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Purpose: To investigate, in sedentary, overweight adults, the effects of 9 months of exercise training (75% peak VO2, 2100 kcal per week) and 1 month of detraining on markers of carbohydrate metabolism including fasting glucose, fasting insulin, insulin sensitivity, and glucose effectiveness.Methods: Five overweight adults with moderate dyslipidemia underwent intravenous glucose tolerance testing before and 24 hours after 9 months of exercise training, and after 5 and 30 days of detraining.Results: Peak VO2 increased 17% (p < 0.01) and body mass decreased 3.5% (-3.1 kg; p < 0.05) with training. Fasting glucose decreased from 5.39 at pretraining to 4.46 mmoL x L-1 (97.1 to 80.3 mg x dL-1) at 24 hr posttraining and remained lower at all posttraining time points compared to pretraining (p < 0.05). Insulin sensitivity was higher and fasting insulin was lower after training compared to pretraining levels (p < 0.05). After 30 days of detraining, insulin sensitivity was still 24% higher than pretraining levels and fasting insulin had only returned to 90% of pretraining values (nonsignificant). Total and LDL cholesterol were significantly improved after training (p < 0.05).Conclusion: In overweight adults, exercise training with a large weekly exercise dose resulted in a significant and prolonged improvement in fasting glucose. These data provide evidence that both acute and chronic improvements in carbohydrate metabolism may result from long-term exercise training. Concurrent with these changes were significant and important improvements in blood lipids and aerobic capacity. These findings have clinical significance for the role of regular exercise in preventing the development of insulin resistance and glucose intolerance in individuals at risk for diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: The standard clinical approach for reducing cardiovascular disease risk due to dyslipidemia is to prescribe changes in diet and physical activity. The purpose of the current study was to determine if, across a range of dietary patterns, there were variable lipoprotein responses to an aerobic exercise training intervention.Methods: Subjects were participants in the STRRIDE I, a supervised exercise program in sedentary, overweight subjects randomized to 6 months of inactivity or 1 of 3 aerobic exercise programs. To characterize diet patterns observed during the study, we calculated a modified z-score that included intakes of total fat, saturated fat, trans fatty acids, cholesterol, omega-3 fatty acids, and fiber as compared with the 2006 American Heart Association diet recommendations. Linear models were used to evaluate relationships between diet patterns and exercise effects on lipoproteins/lipids.Results: Independent of diet, exercise had beneficial effects on low-density lipoprotein cholesterol particle number, low-density lipoprotein cholesterol size, high-density lipoprotein cholesterol, high-density lipoprotein cholesterol size, and triglycerides (P < .05 for all). However, having a diet pattern that closely adhered to American Heart Association recommendations was not related to changes in these or any other serum lipids or lipoproteins in any of the exercise groups.Conclusions: We found that even in sedentary individuals whose habitual diets vary in the extent of adherence to AHA dietary recommendations, a rigorous, supervised exercise intervention can achieve significant beneficial lipid effects. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance and beta-cell dysfunction both are important contributors to the pathogenesis of type 2 diabetes. Exercise training improves insulin sensitivity, but its effects on beta-cell function are less well studied.Research Design and Methods: Sedentary, overweight adults were randomized to control or one of three 8-month exercise programs: 1) low amount/moderate intensity, 2) low amount/vigorous intensity, or 3) high amount/vigorous intensity. Of 387 randomized, 260 completed the study and 237 had complete data. Insulin sensitivity (S(i)), acute insulin response to glucose (AIRg), and the disposition index (DI = S(i) x AIRg) were modeled from an intravenous glucose tolerance test.Results: Compared with control subjects, all three training programs led to increases in DI. However, the moderate-intensity group experienced a significantly larger increase in DI than either of the vigorous-intensity groups and through a different mechanism. The high-amount/vigorous-intensity group improved S(i) and had a compensatory reduction in AIRg, whereas the moderate-intensity group had a similar improvement in S(i) but almost no reduction in AIRg. Importantly, the inactive control group experienced a significant increase in fasting glucose.Conclusions: To the extent that the DI accurately reflects beta-cell function, we observed that both moderate- and vigorous-intensity exercise training improved beta-cell function, albeit through distinct mechanisms. It is not clear which of these mechanisms is preferable for maintenance of metabolic health. While moderate-intensity exercise led to a larger improvement in DI, which may reflect a transition toward a more normal DI, longer-term investigations would be necessary to determine which was more effective at reducing diabetes risk. [ABSTRACT FROM AUTHOR]

