, older men exhibited relatively preserved exercising leg hemodynamic responses. Older women, by contrast, exhibited attenuated hyperemic (young: 52 +/- 3 ml.min(-1).W(-1); vs. older: 40 +/- 4 ml.min(-1).W(-1); P = 0.02) and vasodilatory responses (young: 0.56 +/- 0.06 ml.min(-1).mmHg(-1).W(-1) vs. older: 0.37 +/- 0.04 ml.min(-1).mmHg(-1) W(-1); P < 0.01) to exercise compared with young women. Relative (percentage of maximal) work rate comparisons of all groups combined also revealed attenuated vasodilator responses in older women (P < 0.01 for age x sex x work rate interaction). These sex-specific age differences were not abolished by consideration of hemoglobin, quadriceps muscle, muscle recruitment, and mechanical influences on muscle perfusion. Collectively, these findings suggest that local factors contribute to the sex-specific effects of aging on exercising leg hemodynamics in healthy adults.     

Glucose ingestion blunts hormone-sensitive lipase activity in contracting human skeletal muscle

To examine the effect of attenuated epinephrine and elevated insulin on intramuscular hormone sensitivity lipase activity (HSLa) during exercise, seven men performed 120 min of semirecumbent cycling (60% peak pulmonary oxygen uptake) on two occasions while ingesting either 250 ml of a 6.4% carbohydrate (GLU) or sweet placebo (CON) beverage at the onset of, and at 15 min intervals throughout, exercise. Muscle biopsies obtained before and immediately after exercise were analyzed for HSLa. Blood samples were simultaneously obtained from a brachial artery and a femoral vein before and during exercise, and leg blood flow was measured by thermodilution in the femoral vein. Net leg glycerol and lactate release and net leg glucose and free fatty acid (FFA) uptake were calculated from these measures. Insulin and epinephrine were also measured in arterial blood before and throughout exercise. During GLU, insulin was elevated (120 min: CON, 11.4 +/- 2.4, GLU, 35.3 +/- 6.9 pM, P < 0.05) and epinephrine suppressed (120 min: CON, 6.1 +/- 2.5, GLU, 2.1 +/- 0.9 nM; P < 0.05) compared with CON. Carbohydrate feeding also resulted in suppressed (P < 0.05) HSLa relative to CON (120 min: CON, 1.71 +/- 0.18, GLU, 1.27 +/- 0.16 mmol.min-1.kg dry mass-1). There were no differences in leg lactate or glycerol release when trials were compared, but leg FFA uptake was lower (120 min: CON, 0.29 +/- 0.06, GLU, 0.82 +/- 0.09 mmol/min) and leg glucose uptake higher (120 min: CON, 3.16 +/- 0.59, GLU, 1.37 +/- 0.37 mmol/min) in GLU compared with CON. These results demonstrate that circulating insulin and epinephrine play a role in HSLa in contracting skeletal muscle.     

Muscle metaboreflex modulates the arterial baroreflex dynamic effects on peripheral vascular conductance in humans

