Greater reliance on glycolysis is associated with lower mitochondrial substrate oxidation and insulin sensitivity in infant myogenic MSCs.

Individuals with insulin resistance and obesity display higher skeletal muscle production of nonoxidized glycolytic products (i.e., lactate), and lower complete mitochondrial substrate oxidation to CO2. These findings have also been observed in individuals without obesity and are associated with an increased risk for metabolic disease. The purpose of this study was to determine if substrate preference is evident at the earliest stage of life (birth) and to provide a clinical blood marker (lactate) that could be indicative of a predisposition for metabolic disease later. We used radiolabeled tracers to assess substrate oxidation and insulin sensitivity of myogenically differentiated mesenchymal stem cells (MSCs), a proxy of infant skeletal muscle tissue, derived from umbilical cords of full-term infants. We found that greater production of nonoxidized glycolytic products (lactate, pyruvate, alanine) is directly proportional to lower substrate oxidation and insulin sensitivity in MSCs. In addition, we found an inverse relationship between the ratio of complete glucose oxidation to CO2 and infant blood lactate at 1 mo of age. Collectively, considering that higher lactate was associated with lower MSC glucose oxidation and has been shown to be implicated with metabolic disease, it may be an early indicator of infant skeletal muscle phenotype.NEW & NOTEWORTHY In infant myogenically differentiated mesenchymal stem cells, greater production of nonoxidized glycolytic products was directly proportional to lower substrate oxidation and insulin resistance. Glucose oxidation was inversely correlated with infant blood lactate. This suggests that innate differences in infant substrate oxidation exist at birth and could be associated with the development of metabolic disease later in life. Clinical assessment of infant blood lactate could be used as an early indicator of skeletal muscle phenotype.

Electrical pulse stimulation induces differential responses in insulin action in myotubes from severely obese individuals.

KEY POINTS: Exercise/exercise training can enhance insulin sensitivity through adaptations in skeletal muscle, the primary site of insulin-mediated glucose disposal; however, in humans the range of improvement can vary substantially. The purpose of this study was to determine if obesity influences the magnitude of the exercise response in relation to improving insulin sensitivity in human skeletal muscle. Electrical pulse stimulation (EPS; 24 h) of primary human skeletal muscle myotubes improved insulin action in tissue from both lean and severely obese individuals, but responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise-responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects. ABSTRACT: Exercise/muscle contraction can enhance whole-body insulin sensitivity; however, in humans the range of improvements can vary substantially. In order, to determine if obesity influences the magnitude of the exercise response, this study compared the effects of electrical pulse stimulation (EPS)-induced contractile activity upon primary myotubes derived from lean and severely obese (BMI ≥ 40 kg/m2 ) women. Prior to muscle contraction, insulin action was compromised in myotubes from the severely obese as was evident from reduced insulin-stimulated glycogen synthesis, glucose oxidation, glucose uptake, insulin signal transduction (IRS1, Akt, TBC1D4), and insulin-stimulated GLUT4 translocation. EPS (24 h) increased AMP, IMP, AMPK Thr172 phosphorylation, PGC1α content, and insulin action in myotubes of both the lean and severely obese subjects. However, despite normalizing indices of insulin action to levels seen in the lean control (non-EPS) condition, responses to EPS were blunted with obesity. EPS improved insulin signal transduction in myotubes from lean but not severely obese subjects and EPS increased AMP accumulation and AMPK Thr172 phosphorylation, but to a lesser degree in myotubes from the severely obese. These data reveal that myotubes of severely obese individuals enhance insulin action and stimulate exercise-responsive molecules with contraction, but in a manner and magnitude that differs from lean subjects.

Intellectual development is positively related to intrinsic motivation and course grades for female but not male students.