The purpose of this secondary analysis was to determine what portion of the effects of a Diabetes Prevention Program-like intervention on metabolic syndrome (MetS) could be achieved with exercise alone, as well as to determine the relative importance of exercise intensity and amount to the total exercise effect on MetS. Sedentary, overweight adults with prediabetes were randomly assigned to one of four 6-month interventions: 1) low-amount/moderate-intensity (10 kcal/kg/week at 50% peak V ˙ O 2 ); 2) high-amount/moderate-intensity (16 kcal/kg/week at 50% peak V ˙ O 2 ); 3) high-amount/vigorous-intensity (16 kcal/kg/week at 75% peak V ˙ O 2 ); or 4) diet (7% weight loss) plus low-amount/moderate-intensity (10 kcal/kg/week at 50% peak V ˙ O 2 ). The primary outcome of this secondary analysis was change in the MetS z-score. A total of 130 participants had complete data for all five Adult Treatment Panel (ATP) III MetS criteria. The diet-and-exercise group statistically outperformed the MetS z-score and the ATP III score compared to the exercise alone group. Aerobic exercise alone achieved 24%-50% of the total effect of the combined diet-and-exercise intervention on the MetS score. Low-amount moderate-intensity exercise quantitatively performed equal to or better than the interventions of high-amount moderate-intensity or high-amount vigorous-intensity exercise in improving the MetS score. The combined diet-and-exercise intervention remains more efficacious in improving the MetS z-score. However, all three exercise interventions alone showed improvements in the MetS z-score, suggesting that a modest amount of moderate-intensity exercise is all that is required to achieve approximately half the effect of a diet-and-exercise intervention on the MetS. Clinical Trial Registration: clinicaltrials.gov, identifier NCT00962962., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bennett, Collins, Johnson, Slentz, Willis, Bales, Huffman and Kraus.)

Although many studies have assumed variability reflects variance caused by exercise training, few studies have examined whether interindividual differences in trainability are present following exercise training. The present individual participant data (IPD) meta-analysis sought to: (1) investigate the presence of interindividual differences in trainability for cardiorespiratory fitness (CRF), waist circumference, and body mass; and (2) examine the influence of exercise training and potential moderators on the probability that an individual will experience clinically important differences. The IPD meta-analysis combined data from 1879 participants from eight previously published randomized controlled trials. We implemented a Bayesian framework to: (1) test the hypothesis of interindividual differences in trainability by comparing variability in change scores between exercise and control using Bayes factors; and (2) compare posterior predictions of control and exercise across a range of moderators (baseline body mass index (BMI) and exercise duration, intensity, amount, mode, and adherence) to estimate the proportions of participants expected to exceed minimum clinically important differences (MCIDs) for all three outcomes. Bayes factors demonstrated a lack of evidence supporting a high degree of variance attributable to interindividual differences in trainability across all three outcomes. These findings indicate that interindividual variability in observed changes are likely due to measurement error and external behavioural factors, not interindividual differences in trainability. Additionally, we found that a larger proportion of exercise participants were expected to exceed MCIDs compared with controls for all three outcomes. Moderator analyses identified that larger proportions were associated with a range of factors consistent with standard exercise theory and were driven by mean changes. Practitioners should prescribe exercise interventions known to elicit large mean changes to increase the probability that individuals will experience beneficial changes in CRF, waist circumference and body mass., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Context: Glucagon-like peptide 1 (GLP-1), an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of insulin secretion. However, the physiological actions of circulating GLP-1 have been questioned because of the short half-life of the active peptide. Moreover, there is mounting evidence for localized, intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4)., Objective: To determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels, and whether this is affected by DPP4., Methods: Single-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60-minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline. The main outcome measures were arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg)., Results: Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both α- and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However, a significant interaction between sitagliptin and Ex-9 suggested more GLP-1r activation with DPP4i treatment in subjects with diabetes., Conclusion: GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

As type 2 diabetes remains a leading cause of morbidity and mortality, identifying the most appropriate preventive treatment early in the development of disease is an important public health matter. In general, lifestyle interventions incorporating exercise and weight loss via caloric restriction improve cardiometabolic risk by impacting several key markers of insulin sensitivity and glucose homeostasis. However, variations in the effects of specific types of exercise interventions on these markers have led to conflicting results surrounding the optimal amount, intensity, and mode of exercise for optimal effects. Moreover, the addition of weight loss via caloric restriction to exercise interventions appears to differentially impact changes in body composition, metabolism, and insulin sensitivity compared to exercise alone. Determining the optimal amount, intensity, and mode of exercise having the most beneficial impact on glycemic status is both: (1) clinically important to provide guidelines for appropriate exercise prescription; and (2) physiologically important to understand the pathways by which exercise-with and without weight loss-impacts glycemic status to enhance precision lifestyle medicine. Thus, the purposes of this narrative review are to: (1) summarize findings from the three Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) randomized trials regarding the differential effects of exercise amount, intensity, and mode on insulin action and glucose homeostasis markers; and (2) compare the STRRIDE findings to other published dose-response exercise trials in order to piece together the various physiologic pathways by which specific exercise interventions-with or without weight loss-impact glycemic status., (© 2022. The Author(s).)

