Microvascular Endothelial Dysfunction in Sedentary, Obese Humans Is Mediated by NADPH Oxidase: Influence of Exercise Training.

OBJECTIVE: The objectives of this study were to determine the impact of in vivo reactive oxygen species (ROS) on microvascular endothelial function in obese human subjects and the efficacy of an aerobic exercise intervention on alleviating obesity-associated dysfunctionality. APPROACH AND RESULTS: Young, sedentary men and women were divided into lean (body mass index 18-25; n=14), intermediate (body mass index 28-32.5; n=13), and obese (body mass index 33-40; n=15) groups. A novel microdialysis technique was utilized to detect elevated interstitial hydrogen peroxide (H2O2) and superoxide levels in the vastus lateralis of obese compared with both lean and intermediate subjects. Nutritive blood flow was monitored in the vastus lateralis via the microdialysis-ethanol technique. A decrement in acetylcholine-stimulated blood flow revealed impaired microvascular endothelial function in the obese subjects. Perfusion of apocynin, an NADPH oxidase inhibitor, lowered (normalized) H2O2 and superoxide levels, and reversed microvascular endothelial dysfunction in obese subjects. After 8 weeks of exercise, H2O2 levels were decreased in the obese subjects and microvascular endothelial function in these subjects was restored to levels similar to lean subjects. Skeletal muscle protein expression of the NADPH oxidase subunits p22phox, p47phox, and p67phox was increased in obese relative to lean subjects, where p22phox and p67phox expression was attenuated by exercise training in obese subjects. CONCLUSIONS: This study implicates NADPH oxidase as a source of excessive ROS production in skeletal muscle of obese individuals and links excessive NADPH oxidase-derived ROS to microvascular endothelial dysfunction in obesity. Furthermore, aerobic exercise training proved to be an effective strategy for alleviating these maladies.

Comparison of a field-based test to estimate functional threshold power and power output at lactate threshold.

It has been proposed that field-based tests (FT) used to estimate functional threshold power (FTP) result in power output (PO) equivalent to PO at lactate threshold (LT). However, anecdotal evidence from regional cycling teams tested for LT in our laboratory suggested that PO at LT underestimated FTP. It was hypothesized that estimated FTP is not equivalent to PO at LT. The LT and estimated FTP were measured in 7 trained male competitive cyclists (VO2max = 65.3 ± 1.6 ml O2·kg(-1)·min(-1)). The FTP was estimated from an 8-minute FT and compared with PO at LT using 2 methods; LT(Δ1), a 1 mmol·L(-1) or greater rise in blood lactate in response to an increase in workload and LT(4.0), blood lactate of 4.0 mmol·L(-1). The estimated FTP was equivalent to PO at LT(4.0) and greater than PO at LT(Δ1). VO2max explained 93% of the variance in individual PO during the 8-minute FT. When the 8-minute FT PO was expressed relative to maximal PO from the VO2max test (individual exercise performance), VO2max explained 64% of the variance in individual exercise performance. The PO at LT was not related to 8-minute FT PO. In conclusion, FTP estimated from an 8-minute FT is equivalent to PO at LT if LT(4.0) is used but is not equivalent for all methods of LT determination including LT(Δ1).

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.

Regulation of fat metabolism during resistance exercise in sedentary lean and obese men.

The effect of acute resistance exercise (RE) on whole body energy expenditure (EE) and alpha(2)-adrenergic receptor (alpha(2)-AR) regulation of lipolysis in subcutaneous abdominal adipose tissue (SCAAT) was determined in sedentary lean (LN) and obese (OB) men. Lipolysis was monitored using microdialysis in 10 LN [body mass index (BMI) 20.9 +/- 0.6] and 10 OB (BMI 36.2 +/- 2.7) men before, during, and for 24 h after RE. EE was measured before and immediately after RE for 40 min. Changes in interstitial glycerol were measured in SCAAT with three microdialysis probes perfused with a control solution, phentolamine (alpha(2)-AR antagonist), or propranolol (beta-AR antagonist). EE and fat oxidation (FOX) were significantly (P < 0.001) elevated immediately post-RE compared with pre-RE in LN and OB subjects, with no differences between groups. RE-induced increases in SCAAT glycerol concentrations from rest to peak exercise were greater in LN than in OB men in the control (LN 142.1 +/- 30.8 vs. OB 65.4 +/- 14.2%, P = 0.03) and phentolamine probes (LN 187.2 +/- 29.6 vs. OB 66.7 +/- 11.0%, P = 0.002). Perfusion of propranolol had no effect on interstitial glycerol concentrations over the time course of the experiment in either group. Plasma insulin concentrations were significantly lower (P = 0.002) and plasma growth hormone (GH) was significantly higher (P = 0.03) in LN compared with OB men. The mechanism behind RE contributing to improved body composition may in part be due to enhanced SCAAT lipolysis and improved EE and FOX in response to RE in LN and OB men. The blunted SCAAT lipolytic response to RE in OB compared with LN men is unrelated to RE-induced catecholamine activation of the antilipolytic alpha(2)-ARs and may be due to depressed GH in OB subjects.