We hypothesized that the intellectual development of students, i.e., their beliefs about the nature of knowledge and learning, affects their intrinsic motivation and class performance. Specifically, we hypothesized that students with low intellectual development (i.e., the naive beliefs that knowledge is simple, absolute, and certain) have low intrinsic motivation and low class performance, whereas students with high intellectual development (i.e., more sophisticated beliefs that knowledge is complex, tentative, and evolving) have high intrinsic motivation and class performance. To test this hypothesis, we administered the Learning Context Questionnaire to measure intellectual development. In addition, we administered the Intrinsic Motivation Inventory to assess our students' intrinsic motivation. Furthermore, we performed regression analyses between intellectual development with both intrinsic motivation and class performance. The results document a positive relationship among intellectual development, intrinsic motivation, and class performance for female students only. In sharp contrast, there was a negative relationship between intellectual development, intrinsic motivation, and class performance for male students. The slope comparisons documented significant differences in the slopes relating intellectual development, intrinsic motivation, and class performance between female and male students. Thus, female students with more sophisticated beliefs that knowledge is personally constructed, complex, and evolving had higher intrinsic motivation and class performance. In contrast, male students with the naive beliefs that the structure of knowledge is simple, absolute, and certain had higher levels of intrinsic motivation and class performance. The results suggest that sex influences intellectual development, which has an effect on intrinsic motivation for learning a specific topic.

Fasting plasma lactate as a possible early clinical marker for metabolic disease risk.

BACKGROUND AND AIM: Elevated fasting plasma lactate concentrations are evident in individuals with metabolic diseases. However, it has yet to be determined if these associations exist in a young, healthy population as a possible early marker for metabolic disease risk. The purpose of this study was to determine if indices of the metabolic syndrome are related to plasma lactate concentrations in this population. METHODS: Fifty (29 ± 7 yr) men (n = 19) and women (n = 31) classified as overweight (26.4 ± 1.8 kg/m2) participated in this observational study. Blood pressure and blood metabolites were measured after an overnight fast. Lactate was also measured before and after a three-day eucaloric high-fat (70 %) diet. The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. Visceral adipose tissue mass was determined via dual X-ray absorptiometry. RESULTS: Triglycerides (r = 0.55, p=<0.0001), HOMA-IR (r = 0.53, p=<0.0001), and systolic and diastolic (both, r = 0.36, p = 0.01) blood pressures associated with fasting plasma lactate. No differences in visceral adipose tissue existed between the sexes (p = 0.41); however, the relationship between visceral adipose tissue and lactate existed only in females (r = 0.59, p = 0.02) but not in males (p = 0.53). Fasting lactate and HOMA-IR increased in males (p = 0.01 and p = 0.02, respectively), but not females, following a three-day high-fat diet. CONCLUSION: Indices of the metabolic syndrome associated with fasting plasma lactates in young relatively healthy individuals. Fasting lactate also increased in a sex-specific manner after a three-day high fat diet. Thus, lactate could become a clinical marker for metabolic disease risk.

Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT.

While the benefits of exercise are clear, many unresolved issues surround the optimal exercise prescription. Many organizations recommend aerobic training (AT) and resistance training (RT), yet few studies have compared their effects alone or in combination. The purpose of this study, part of Studies Targeting Risk Reduction Interventions Through Defined Exercise-Aerobic Training and/or Resistance Training (STRRIDE/AT/RT), was to compare the effects of AT, RT, and the full combination (AT/RT) on central ectopic fat, liver enzymes, and fasting insulin resistance [homeostatic model assessment (HOMA)]. In a randomized trial, 249 subjects [18-70 yr old, overweight, sedentary, with moderate dyslipidemia (LDL cholesterol 130-190 mg/dl or HDL cholesterol ≤ 40 mg/dl for men or ≤ 45 mg/dl for women)] performed an initial 4-mo run-in period. Of these, 196 finished the run-in and were randomized into one of the following 8-mo exercise-training groups: 1) RT, which comprised 3 days/wk, 8 exercises, 3 sets/exercise, 8-12 repetitions/set, 2) AT, which was equivalent to ∼19.2 km/wk (12 miles/wk) at 75% peak O(2) uptake, and 3) full AT + full RT (AT/RT), with 155 subjects completing the intervention. The primary outcome variables were as follows: visceral and liver fat via CT, plasma liver enzymes, and HOMA. AT led to significant reductions in liver fat, visceral fat, alanine aminotransferase, HOMA, and total and subcutaneous abdominal fat (all P < 0.05). RT resulted in a decrease in subcutaneous abdominal fat (P < 0.05) but did not significantly improve the other variables. AT was more effective than RT at improving visceral fat, liver-to-spleen ratio, and total abdominal fat (all P < 0.05) and trended toward a greater reduction in liver fat score (P < 0.10). The effects of AT/RT were statistically indistinguishable from the effects of AT. These data show that, for overweight and obese individuals who want to reduce measures of visceral fat and fatty liver infiltration and improve HOMA and alanine aminotransferase, a moderate amount of aerobic exercise is the most time-efficient and effective exercise mode.