Introduction: To determine the relative contributions of various amounts and intensities of exercise alone to a combined lifestyle intervention on health-related quality of life (HrQoL) measures., Research Design and Methods: Participants (n=162) were sedentary, overweight/obese, with pre-diabetes, and randomized to one of four 6-month interventions: (1) high amount/moderate intensity exercise-energy expenditure of 16 kcal/kg of body weight/week (KKW) at 50% oxygen consumption (V̇O 2 ) reserve; (2) high/vigorous-16 KKW at 75% V̇O 2 reserve; (3) low/moderate-10 KKW at 50% V̇O 2 reserve; (4) low/moderate plus diet-10 KKW at 50% V̇O 2 reserve plus a calorically restricted diet. The 36-Item Short-Form Survey (SF-36) and Satisfaction with Physical Function and Appearance (SPF/SPA) survey were assessed at baseline and post-intervention. Analyses of covariance determined differences in change scores among groups (p<0.05). Paired t-tests determined significant pre-intervention versus post-intervention scores within groups (p<0.05)., Results: Across the intervention, all groups (p<0.05) improved the physical component, SPF, and SPA scores. Only the low/moderate/diet group (p<0.001) significantly improved the mental component score. The high/vigorous group achieved 84.5% of the low/moderate/diet group effect for change in physical component score, and the low/moderate group achieved 83.7% of the low/moderate/diet group effect for change in mental component score., Conclusions: In general, a low amount of moderate intensity exercise combined with diet was the most effective intervention for improving HrQoL. Of the exercise-only interventions, vigorous intensity exercise provided the greatest impact on changes in physical function. On the other hand, low amounts of moderate intensity exercise provided the greatest impact on mental well-being, potentially being a more attainable exercise dose for previously sedentary individuals with pre-diabetes to achieve., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study tested the hypothesis that greater mean changes in cardiorespiratory fitness (CRF), in either the absence or presence of reduced interindividual variability, explain larger CRF response rates following higher doses of exercise training., Methods: We retrospectively analyzed CRF data from eight randomized controlled trials (RCT; n = 1590 participants) that compared at least two doses of exercise training. CRF response rates were calculated as the proportion of participants with individual confidence intervals (CIs) placed around their observed response that lay above 0.5 metabolic equivalents (MET). CIs were calculated using no-exercise control group-derived typical errors and were placed around each individual's observed CRF response (post minus pre-training CRF). CRF response rates, mean changes, and interindividual variability were compared across exercise groups within each RCT., Results: Compared with lower doses, higher doses of exercise training yielded larger CRF response rates in eight comparisons. For most of these comparisons (7/8), the higher dose of exercise training had a larger mean change in CRF but similar interindividual variability. Exercise groups with similar CRF response rates also had similar mean changes., Conclusion: Our findings demonstrate that larger CRF response rates following higher doses of exercise training are attributable to larger mean changes rather than reduced interindividual variability. Following a given dose of exercise training, the proportion of individuals expected to improve their CRF beyond 0.5 METs is unrelated to the heterogeneity of individual responses., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The goal was studying the differential effects of aerobic training (AT) vs. resistance training (RT) on cardiac and peripheral arterial capacity on cardiopulmonary (CP) and peripheral vascular (PV) function in sedentary and obese adults. Methods: In a prospective randomized controlled trial, we studied the effects of 6 months of AT vs. RT in 21 subjects. Testing included cardiac and vascular ultrasoundography and serial CP for ventricular-arterial coupling (Ees/Ea), strain-based variables, brachial artery flow-mediated dilation (BAFMD), and peak VO 2 (pVO 2; mL/kg/min) and peak O 2 -pulse (O 2 p; mL/beat). Results: Within the AT group ( n = 11), there were significant increases in rVO 2 of 4.2 mL/kg/min (SD 0.93) ( p = 0.001); O 2 p of 1.9 mL/beat (SD 1.3) ( p = 0.008) and the brachial artery post-hyperemia peak diameter 0.18 mm (SD 0.08) ( p = 0.05). Within the RT group ( n = 10) there was a significant increase in left ventricular end diastolic volume 7.0 mL (SD 9.8; p = 0.05) and percent flow-mediated dilation (1.8%) (SD 0.47) ( p = 0.004). Comparing the AT and RT groups, post exercise, rVO 2 2.97, (SD 1.22), ( p = 0.03), O 2 p 0.01 (SD 1.3), ( p = 0.01), peak hyperemic blood flow volume (1.77 mL) (SD 140.69) ( p = 0.009), were higher in AT, but LVEDP 115 mL (SD 7.0) ( p = 0.05) and Ees/Ea 0.68 mmHg/ml (SD 0.60) p = 0.03 were higher in RT. Discussion: The differential effects of AT and RT in this hypothesis generating study have important implications for exercise modality and clinical endpoints., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lekavich, Allen, Bensimhon, Bateman, Slentz, Samsa, Kenjale, Duscha, Douglas and Kraus.)