We aimed to investigate the interaction between the arterial baroreflex and muscle metaboreflex [as reflected by alterations in the dynamic responses shown by leg blood flow (LBF: by the ultrasound Doppler method), leg vascular conductance (LVC), mean arterial blood pressure (MAP), and heart rate (HR)] in humans. In 12 healthy subjects (10 men and 2 women), who performed sustained 1-min handgrip exercise at 50% maximal voluntary contraction followed immediately by an imposed postexercise muscle ischemia (PEMI), 5-s periods of neck pressure (NP; 50 mmHg) or neck suction (NS; -60 mmHg) were used to evaluate carotid baroreflex function both at rest (Con) and during PEMI. First, the decreases in LVC and LBF and the augmentation of MAP elicited by NP were all greater during PEMI than in Con (DeltaLVC, -1.2 +/- 0.2 vs. -1.9 +/- 0.2 ml.min(-1).mmHg(-1); DeltaLBF, -97.3 +/- 11.2 vs. -177.0 +/- 21.8 ml/min; DeltaMAP, 6.7 +/- 1.2 vs. 11.5 +/- 1.4 mmHg, Con vs. PEMI; each P < 0.05). Second, in Con, NS significantly increased both LVC and LBF (DeltaLVC, 0.9 +/- 0.2 ml.min(-1).mmHg(-1); DeltaLBF, 46.6 +/- 9.8 ml/min; significant change from baseline: each P < 0.05), and, whereas during PEMI no significant increases in LVC and LBF occurred during NS itself (DeltaLVC, 0.2 +/- 0.1 ml.min(-1).mmHg(-1); DeltaLBF, 10.8 +/- 9.6 ml/min; each P > 0.05), a decrease was evident in each parameters at 5 s after the cessation of NS. Third, during PEMI, the decrease in MAP elicited by NS was smaller (DeltaMAP, -8.4 +/- 1.0 vs. -5.8 +/- 0.4 mmHg, Con vs. PEMI; P < 0.05), and it recovered to its initial level more quickly after NS (vs. Con). Finally, however, the HR responses to NS and NP were not different between PEMI and Con. These results suggest that during muscle metaboreflex activation in humans, the arterial baroreflex dynamic effect on peripheral vascular conductance is modulated, as exemplified by 1) an augmentation of the NP-induced LVC decrease, and 2) a loss of the NS-induced LVC increase.     

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with (2)H(2)O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (~450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 micromol/l (P < 0.001), EGP from 15.7 to 2.0 micromol x kg(-1) x min(-1) (P < 0.01), GNG from 8.2 to 3.7 micromol x kg(-1). min(-1) (P < 0.05), and GL from 7.4 to -1.7 micromol x kg(-1). min(-1) (P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 micromol/l (P < 0.001). EGP decreased 64% less than during insulin alone (-5.1 +/- 0.7 vs. -13.7 +/- 3.4 micromol x kg(-1). min(-1)). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (-2.6 vs. -4.5 micromol x kg(-1). min(-1), not significant). In contrast, GL decreased 66% less than during insulin alone (-3.1 vs. -9.2 micromol x kg(-1). min(-1), P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.     

Forearm blood flow follows work rate during submaximal dynamic forearm exercise independent of sex.

To test the hypothesis that sex influences forearm blood flow (FBF) during exercise, 15 women and 16 men of similar age [women 24.3 +/- 4.0 (SD) vs. men 24.9 +/- 4.5 yr] but different forearm muscle strength (women 290.7 +/- 44.4 vs. men 509.6 +/- 97.8 N; P < 0.05) performed dynamic handgrip exercise as the same absolute workload was increased in a ramp function (0.25 W/min). Task failure was defined as the inability to maintain contraction rate. Blood pressure and FBF were measured on separate arms during exercise by auscultation and Doppler ultrasound, respectively. Muscle strength was positively correlated with endurance time (r = 0.72, P < 0.01) such that women had a shorter time to task failure than men (450.5 +/- 113.0 vs. 831.3 +/- 272.9 s; P < 0.05). However, the percentage of maximal handgrip strength achieved at task failure was similar between sexes (14% maximum voluntary contraction). FBF was similar between women and men throughout exercise and at task failure (women 13.6 +/- 5.3 vs. men 14.5 +/- 4.9 ml.min(-1).100 ml(-1)). Mean arterial pressure was lower in women at rest and during exercise; thus calculated forearm vascular conductance (FVC) was higher in women during exercise but similar between sexes at task failure (women 0.13 +/- 0.05 vs. men 0.11 +/- 0.04 ml.min(-1).100 ml(-1).mmHg(-1)). In conclusion, the similar FBF during exercise was achieved by a higher FVC in the presence of a lower MAP in women than men. Still, FBF remained coupled to work rate (and presumably metabolic demand) during exercise irrespective of sex.     

No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise.