The association between lactate and muscle aerobic substrate oxidation: Is lactate an early marker for metabolic disease in healthy subjects?

Fasting plasma lactate concentrations are elevated in individuals with metabolic disease. The aim of this study was to determine if the variance in fasting lactate concentrations were associated with factors linked with cardiometabolic health even in a young, lean cohort. Young (age 22 ± 0.5; N = 30) lean (BMI (22.4 ± 0.4 kg/m2 ) women were assessed for waist-to-hip ratio, aerobic capacity (VO2 peak), skeletal muscle oxidative capacity (near infrared spectroscopy; fat oxidation from muscle biopsies), and fasting glucose and insulin (HOMA-IR). Subjects had a mean fasting lactate of 0.9 ± 0.1 mmol/L. The rate of deoxygenation of hemoglobin/myoglobin (R2  = .23, p = .03) in resting muscle and skeletal muscle homogenate fatty acid oxidation (R2  = .72, p = .004) were inversely associated with fasting lactate. Likewise, cardiorespiratory fitness (time to exhaustion during the VO2 peak test) was inversely associated with lactate (R2  = .20, p = .05). Lactate concentration was inversely correlated with HDL:LDL (R2  = .57, p = .02) and positively correlated with the waist to hip ratio (R2  = .52, p = .02). Plasma lactate was associated with various indices of cardiometabolic health. Thus, early determination of fasting lactate concentration could become a common biomarker used for identifying individuals at early risk for metabolic diseases.

Prescribed exercise to Reduce Recidivism After Weight Loss-Pilot (PREVAIL-P): Design, methods and rationale.

Clinically significant weight loss is associated with health benefits for overweight and obese adults. Participation in adequate amounts of physical activity is critical for weight maintenance. However, the recommended amount of physical activity needed to promote weight maintenance is based primarily on retrospective studies that quantified physical activity levels through questionnaires which tend to overestimate physical activity levels. In addition, the present literature has provided little data on the impact of these physical activity levels on cardiovascular and diabetes risk factors, which may have equal or more clinical importance than weight changes. The Prescribed Exercise to Reduce Recidivism After Weight Loss-Pilot (PREVAIL-P) study will evaluate the effect of aerobic exercise training amount on weight maintenance following clinically significant weight loss in overweight and obese adults (BMI 25-40 kg/m2) age 30-65 years. Participants (N = 39) will complete a 10-week OPTIFAST® weight loss program with supervised aerobic exercise training. Individuals who achieve ≥7% weight loss from baseline will be subsequently randomized to levels of aerobic training consistent with physical activity recommendations (PA-REC) or weight maintenance recommendations (WM-REC) for 18 additional weeks. The primary outcome of the PREVAIL-P study will be change in weight from the completion of OPTIFAST® program to the end of the study. Notable secondary measures include changes in clinically relevant cardiometabolic risk factors between study groups (e.g. blood lipids concentrations, oral glucose tolerance, arterial stiffness). This pilot study will be used to estimate the effect sizes needed for a randomized controlled trial on this topic.

Effect of exercise intensity and volume on persistence of insulin sensitivity during training cessation.