Purpose: The main purpose of this study was to determine the differential effects of aerobic training (AT), resistance training (RT), and a combination of aerobic and resistance training (AT/RT) on changes in self-rated HrQoL measures, including the Short-Form 36 (SF-36) survey and Satisfaction with Physical Function and Appearance survey. We also sought to determine if combination training (AT/RT) has a more or less additive effect compared to AT or RT alone on self-rated HrQoL measures. Materials and Methods: Participants ( n = 137) completed one of three 8-month exercise interventions: (1) AT: 14 kcal exercise expenditure per kg of body weight per week (KKW; equivalent to roughly 12 miles/week) at 65-80% of peak oxygen consumption; (2) RT: 3 days per week, 8 exercises, 3 sets per exercise, 8-12 repetitions per set; (3) AT/RT: full combination of the AT and RT interventions. The SF-36 survey, Satisfaction with Physical Function and Appearance survey, physical fitness, and anthropometrics were assessed at baseline and post-intervention. Paired t -tests determined significant pre- vs. post-intervention scores within groups ( p < 0.05). Analyses of covariance determined differences in change scores among groups ( p < 0.05). Results: On average, participants were 49.0 ± 10.6 years old, obese (BMI: 30.6 ± 3.2 kg/m 2 ), female (57.7%), and Caucasian (84.7%). Following the 8-month intervention, exercise groups improved peak VO 2 (all groups), strength (RT and AT/RT), and anthropometric measures (AT and AT/RT). For the SF-36, RT ( p = 0.03) and AT/RT ( p < 0.001) significantly improved their physical component score; only AT/RT ( p < 0.001) significantly improved their mental component score. Notably, all groups significantly improved both their satisfaction with physical function and appearance scores (All Groups: p < 0.001 for both outcomes). Conclusions: We found that aerobic, resistance, or combination exercise training improves several components of self-rated HrQoL, including physical function, appearance, and mental well-being. Clinical Trial Registration : No. NCT00275145., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Collins, Fos, Ross, Slentz, Davis, Willis, Piner, Bateman, Houmard and Kraus.)

Background: Lipoprotein Insulin Resistance Index (LP-IR) and Diabetes Risk Index are novel spectroscopic multimarkers of insulin resistance and type 2 diabetes risk. As the Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) randomized trials have previously demonstrated the ability of exercise training to improve traditional markers of insulin action, the aim of this study was to examine the effects of exercise amount, intensity, and mode on LP-IR and the Diabetes Risk Index., Methods: A total of 503 adults with dyslipidemia [STRRIDE I ( n = 194), STRRIDE AT/RT ( n = 139)] or prediabetes [STRRIDE-PD ( n = 170)] were randomized to control or one of 10 exercise interventions, ranging from doses of 8-23 kcal/kg/week; intensities of 50-75% V̇O 2peak ; and durations of 6-8 months. Two groups included resistance training and one included dietary intervention (7% weight loss goal). Fasting plasma samples were obtained at baseline and 16-24 h after the final exercise bout. LP-IR, the Diabetes Risk Index, and concentrations of the branched chain amino acids valine and leucine were determined using nuclear magnetic resonance spectroscopy. LP-IR and the Diabetes Risk Index scores range from 0-100 and 1-100, respectively (greater scores indicate greater risk). Paired t-tests determined significance within groups ( p < 0.05)., Results: After training, six exercise groups significantly improved LP-IR (ranging from -4.4 ± 8.2 to -12.4 ± 14.1), and four exercise groups significantly improved the Diabetes Risk Index (ranging from -2.8 ± 8.2 to -8.3 ± 10.4). The most beneficial interventions for both LP-IR and the Diabetes Risk Index were low amount/moderate intensity aerobic, aerobic plus resistance, and aerobic plus diet., Summary: Multiple exercise interventions improved LP-IR and the Diabetes Risk Index. In those with dyslipidemia, adding resistance to aerobic training elicited a synergistic effect on insulin resistance and type 2 diabetes risk. In individuals with prediabetes, combining a dietary intervention and weight loss with aerobic training resulted in the most robust type 2 diabetes risk improvement., Competing Interests: IS, JO, and MC are employees of LabCorp. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ross, Slentz, Zidek, Huffman, Shalaurova, Otvos, Connelly, Kraus, Bales, Houmard and Kraus.)

Introduction: Low potassium intake can affect cardiovascular disease (CVD) risk and cardiometabolic risk factors., Objective: We hypothesize that potassium chloride (KCl) supplementation can improve cardiovascular risk metabolomic profile., Methods: In this secondary analysis of a pilot randomized clinical trial (RCT) of 26 participants with prediabetes randomized to KCl or placebo, we performed targeted mass-spectrometry-based metabolomic profiling on baseline and 12-week (end-of-study) plasma samples. Principal component analysis (PCA) was used to reduce the many correlated metabolites into fewer, independent factors that retain most of the information in the original data., Results: Those taking KCl had significant reductions (corresponding to lower cardiovascular risk) in the branched-chain amino acids (BCAA) factor (P = 0.004) and in valine levels (P = 0.02); and non-significant reductions in short-chain acylcarnitines (SCA) factor (P = 0.11)., Conclusions: KCl supplementation may improve circulating BCAA levels, which may reflect improvements in overall cardiometabolic risk profile., Clinical Trials Registry: Clinicaltrials.gov identifier: NCT02236598; https://clinicaltrials.gov/ct2/show/NCT02236598.