The systemic flux of glycerol and palmitate [a representative nonesterified free fatty acid (NEFA)] was assessed in three different phases of the menstrual cycle at rest and during moderate-intensity exercise. It was hypothesized that circulating glycerol and NEFA turnover would be greatest in the midfollicular (MF) phase of the menstrual cycle, when estrogen is elevated but progesterone low, followed by the midluteal phase (ML; high estrogen and progesterone), and lowest in the early follicular (EF) phase of the menstrual cycle (low estrogen and progesterone). Subjects included moderately active, eumenorrheic, healthy women. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting and exercise (50% maximal oxygen uptake, 90 min) measurements of tracer-determined glycerol and palmitate kinetics were made. There was a significant increase in both glycerol and palmitate turnover from rest to exercise in all phases of the menstrual cycle (P<0.0001). No significant differences, however, were observed between cycle phases in the systemic flux of glycerol or palmitate, at rest or during exercise. Maximal peripheral lipolysis during exercise, as represented by glycerol rate of appearance at 90 min, equaled 8.45+/-0.96, 8.35+/-1.12, and 7.71+/-0.96 micromol.kg-1.min-1 in the EF, MF, and ML phases, respectively. Circulating free fatty acid utilization also peaked at 90 min of exercise, as indicated by the palmitate rate of disappearance (3.31+/-0.35, 3.17+/-0.39, and 3.47+/-0.26 micromol.kg-1.min-1) in the EF, MF, and ML phases, respectively. In conclusion, systemic rates of glycerol and NEFA turnover (as represented by palmitate flux) were not significantly affected by the cyclic fluctuations in estrogen and progesterone that occur throughout the normal menstrual cycle, either at rest or during 90 min of moderate exercise.     

Lipolysis and lipid oxidation in cirrhosis and after liver transplantation

On the basis of the finding that plasma glycerol concentration is not controlled by clearance in healthy humans, it has been proposed that elevated plasma free fatty acid (FFA) and glycerol concentrations in cirrhotic subjects are caused by accelerated lipolysis. This proposal has not been validated. We infused 10 volunteers, 10 cirrhotic subjects, and 10 patients after orthotopic liver transplantation (OLT) with [1-(13)C]palmitate and [(2)H(5)]glycerol to compare fluxes (R(a)) and FFA oxidation. Cirrhotic subjects had higher plasma palmitate (52%) and glycerol (33%) concentrations than controls. Palmitate R(a) was faster (1.45+/-0.18 vs. 0.85+/-0.17 micromol x kg(-1) x min(-1)) but glycerol R(a) and clearance slower (1.20+/-0.09 vs. 1.90+/-0.24 micromol x kg(-1) x min(-1) and 21.2+/-1.2 vs. 44.7+/- 4.9 ml x kg(-) x h(-1), respectively) than in controls. After OLT, plasma palmitate and glycerol concentrations and palmitate R(a) did not differ, but glycerol R(a) (1.16+/-0.11 micromol x kg(-1) x min(-1)) and clearance (26.7+/-2.4 ml x kg(-1) x h(-1)) were slower than in controls. We conclude that 1) impaired reesterification, not accelerated lipolysis, elevates FFA in cirrhotic subjects; 2) normalized FFA after OLT masks impaired reesterification; and 3) plasma glycerol concentration poorly reflects lipolytic rate in cirrhosis and after OLT.     

Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise

We examined 1) the effect of L-carnitine supplementation on free fatty acid (FFA) utilization during exercise and 2) exercise-induced alterations in plasma levels and skeletal muscle exchange of carnitine. Seven moderately trained human male subjects serving as their own controls participated in two bicycle exercise sessions (120 min, 50% of VO2max). The second exercise was preceded by 5 days of oral carnitine supplementation (CS; 5 g daily). Despite a doubling of plasma carnitine levels, with CS, there were no effects on exercise-induced changes in arterial levels and turnover of FFA, the relation between leg FFA inflow and FFA uptake, or the leg exchange of other substrates. Heart rate during exercise after CS decreased 7-8%, but O2 uptake was unchanged. Exercise before CS induced a fall from 33.4 +/- 1.6 to 30.8 +/- 1.0 (SE) mumol/l in free plasma carnitine despite a release (2.5 +/- 0.9 mumol/min) from the leg. Simultaneously, acylated plasma carnitine rose from 5.0 +/- 1.0 to 14.2 +/- 1.4 mumol/l, with no evidence of leg release. Consequently, total plasma carnitine increased. We concluded that in healthy subjects CS does not influence muscle substrate utilization either at rest or during prolonged exercise and that free carnitine released from muscle during exercise is presumably acylated in the liver and released to plasma.