The purpose of this study was to determine whether exercise prescriptions differing in volume or intensity also differ in their ability to retain insulin sensitivity during an ensuing period of training cessation. Sedentary, overweight/obese subjects were assigned to one of three 8-mo exercise programs: 1) low volume/moderate intensity [equivalent of approximately 12 miles/wk, 1,200 kcal/wk at 40-55% peak O(2) consumption (Vo(2peak)), 200 min exercise/wk], 2) low volume/vigorous intensity ( approximately 12 miles/wk, 1,200 kcal/wk at 65-80% Vo(2peak), 125 min/wk), and 3) high volume/vigorous intensity ( approximately 20 miles/wk, 2,000 kcal/wk at 65-80% Vo(2peak), 200 min/wk). Insulin sensitivity (intravenous glucose tolerance test, S(I)) was measured when subjects were sedentary and at 16-24 h and 15 days after the final training bout. S(I) increased with training compared with the sedentary condition (P < or = 0.05) at 16-24 h with all of the exercise prescriptions. S(I) decreased to sedentary, pretraining values after 15 days of training cessation in the low-volume/vigorous-intensity group. In contrast, at 15 days S(I) was significantly elevated compared with sedentary (P < or = 0.05) in the prescriptions utilizing 200 min/wk (low volume/moderate intensity, high volume/vigorous intensity). In the high-volume/vigorous-intensity group, indexes of muscle mitochondrial density followed a pattern paralleling insulin action by being elevated at 15 days compared with pretraining; this trend was not evident in the low-volume/moderate-intensity group. These findings suggest that in overweight/obese subjects a relatively chronic persistence of enhanced insulin action may be obtained with endurance-oriented exercise training; this persistence, however, is dependent on the characteristics of the exercise training performed.

Plasma lactate as a marker of metabolic health: Implications of elevated lactate for impairment of aerobic metabolism in the metabolic syndrome.

BACKGROUND: Fasting lactate is elevated in metabolic diseases and could possibly be predictive of the risk of developing the metabolic syndrome. METHODS: Plasma samples were analyzed for fasting lactate to compare lean subjects, nondiabetic subjects with severe obesity, and metabolically impaired subjects. Subjects with severe obesity were studied 1 week before and 1 week to 9 months after gastric bypass surgery. Subjects with components of the metabolic syndrome were studied before and after 6 months of an exercise intervention. RESULTS: Metabolically impaired subjects had higher fasting lactate concentrations (P < .0001) and respond to a glucose or insulin challenge with higher lactates than non-obese subjects (P < .004). Lactate was significantly reduced a week after gastric bypass surgery (P < .05) and further reduced 1 to 9 months after surgery (0.95 ± 0.04 mM in non-obese, 1.26 ± 0.12 mM in subjects with severe obesity, and 0.68 ± 0.03 mM 1-3 months after gastric bypass). Six months of chronic exercise resulted in a 16% reduction (P = .028) in fasting lactate. CONCLUSION: Fasting plasma lactate was elevated in obese subjects with the metabolic syndrome compared with healthy lean individuals. Lactate was reduced by exercise and bariatric surgery, interventions that improve metabolic health and risk for subsequent disease. The results of this study and those previously published by our research group suggest that elevated lactate may be caused by an impairment in aerobic metabolism and may offer a metric assessing the severity of the metabolic syndrome.

Mechanism for improved insulin sensitivity after gastric bypass surgery.

CONTEXT: Surgical treatments of obesity have been shown to induce rapid and prolonged improvements in insulin sensitivity. OBJECTIVE: The aim of the study was to investigate the effects of gastric bypass surgery and the mechanisms that explain the improvement in insulin sensitivity. DESIGN: We performed a cross-sectional, nonrandomized, controlled study. SETTING: This study was conducted jointly between the Departments of Exercise Science and Physiology at East Carolina University in Greenville, North Carolina. SUBJECTS: Subjects were recruited into four groups: 1) lean [body mass index (BMI) < 25 kg/m(2); n = 93]; 2) weight-matched (BMI = 25 to 35 kg/m(2); n = 310); 3) morbidly obese (BMI > 35 kg/m(2); n = 43); and 4) postsurgery patients (BMI approximately 30 kg/m(2); n = 40). Postsurgery patients were weight stable 1 yr after surgery. MAIN OUTCOME MEASURES: Whole-body insulin sensitivity, muscle glucose transport, and muscle insulin signaling were assessed. RESULTS: Postsurgery subjects had insulin sensitivity index values that were similar to the lean and higher than morbidly obese and weight-matched control subjects. Glucose transport was higher in the postsurgery vs. morbidly obese and weight-matched groups. IRS1-pSer(312) in the postsurgery group was lower than morbidly obese and weight-matched groups. Inhibitor kappaBalpha was higher in the postsurgery vs. the morbidly obese and weight-matched controls, indicating reduced inhibitor of kappaB kinase beta activity. CONCLUSIONS: Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the weight-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addition to, weight loss. Improved insulin sensitivity is related to reduced inhibitor of kappaB kinase beta activity and enhanced insulin signaling in muscle.