Neutrophil dysfunction is a common feature of aging, and is associated with the pathogenesis of many age-related diseases, including type 2 diabetes mellitus (T2DM). Although exercise training improves metabolic health, decreases risk of T2DM, and is associated with improving neutrophil functions, involvement in regular physical activity declines with age. The aim of this study was to determine if neutrophil functions could be improved in association with changes in fitness and metabolic parameters in older adults at risk for T2DM using 10-weeks of low volume high-intensity interval exercise training (HIIT). Ten older (71 ± 5 years) sedentary adults with prediabetes (HbA1c: 6.1 ± 0.3%) completed 10 weeks of a supervised HIIT program. Three 30 min sessions/week consisted of ten 60 s intervals of low intensity [50-60% heart rate reserve (HRR)] separated with similar durations of high intensity intervals (80-90% HRR). Before and after training, glucose and insulin sensitivity, neutrophil chemotaxis, bacterial phagocytosis, reactive oxygen species (ROS) production, and mitochondrial functions were assessed. Exercise-mediated changes in cardiorespiratory fitness (VO 2 peak ) and neutrophil functions were compared to six young (23 ± 1 years) healthy adults. Following training, significant reductions in fasting glucose and insulin were accompanied by improved glucose control and insulin sensitivity (all p < 0.05). Before exercise training, VO 2 peak in the old participants was significantly less than that of the young controls ( p < 0.001), but increased by 16 ± 11% following training ( p = 0.002) resulting in a 6% improvement of the deficit. Neutrophil chemotaxis, phagocytosis and stimulated ROS production were significantly less than that of the young controls, while basal ROS were higher before training (all p < 0.05). Following training, chemotaxis, phagocytosis and stimulated ROS increased while basal ROS decreased, similar to levels observed in the young controls (all p < 0.05) and reducing the deficit of the young controls between 2 and 154%. In five of the adults with prediabetes, neutrophil mitochondrial functions were significantly poorer than the six young controls before training. Following training, mitochondrial functions improved toward those observed in young controls (all p < 0.05), reducing the deficit of the young controls between 14.3 and 451%. Ten weeks of HIIT in older adults at risk for T2DM reduced disease risk accompanied by improved primary and bioenergetic neutrophil functions. Our results are consistent with a reduced risk of infections mediated by relationships in exercise induced systemic and cellular metabolic features. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02441205, registered on May 12th, 2015., (Copyright © 2020 Bartlett, Slentz, Willis, Hoselton, Huebner, Kraus, Moss, Muehlbauer, Spielmann, Muoio, Koves, Wu, Huffman, Lord and Kraus.)

Background: Understanding group responses to a given exercise exposure is becoming better developed; however, understanding of individual responses to specific exercise exposures is significantly underdeveloped and must advance before personalized exercise medicine can become a functional reality. Herein, utilizing data from the STRRIDE studies, we address some of the key issues surrounding our efforts to develop better understanding of individual exercise responsiveness., Methods: We assessed individual cardiometabolic and cardiorespiratory fitness responses in subjects successfully completing STRRIDE I ( n = 227) and STRRIDE II ( n = 155). Subjects were previously sedentary, overweight or obese men and women with mild-to-moderate dyslipidemia. Subjects were randomized to either an inactive control group or to an exercise training program. Training groups varied to test the differential effects of exercise amount, intensity, and mode on cardiometabolic health outcomes. Measures included fasting plasma glucose, insulin, and lipids; blood pressure, minimal waist circumference, visceral adipose tissue, and peak VO 2 . Absolute change scores were calculated for each subject as post-intervention minus pre-intervention values in order to evaluate the heterogeneity of health factor responsiveness to exercise training., Results: For subjects completing one of the aerobic training programs, change in peak VO 2 ranged from a loss of 37% to a gain of 77%. When ranked by magnitude of change, we observed discordant responses among changes in peak VO 2 with changes in visceral adipose tissue, HDL-C, triglycerides, and fasting plasma insulin. There was also not a clear, direct relationship observed between magnitudes of individual response in the aforementioned variables with aerobic training adherence levels. This same pattern of highly variable and discordant responses was displayed even when considering subjects with adherence levels greater than 70%., Conclusion: Our findings illustrate the unclear relationship between magnitude of individual response for a given outcome with training adherence and specific exercise exposure. These discordant and heterogeneous responses highlight the difficult nature of developing understanding for how individuals will respond to any given exposure. Further investigation into the biological, physiological, and genetics factors affecting individual responsiveness is vital to making personalized exercise medicine a reality., (Copyright © 2019 Ross, Slentz and Kraus.)

Background Substantial heterogeneity exists in the cardiorespiratory fitness (CRF) change in response to exercise training, and its long-term prognostic implication is not well understood. We evaluated the association between the short-term supervised training-related changes in CRF and CRF levels 10 years later. Methods and Results STRRIDE (Studies of a Targeted Risk Reduction Intervention Through Defined Exercise) trial participants who were originally randomized to exercise training for 8 months and participated in the 10-year follow-up visit were included. CRF levels were measured at baseline, after training (8 months), and at 10-year follow-up as peak oxygen uptake (vo 2 , mL/kg per min) using the maximal treadmill test. Participants were stratified into low, moderate, and high CRF response groups according to the training regimen-specific tertiles of CRF change. The study included 80 participants (age: 52 years; 35% female). At 10-year follow-up, the high-response CRF group had the least decline in CRF compared with the moderate- and low-response CRF groups (-0.35 versus -2.20 and -4.25 mL/kg per minute, respectively; P =0.02). This result was largely related to the differential age-related changes in peak oxygen pulse across the 3 groups (0.58, -0.23, and -0.86 mL/beat, respectively; P =0.03) with no difference in the peak heart rate change. In adjusted linear regression analysis, high response was significantly associated with greater CRF at follow-up independent of other baseline characteristics (high versus low [reference] CRF response: standard β=0.25; P =0.004). Conclusions Greater CRF improvement in response to short-term training is associated with higher CRF levels 10 years later. Lack of CRF improvements in response to short-term training may identify individuals at risk for exaggerated CRF decline with aging.