High-intensity exercise to promote accelerated improvements in cardiorespiratory fitness (HI-PACE): study protocol for a randomized controlled trial.

BACKGROUND: African Americans have a disproportionate prevalence and incidence of type 2 diabetes compared with Caucasians. Recent evidence indicates that low cardiorespiratory fitness (CRF) level, an independent risk factor for type 2 diabetes, is also more prevalent in African Americans than Caucasians. Numerous studies in Caucasian populations suggest that vigorous exercise intensity may promote greater improvements in CRF and other type 2 diabetes risk factors (e.g., reduction of glucose/insulin levels, pulse wave velocity, and body fat) than moderate intensity. However, current evidence comparing health benefits of different aerobic exercise intensities on type 2 diabetes risk factors in African Americans is negligible. This is clinically important as African Americans have a greater risk for type 2 diabetes and are less likely to meet public health recommendations for physical activity than Caucasians. The purpose of the HI-PACE (High-Intensity exercise to Promote Accelerated improvements in CardiorEspiratory fitness) study is to evaluate whether high-intensity aerobic exercise elicits greater improvements in CRF, insulin action, and arterial stiffness than moderate-intensity exercise in African Americans. METHODS/DESIGN: A randomized controlled trial will be performed on overweight and obese (body mass index of 25-45 kg/m2) African Americans (35-65 years) (n = 60). Participants will be randomly assigned to moderate-intensity (MOD-INT) or high-intensity (HIGH-INT) aerobic exercise training or a non-exercise control group (CON) for 24 weeks. Supervised exercise will be performed at a heart rate associated with 45-55% and 70-80% of VO2 max in the MOD-INT and HIGH-INT groups, respectively, for an exercise dose of 600 metabolic equivalents of task (MET)-minutes per week (consistent with public health recommendations). The primary outcome is change in CRF. Secondary outcomes include change in insulin sensitivity (measured via an intravenous glucose tolerance test), skeletal muscle mitochondrial oxidative capacity (via near-infrared spectroscopy), skeletal muscle measurements (i.e., citrate synthase, COX IV, GLUT-4, CPT-1, and PGC1-α), arterial stiffness (via carotid-femoral pulse wave velocity), body fat, C-reactive protein, and psychological outcomes (quality of life/exercise enjoyment). DISCUSSION: The anticipated results of the HI-PACE study will provide vital information on the health effects of high-intensity exercise in African Americans. This study will advance health disparity research and has the potential to influence future public health guidelines for physical activity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02892331 . Registered on September 8, 2016.

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.

Randomized trial reveals that physical activity and energy expenditure are associated with weight and body composition after RYGB.

OBJECTIVE: This study investigated the associations of both physical activity time (PA) and energy expenditure (EE) with weight and fat mass (FM) loss in patients following Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Ninety-six nondiabetic patients were included in this analysis. Post-RYGB patients were randomized in one of two treatments: A 6-month exercise training program (RYBG+EX) or lifestyle educational classes (RYGB). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography. Components of PA and EE were quantified by a multisensory device. Dose-response relationships of both PA and EE with weight loss and body composition were explored according to quartiles of change in steps per day. RESULTS: Patients in the highest quartiles of steps per day change lost more FM (3rd = -19.5 kg and 4th = -22.7 kg, P < 0.05) and abdominal adipose tissue (4th = -313 cm2 , P < 0.05), maintained skeletal muscle mass (3rd = -3.1 cm2 and 4th = -4.5 cm2 , P < 0.05), and had greater reductions in resting metabolic rate. Decreases in sedentary EE and increases in light EE and age were significant predictors of both Δweight and ΔFM (R2 = 73.8% and R2 = 70.6%, respectively). CONCLUSIONS: Nondiabetic patients who perform higher, yet still modest, amounts of PA following RYGB have greater energy deficits and lose more weight and FM, while maintaining higher skeletal muscle mass.