Impact of hormone replacement therapy on exercise training-induced improvements in insulin action in sedentary overweight adults.

Exercise training (ET) and hormone replacement therapy (HRT) are both recognized influences on insulin action, but the influence of HRT on responses to ET has not been examined. To determine if HRT use provided additive benefits for the response of insulin action to ET, we evaluated the impact of HRT use on changes in insulin during the course of a randomized, controlled, aerobic ET intervention. Subjects at baseline were sedentary, dyslipidemic, and overweight. These individuals were randomized to 6 months of one of 3 aerobic ET interventions or continued physical inactivity. In 206 subjects, an insulin sensitivity index (S(I)) was obtained with a frequently sampled intravenous glucose tolerance test pre- and post-ET. Baseline and postintervention fitness, regional adiposity, general adiposity, skeletal muscle biochemistry and histology, and serum lipoproteins were measured as other putative mediators influencing insulin action. Two-way analyses of variance were used to determine if sex or HRT use influenced responses to exercise training. Linear modeling was used to determine if predictors for response in S(I) differed by sex or HRT use(.) Women who used HRT (HRT+) demonstrated significantly greater improvements in S(I) with ET than women not using HRT (HRT-). In those HRT+ women, plasma triglyceride change best correlated with change in S(I). For HRT- women, capillary density change and, for men, subcutaneous adiposity change best correlated with change in S(I). In summary, in an ET intervention, HRT use appears to be associated with more robust responses in insulin action. Furthermore, relationships between ET-induced changes in insulin action and potential mediators of change in insulin action are different for men, and for women on or off HRT. These findings have implications for the relative utility of ET for improving insulin action in middle-aged men and women, particularly in the setting of differences in HRT use.

Exercise Effects on Adipose Tissue Postprandial Lipolysis and Blood Flow in Children.

Poor suppression of lipolysis and blunted increase in blood flow after meal ingestion in obese adults may indicate resistance to the antilipolytic action of insulin. Exercise may be used to normalize lipolytic responses to food intake by increasing insulin sensitivity. PURPOSE: To determine if acute bouts of aerobic exercise and/or excise training alter lipolytic and blood flow responses to food intake in lean (LN) and obese (OB) children. METHODS: Sixty-five children (9-11 yr) were randomized into acute exercise (EX: 16 LN and 28 OB) or control (CON: 9 LN and 12 OB) groups that exercised (EX), or rested (CON) between standardized breakfast and lunch. Microdialysis probes were inserted into the subcutaneous abdominal adipose tissue to monitor interstitial glycerol (lipolysis) and blood flow. Changes in interstitial glycerol and nutritive flow were calculated from dialysate samples before and after each meal. A subgroup (OB = 15 and LN = 9) from the acute exercise group underwent 16 wk of aerobic exercise training. RESULTS: Poor suppression of lipolysis and a blunted increase in adipose tissue nutritive blood flow in response to breakfast was associated with BMI percentile (r = 0.3, P < 0.05). These responses were normalized at lunch in the OB in the EX (P < 0.05), but not in OB in the CON. Sixteen weeks of exercise training did not improve meal-induced blood flow and marginally altered the antilipolytic response to the two meals (P = 0.06). CONCLUSIONS: Daily bouts of acute aerobic exercise should be used to improve the antilipolytic and nutritive blood flow response to a subsequent meal in obese children.

Exercise training amount and intensity effects on metabolic syndrome (from Studies of a Targeted Risk Reduction Intervention through Defined Exercise).