Ranolazine reduces angina frequency and increases exercise capacity. We hypothesized that exercise training with ranolazine would allow subjects to train at greater intensities, resulting in greater improvements in exercise capacity, physical activity, and health-related quality of life (HRQOL). In a pilot study, subjects with chronic stable angina pectoris were randomized to ranolazine (n = 13) or placebo (n = 16). After a 2-week drug titration period, subjects participated in a 12-week exercise program. Peak VO 2 , physical activity (via accelerometer), and HRQOL were assessed before and after training. After exercise training, peak VO 2 increased twice as much with ranolazine (2.1 ± 3.4 ml/kg/min) as with placebo (0.9 ± 1.5) (both p <0.05). After exercise training, both groups significantly improved HRQOL score (p <0.05); however, the improvement with ranolazine (19 ± 21) was almost 50% greater than with placebo (13 ± 18). There was a significant decrease in maximal heart rate after training with ranolazine but not with placebo (group difference, p = 0.04). Oxygen pulse (peak VO 2 /peak HR) increased in both groups after training; but, the increase was 4 times greater with ranolazine - resulting in a significant difference between groups (p = 0.044). In conclusion, patients with angina, the addition of ranolazine to an exercise program may improve aerobic fitness, physical activity, and HRQOL beyond the results of an exercise training program alone. Exercise training with ranolazine led to significantly greater increases in oxygen pulse, which is significantly correlated with stroke volume and is an independent predictor of mortality., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: STRRIDE (Studies Targeting Risk Reduction Interventions through Defined Exercise) was an eight-month exercise study conducted from 1998-2003. Subjects were randomized to control or one of three exercise groups differing in intensity and amount. To determine if there were legacy effects, we invited 161 individuals who completed the intervention phase to return for a 10-year Reunion study. Methods: Subjects completed medical history and physical activity questionnaires. Height, body weight, blood pressure, waist circumference, and peak VO 2 were measured. Fasting blood samples were analyzed for glucose, insulin and lipids. Of 161 original subjects, 153 were within 10 years of STRRIDE completion. Of these, 28 were lost to follow-up and 21 declined to participate in the Reunion study. Overall, 104 subjects (83% eligible) participated. Change over time was computed as the 10-year Reunion value minus the pre-intervention value. Significant within group changes were calculated using two-tailed t -tests. ANCOVA determined differences among groups with pre-intervention values as covariates. Bonferroni corrections were applied to account for multiple comparisons. Results: Ten years after completing STRRIDE, there were a number of group-specific health and fitness legacy effects. Original participation in either the moderate intensity exercise or control group resulted in a 10.5% decrease in peak VO 2 over the ensuing 10 years. Conversely, both vigorous intensity groups experienced only a 4.7% decrement in cardiorespiratory fitness over that time period. As compared to controls, all three exercise groups experienced smaller increases in waist circumference. Those who participated in moderate intensity exercise experienced the greatest 10-year reduction in fasting insulin. Compared to all other groups, the moderate intensity subjects had greater reductions in mean arterial pressure at the Reunion timepoint. Summary: Ten years after completing a randomized eight-month exercise training intervention, previously sedentary individuals exhibited group-specific differences consistent with an intervention-based legacy effect on cardiorespiratory fitness and cardiometabolic parameters. These findings highlight the critical need to better understand the sustained legacy health effects of exercise training interventions.