Relationship among physical activity, sedentary behaviors, and cardiometabolic risk factors during gastric bypass surgery-induced weight loss.

BACKGROUND: The impact of daily physical activity (PA) on the cardiometabolic risk of bariatric surgery patients is not known. OBJECTIVE: We examined the influence of physical activity and sedentary behavior on modifying cardiometabolic risk after Roux-en-Y gastric bypass (RYGB) surgery. SETTING: University of Pittsburgh Medical Center and East Carolina University bariatric surgery centers. METHODS: Data from 43 women and 7 men who completed testing at 1-3 months after RYGB surgery and again at 9 months postsurgery were analyzed. Outcomes measured included PA level (min/d), steps/d, sedentary time, and body composition. Insulin sensitivity was determined with an intravenous glucose tolerance test. Weight and blood lipid profiles also were obtained. RESULTS: Patients reduced body mass index by a mean of -8.0±3.4 kg/m2 (P<.001), increased moderate-to-vigorous PA by 17.0±47.0 min/d (P = .014), and decreased sedentary time (-47.9±101.0 min/d, P = .002). However, 24% of patients decreased overall PA (P<.001), and 39% increased sedentary behavior (P<.001). Changes in overall PA (rho = -.33, P = .006) and steps/d (rho = -.31, P = .0106) were related to weight loss. Insulin sensitivity was associated with light PA before (rho = .37, P<.001) and after (rho = .37, P = .015) intervention. Increasing overall PA also was related to higher levels of high-density lipoprotein cholesterol (rho = .33, P<.01). Decreasing sedentary time was related to decreased fat mass (rho = .35, P = .012) but not to other cardiometabolic risk factors. CONCLUSIONS: The majority of patients increased PA (76%) and decreased sedentary time (61%) after RYGB surgery, but the amount of PA and sedentary time varied substantially. Higher PA, even at low intensity levels, was related to beneficial outcomes in body composition, insulin sensitivity, and high-density lipoprotein cholesterol.

Exercise and Weight Loss Improve Muscle Mitochondrial Respiration, Lipid Partitioning, and Insulin Sensitivity After Gastric Bypass Surgery.

Both Roux-en-Y gastric bypass (RYGB) surgery and exercise can improve insulin sensitivity in individuals with severe obesity. However, the impact of RYGB with or without exercise on skeletal muscle mitochondria, intramyocellular lipids, and insulin sensitivity index (SI) is unknown. We conducted a randomized exercise trial in patients (n = 101) who underwent RYGB surgery and completed either a 6-month moderate exercise (EX) or a health education control (CON) intervention. SI was determined by intravenous glucose tolerance test. Mitochondrial respiration and intramyocellular triglyceride, sphingolipid, and diacylglycerol content were measured in vastus lateralis biopsy specimens. We found that EX provided additional improvements in SI and that only EX improved cardiorespiratory fitness, mitochondrial respiration and enzyme activities, and cardiolipin profile with no change in mitochondrial content. Muscle triglycerides were reduced in type I fibers in CON, and sphingolipids decreased in both groups, with EX showing a further reduction in a number of ceramide species. In conclusion, exercise superimposed on bariatric surgery-induced weight loss enhances mitochondrial respiration, induces cardiolipin remodeling, reduces specific sphingolipids, and provides additional improvements in insulin sensitivity.

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S(I)) in obese patients. Regular exercise can also improve S(I) in obese individuals; however, it is unknown whether exercise and RYGB surgery-induced weight loss would additively improve S(I) and other cardiometabolic factors. METHODS: We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1-3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S(I) and glucose effectiveness (S(G)), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week). RESULTS: 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S(I) improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min⁻¹/µU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S(I) improvement (PP: CON vs. EX; +1.57 vs. +2.69 min⁻¹/µU/ml, P = 0.019) above that of surgery. Exercise also improved S(G) (ITT: CON vs. EX; +0.0023 vs. +0.0063 min⁻¹, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group. CONCLUSION: Moderate exercise following RYGB surgery provides additional improvements in S(I), S(G), and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00692367. FUNDING: This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153).