Although exercise improves individual risk factors for metabolic syndrome (MS), there is little research on the effect of exercise on MS as a whole. The objective of this study was to determine how much exercise is recommended to decrease the prevalence of MS. Of 334 subjects randomly assigned, 227 finished and 171 (80 women, 91 men) had complete data for all 5 Adult Treatment Panel III-defined MS risk factors and were included in this analysis. Subjects were randomly assigned to a 6-month control or 1 of 3 eight-month exercise training groups of (1) low amount/moderate intensity (equivalent to walking approximately 19 km/week), (2) low amount/vigorous intensity (equivalent to jogging approximately 19 km/week), or (3) high amount/vigorous intensity (equivalent to jogging approximately 32 km/week). The low-amount/moderate-intensity exercise prescription improved MS relative to inactive controls (p <0.05). However, the same amount of exercise at vigorous intensity was not significantly better than inactive controls, suggesting that lower-intensity exercise may be more effective in improving MS. The high-amount/vigorous-intensity group improved MS relative to controls (p <0.0001), the low-amount/vigorous-intensity group (p = 0.001), and the moderate-intensity group (p = 0.07), suggesting an exercise-dose effect. In conclusion, a modest amount of moderate-intensity exercise in the absence of dietary changes significantly improved MS and thus supported the recommendation that adults get 30 minutes of moderate-intensity exercise every day. A higher amount of vigorous exercise had greater and more widespread benefits. Finally, there was an indication that moderate-intensity may be better than vigorous-intensity exercise for improving MS.

Inactivity, exercise training and detraining, and plasma lipoproteins. STRRIDE: a randomized, controlled study of exercise intensity and amount.

Exercise has beneficial effects on lipoproteins. Little is known about how long the effects persist with detraining or whether the duration of benefit is effected by training intensity or amount. Sedentary, overweight subjects (n = 240) were randomized to 6-mo control or one of three exercise groups: 1) high-amount/vigorous-intensity exercise; 2) low-amount/vigorous-intensity exercise; or 3) low-amount/moderate-intensity exercise. Training consisted of a gradual increase in amount of exercise followed by 6 mo of exercise at the prescribed level. Exercise included treadmill, elliptical trainer, and stationary bicycle. The number of minutes necessary to expend the prescribed kilocalories per week (14 kcal x kg body wt(-1) x wk(-1) for both low-amount groups; 23 kcal x kg body wt(-1) x wk(-1) for high-amount group) was calculated for each subject. Average adherence was 83-92% for the three groups; minutes per week were 207, 125, and 203 and sessions per week were 3.6, 2.9, and 3.5 for high-amount/vigorous-intensity, low-amount/vigorous intensity, and low-amount/moderate-intensity groups, respectively. Plasma was obtained at baseline, 24 h, 5 days, and 15 days after exercise cessation. Continued inactivity resulted in significant increases in low-density lipoprotein (LDL) particle number, small dense LDL, and LDL-cholesterol. A modest amount of exercise training prevented this deterioration. Moderate-intensity but not vigorous-intensity exercise resulted in a sustained reduction in very-low-density lipoprotein (VLDL)-triglycerides over 15 days of detraining (P < 0.05). The high-amount group had significant improvements in high-density lipoprotein (HDL)-cholesterol, HDL particle size, and large HDL levels that were sustained for 15 days after exercise stopped. In conclusion, physical inactivity has profound negative effects on lipoprotein metabolism. Modest exercise prevented this. Moderate-intensity but not vigorous-intensity exercise resulted in sustained VLDL-triglyceride lowering. Thirty minutes per day of vigorous exercise, like jogging, has sustained beneficial effects on HDL metabolism.

Response of high-sensitivity C-reactive protein to exercise training in an at-risk population.

BACKGROUND: High-sensitivity C-reactive protein (hsCRP) is promoted as an independent predictor of atherosclerotic risk. In addition, cardiorespiratory fitness is inversely related to hsCRP in single-sex cross-sectional analyses. Our objective was to determine if modulating fitness with exercise training imposes changes in high-sensitivity C-reactive protein in a mixed-sex population at risk for cardiovascular disease. METHODS: We studied baseline and postintervention plasma hsCRP in 193 sedentary, overweight to mildly obese, dyslipidemic men and women who were randomized to 6 months of inactivity or 1 of 3 aerobic exercise groups: low amount-moderate intensity (energy equivalent of approximately 19.3 km/wk at 40%-55% peak VO2), low amount-high intensity (energy equivalent of approximately 19.3 km/wk at 65%-80% peak VO2), or high amount-high intensity (energy equivalent of approximately 32.2 km/wk at 65%-80% peak VO2). RESULTS: At baseline, the study population was at intermediate to high cardiovascular risk as defined by hsCRP. Cardiorespiratory fitness was inversely related to hsCRP (P < .001) even after adjusting for significant and expected sex differences. Fitness, hormone replacement therapy use, and high-density lipoprotein cholesterol accounted for the sex difference in baseline hsCRP. Fitness, high-density lipoprotein cholesterol, fasting insulin, hormone replacement therapy, and visceral adiposity were all independent predictors for baseline hsCRP (r2 = 0.34 for the entire model, P < .0001). However, despite significant improvements in fitness, visceral adiposity, subcutaneous adiposity, and insulin sensitivity, hsCRP did not change in response to exercise training (P > .20). CONCLUSIONS: Cardiorespiratory fitness is inversely related to hsCRP independent of sex and accounts for most of the large sex disparity in hsCRP. Nonetheless, in the absence of a significant change in diet, 6 months of aerobic exercise training does not produce a significant change in hsCRP in an at-risk population.