Background and Aims: GlycA is a relatively new biomarker for inflammation as well as cardiometabolic disease risk. However, the effect of exercise on GlycA is largely unknown. Therefore, the purpose of this study was to examine the effects of regular exercise on the inflammatory marker GlycA across seven studies and 14 exercise interventions., Methods: Nuclear magnetic resonance spectroscopy, specifically signal amplitudes originating from the N-acetyl methyl group protons of the N-acetylglucosamine residues on the glycan branches of glycoproteins, was used to quantify GlycA concentrations. GlycA was measured before and after completion of an exercise intervention in 1568 individuals across seven studies and 14 exercise interventions. Random effects inverse variance weighting models were used to pool effects across interventions., Results: Combined analysis of unadjusted data showed that regular exercise significantly (p = 2 × 10 -6 ) reduced plasma GlycA (-8.26 ± 1.8 μmol/L). This reduction remained significant (-9.12 ± 1.9 μmol/L, p = 1.22 × 10 -6 ) following adjustment for age, sex, race, baseline BMI, and baseline GlycA. Changes in GlycA were correlated with changes in traditional inflammatory markers, C-reactive protein, interleukin-6, and fibrinogen, however, these correlations were relatively weak (range r: 0.21-0.38, p < 0.0001)., Conclusions: Regular exercise significantly reduced plasma GlycA across 14 different exercise interventions despite differences in exercise programs and study populations. The current study provides a greater understanding of the use of exercise as a potential therapy for the reduction of systemic inflammation. Further research is needed to understand the mechanisms behind the exercise-related reductions in GlycA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Genetic variation is associated with a number of lifestyle behaviours; it may be associated with adherence and individual responses to exercise training. We tested single nucleotide polymorphisms (SNPs) in the acid ceramidase gene ( ASAH1 ) for association with subject adherence and physiologic benefit with exercise training in two well-characterised randomised, controlled 8-month exercise interventions: STRRIDE I ( n = 239) and STRRIDE II ( n = 246). Three ASAH1 non-coding SNPs in a linkage disequilibrium block were associated with non-completion: rs2898458(G/T), rs7508(A/G), and rs3810(A/G) were associated with non-completion in both additive (OR = 1.8, 1.8, 2.0; P < 0.05 all) and dominant (OR = 2.5, 2.6, 3.5; P < 0.05 all) models; with less skeletal muscle ASAH expression ( p < 0.01) in a subset ( N = 60); and poorer training response in cardiorespiratory fitness (peak VO 2 change rs3810 r 2 = 0.29, P = 0.04; rs2898458 r 2 = 0.29, P = 0.08; rs7508 r 2 = 0.28, p = 0.09); and similar in direction and magnitude in both independent exploratory and replication studies. Adherence to exercise may be partly biologically and genetically moderated through metabolic regulatory pathways participating in skeletal muscle adaptation to exercise training.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease in which adults have significant joint issues leading to poor health. Poor health is compounded by many factors, including exercise avoidance and increased risk of opportunistic infection. Exercise training can improve the health of patients with RA and potentially improve immune function; however, information on the effects of high-intensity interval training (HIIT) in RA is limited. We sought to determine whether 10 weeks of a walking-based HIIT program would be associated with health improvements as measured by disease activity and aerobic fitness. Further, we assessed whether HIIT was associated with improved immune function, specifically antimicrobial/bacterial functions of neutrophils and monocytes., Methods: Twelve physically inactive adults aged 64 ± 7 years with either seropositive or radiographically proven (bone erosions) RA completed 10 weeks of high-intensity interval walking. Training consisted of 3 × 30-minute sessions/week of ten ≥ 60-second intervals of high intensity (80-90% VO 2reserve ) separated by similar bouts of lower-intensity intervals (50-60% VO 2reserve ). Pre- and postintervention assessments included aerobic and physical function; disease activity as measured by Disease Activity score in 28 joints (DAS28), self-perceived health, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR); plasma interleukin (IL)-1β, IL-6, chemokine (C-X-C motif) ligand (CXCL)-8, IL-10, and tumor necrosis factor (TNF)-α concentrations; and neutrophil and monocyte phenotypes and functions., Results: Despite minimal body composition change, cardiorespiratory fitness increased by 9% (change in both relative and absolute aerobic capacity; p < 0.001), and resting blood pressure and heart rate were both reduced (both p < 0.05). Postintervention disease activity was reduced by 38% (DAS28; p = 0.001) with significant reductions in ESR and swollen joints as well as improved self-perceived health. Neutrophil migration toward CXCL-8 (p = 0.003), phagocytosis of Escherichia coli (p = 0.03), and ROS production (p < 0.001) all increased following training. The frequency of cluster of differentiation 14-positive (CD14 + )/CD16 + monocytes was reduced (p = 0.002), with both nonclassical (CD14 dim /CD16 bright ) and intermediate (CD14 bright /CD16 positive ) monocytes being reduced (both p < 0.05). Following training, the cell surface expression of intermediate monocyte Toll-like receptor 2 (TLR2), TLR4, and HLA-DR was reduced (all p < 0.05), and monocyte phagocytosis of E. coli increased (p = 0.02). No changes were observed for inflammatory markers IL-1β, IL-6, CXCL-8, IL-10, CRP, or TNF-α., Conclusions: We report for the first time, to our knowledge, that a high-intensity interval walking protocol in older adults with stable RA is associated with reduced disease activity, improved cardiovascular fitness, and improved innate immune functions, indicative of reduced infection risk and inflammatory potential. Importantly, the exercise program was well tolerated by these patients., Trial Registration: ClinicalTrials.gov, NCT02528344 . Registered on 19 August 2015.

Purpose: The purpose of this study is to evaluate the effect of exercise training with modest or greater weight loss (≥3%) or not (<3%) on insulin sensitivity, lipoprotein concentrations, and lipoprotein particle size in overweight and obese participants., Methods: Adults (N = 163, body mass index: 25-37 [kg/m2]) participated in 8 months of exercise training. Insulin sensitivity, lipid concentrations, lipid particle size and other cardiometabolic variables were measured at baseline and follow-up. Participants were categorized by whether they achieved at least modest weight loss (≥ 3%) or not (<3%) following the intervention., Results: A greater improvement in insulin sensitivity was observed in adults performing exercise training with at least modest weight loss (2.2 mU·l-1 ·min -1, CI: 1.5 to 2.8) compared to those who did not (0.8 mU·l-1 ·min -1, CI: 0.5 to 1.2). Similar results were observed for acute insulin response, triglycerides, non-HDL cholesterol concentration, low density lipoprotein (LDL) particle size and high density lipoprotein (HDL) particle size (p<0.05), when all exercise groups were combined. No significant results across weight loss categories were observed for LDL, HDL, glucose, or insulin levels., Conclusion: The present study suggests that aerobic exercise combined with at least modest weight loss leads to greater improvements in insulin sensitivity, triglycerides as well as other non-traditional lipid risk factors (non-HDL cholesterol, HDL/LDL particle size). Clinicians should advocate patients who are overweight/obese to exercise and obtain modest weight loss for improved cardiovascular benefits., Competing Interests: The authors have declared that no competing interests exist.