L-citrulline reduces time to exhaustion and insulin response to a graded exercise test.

PURPOSE: Oral L-arginine supplementation has been shown to improve treadmill time to exhaustion and resting insulin sensitivity in individuals with peripheral vascular disease and type 2 diabetes, respectively. Furthermore, L-citrulline supplementation increases plasma L-arginine concentration to a level higher than that achieved by oral L-arginine supplementation. The purpose of this investigation was therefore to determine whether time to exhaustion during a graded treadmill test, as well as plasma insulin and glucose profiles, could be improved with oral L-citrulline supplementation in healthy individuals. METHODS: Seventeen young (18-34 yr), healthy male and female volunteers performed incremental treadmill tests to exhaustion following either placebo or citrulline ingestion (3 g 3 h before test, or 9 g over 24 h prior to testing). RESULTS: Steady-state submaximal respiratory exchange ratio and VO2max were not significantly different between placebo and citrulline trials. Treadmill time to exhaustion was lower following citrulline ingestion than during placebo trials (888.2 +/- 17.7 vs 895.4 +/- 17.9 s; P < 0.05; N = 17), which was accompanied by a higher rating of perceived exertion during exercise in the L-citrulline compared with the placebo condition. There was also an increase in plasma insulin in response to this high-intensity exercise in the placebo, but not in the L-citrulline, condition (P < 0.05). CONCLUSIONS: It can be concluded that, contrary to the hypothesized improvement in treadmill time following L-citrulline ingestion, there is a reduction in treadmill time following L-citrulline ingestion over the 24 h prior to testing. The normal response of increased plasma insulin following high-intensity exercise is also not present in the L-citrulline condition, indicating that L-citrulline ingestion may reduce nitric oxide-mediated pancreatic insulin secretion or increased insulin clearance.

Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects.

Increases in intramyocellular long-chain fatty acyl-CoAs (LCACoA) have been implicated in the pathogenesis of insulin resistance in skeletal muscle. To test this hypothesis, we measured muscle (vastus lateralis) LCACoA content and insulin action in morbidly obese patients (n = 11) before and after weight loss (gastric bypass surgery). The intervention produced significant weight loss (142.3 +/- 6.8 vs. 79.6 +/- 4.1 kg for before versus after surgery, respectively). Fasting insulin decreased by approximately 84% (23.3 +/- 3.8 vs. 3.8 +/- 0.5 mU/ml), and insulin sensitivity, as determined by minimal model, increased by approximately 360% (1.2 +/- 0.3 vs. 4.1 +/- 0.5 min(-1). [ micro U/kg(-1)]) indicating enhanced insulin action. Muscle palmityl CoA (16:0; 0.54 +/- 0.08 vs. 0.35 +/- 0.04 nmol/g wet wt) concentration decreased by approximately 35% (P < 0.05) with weight loss, whereas stearate CoA (18:0; -17%; 0.65 +/- 0.05 vs. 0.54 +/- 0.03 nmol/g wet wt) and linoleate CoA (18:2; -30%; 2.47 +/- 0.27 vs. 1.66 +/- 0.19 nmol/g wet wt) were also reduced (P < 0.05). There were no statistically significant declines in muscle palmitoleate CoA (16:1), oleate CoA (18:1), or total LCACoA content. These data suggest that a reduction in intramuscular LCACoA content may be responsible, at least in part, for the enhanced insulin action observed with weight loss in obese individuals.

Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells.

In humans, skeletal muscle is a major site of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) expression, but its function in this tissue is unclear. We investigated the role of hPPAR-alpha in regulating muscle lipid utilization by studying the effects of a highly selective PPAR-alpha agonist, GW7647, on [(14)C]oleate metabolism and gene expression in primary human skeletal muscle cells. Robust induction of PPAR-alpha protein expression occurred during muscle cell differentiation and corresponded with differentiation-dependent increases in oleate oxidation. In mature myotubes, 48-h treatment with 10-1,000 nmol/l GW7647 increased oleate oxidation dose-dependently, up to threefold. Additionally, GW7647 decreased oleate esterification into myotube triacylglycerol (TAG), up to 45%. This effect was not abolished by etomoxir, a potent inhibitor of beta-oxidation, indicating that PPAR-alpha-mediated TAG depletion does not depend on reciprocal changes in fatty acid catabolism. Consistent with its metabolic actions, GW7647 induced mRNA expression of mitochondrial enzymes that promote fatty acid catabolism; carnitine palmityltransferase 1 and malonyl-CoA decarboxylase increased approximately 2-fold, whereas pyruvate dehydrogenase kinase 4 increased 45-fold. Expression of several genes that regulate glycerolipid synthesis was not changed by GW7647 treatment, implicating involvement of other targets to explain the TAG-depleting effect of the compound. These results demonstrate a role for hPPAR-alpha in regulating muscle lipid homeostasis.

Analysis of insulin-stimulated insulin receptor activation and glucose transport in cultured skeletal muscle cells from obese subjects.

Obesity is associated with impaired insulin-stimulated glucose disposal in the skeletal muscle, but whether this is an intrinsic or acquired factor is unknown. In many patients with type 2 diabetes mellitus (T2D) and their nondiabetic relatives, who have a genetic predisposition for diabetes, insulin resistance is maintained in cultured muscle cells. To study the association of obesity with defects in insulin action, we investigated insulin stimulation of both insulin receptor (IR) autophosphorylation and subsequent glucose transport in primary skeletal muscle cell cultures obtained from both nonobese and obese nondiabetic subjects. In these 2 groups, there was no difference in the ability of insulin to induce autophosphorylation of the IR, phosphorylation of the downstream serine kinase Akt/PKB, or stimulation of glucose transport. Moreover, there were no major differences in cultured muscle cell content of either the IR, the IR antagonist PC-1, or GLUT 1 and GLUT 4. These data therefore indicate that the insulin resistance associated with obesity is not maintained in cultured muscle cells and suggest that this insulin resistance is an acquired feature of obesity.

Inactivity, exercise, and visceral fat. STRRIDE: a randomized, controlled study of exercise intensity and amount.

Despite the importance of randomized, dose-response studies for proper evaluation of effective clinical interventions, there have been no dose-response studies on the effects of exercise amount on abdominal obesity, a major risk factor for metabolic syndrome, diabetes, and cardiovascular disease. One hundred seventy-five sedentary, overweight men and women with mild to moderate dyslipidemia were randomly assigned to participate for 6 mo in a control group or for approximately 8 mo in one of three exercise groups: 1) low amount, moderate intensity, equivalent to walking 12 miles/wk (19.2 km) at 40-55% of peak oxygen consumption; 2) low amount, vigorous intensity, equivalent to jogging 12 miles/wk at 65-80% of peak oxygen consumption; or 3) high amount, vigorous intensity, equivalent to jogging 20 miles/wk (32.0 km). Computed tomography scans were analyzed for abdominal fat. Controls gained visceral fat (8.6 +/- 17.2%; P = 0.001). The equivalent of 11 miles of exercise per week, at either intensity, prevented significant accumulation of visceral fat. The highest amount of exercise resulted in decreased visceral (-6.9 +/- 20.8%; P = 0.038) and subcutaneous (-7.0 +/- 10.8%; P < 0.001) abdominal fat. Significant gains in visceral fat over only 6 mo emphasize the high cost of continued inactivity. A modest exercise program, consistent with recommendations from the Centers for Disease Control/American College of Sports Medicine (CDC/ACSM), prevented significant increases in visceral fat. Importantly, a modest increase over the CDC/ACSM exercise recommendations resulted in significant decreases in visceral, subcutaneous, and total abdominal fat without changes in caloric intake.