Objective: Measures of HDL (high-density lipoprotein) function are associated with cardiovascular disease. However, the effects of regular exercise on these measures is largely unknown. Thus, we examined the effects of different doses of exercise on 3 measures of HDL function in 2 randomized clinical exercise trials., Approach and Results: Radiolabeled and boron dipyrromethene difluoride-labeled cholesterol efflux capacity and HDL-apoA-I (apolipoprotein A-I) exchange were assessed before and after 6 months of exercise training in 2 cohorts: STRRIDE-PD (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes; n=106) and E-MECHANIC (Examination of Mechanisms of exercise-induced weight compensation; n=90). STRRIDE-PD participants completed 1 of 4 exercise interventions differing in amount and intensity. E-MECHANIC participants were randomized into 1 of 2 exercise groups (8 or 20 kcal/kg per week) or a control group. HDL-C significantly increased in the high-amount/vigorous-intensity group (3±5 mg/dL; P =0.02) of STRRIDE-PD, whereas no changes in HDL-C were observed in E-MECHANIC. In STRRIDE-PD, global radiolabeled efflux capacity significantly increased 6.2% (SEM, 0.06) in the high-amount/vigorous-intensity group compared with all other STRRIDE-PD groups (range, -2.4 to -8.4%; SEM, 0.06). In E-MECHANIC, non-ABCA1 (ATP-binding cassette transporter A1) radiolabeled efflux significantly increased 5.7% (95% CI, 1.2-10.2%) in the 20 kcal/kg per week group compared with the control group, with no change in the 8 kcal/kg per week group (2.6%; 95% CI, -1.4 to 6.7%). This association was attenuated when adjusting for change in HDL-C. Exercise training did not affect BODIPY-labeled cholesterol efflux capacity or HDL-apoA-I exchange in either study., Conclusions: Regular prolonged vigorous exercise improves some but not all measures of HDL function. Future studies are warranted to investigate whether the effects of exercise on cardiovascular disease are mediated in part by improving HDL function., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00962962 and NCT01264406., (© 2018 American Heart Association, Inc.)

GlycA is a new composite measure of systemic inflammation and a predictor of many inflammatory diseases. GlycA is the nuclear magnetic resonance spectroscopy-derived signal arising from glucosamine residues on acute-phase proteins. This study aimed to evaluate how exercise-based lifestyle interventions modulate GlycA in persons at risk for type 2 diabetes. GlycA, fitness, and body habitus were measured in 169 sedentary adults (45-75 years) with prediabetes randomly assigned to one of four six-month exercise-based lifestyle interventions. Interventions included exercise prescription based on the amount (energy expenditure (kcal/kg weight/week (KKW)) and intensity (%VO 2peak ). The groups were (1) low-amount/moderate-intensity (10KKW/50%) exercise; (2) high-amount/moderate-intensity (16KKW/50%) exercise; (3) high-amount/vigorous-intensity (16KKW/75%) exercise; and (4) a Clinical Lifestyle (combined diet plus low-amount/moderate-intensity exercise) intervention. Six months of exercise training and/or diet-reduced GlycA (mean Δ: -6.8 ± 29.2  μ mol/L; p = 0.006) and increased VO 2peak (mean Δ: 1.98 ± 2.6 mL/kg/min; p < 0.001). Further, visceral (mean Δ: -21.1 ± 36.6 cm 2 ) and subcutaneous fat (mean Δ: -24.3 ± 41.0 cm 2 ) were reduced, while liver density (mean Δ: +2.3 ± 6.5HU) increased, all p < 0.001. When including individuals in all four interventions, GlycA reductions were associated with reductions in visceral adiposity ( p < 0.03). Exercise-based lifestyle interventions reduced GlycA concentrations through mechanisms related to exercise-induced modulations of visceral adiposity. This trial is registered with Clinical Trial Registration Number NCT00962962.

Due to the beneficial effects on a wide range of modern medical conditions, most professional societies recommend regular aerobic exercise as part of a healthy lifestyle. Many of the exercise-related health benefits exhibit a dose-response relationship: Up to a point, more exercise is more beneficial. However, recent studies have suggested that different exercise intensities may provide distinct health benefits, independent of energy expenditure (i.e., exercise dose). One of these benefits, primarily mediated by the skeletal muscle, is exercise-related changes in insulin action and glucose homeostasis. Glucose uptake in the exercising muscle occurs through insulin-independent mechanisms whose downstream signaling events ultimately converge with insulin-signaling pathways, a fact that may explain why exercise and insulin have additive effect on skeletal muscle glucose uptake. Although the existing evidence is somewhat conflicting, well-controlled randomized studies suggest that, when controlled for total energy expenditure, moderate-intensity aerobic exercise improves insulin sensitivity more than vigorous-intensity aerobic exercise. The mechanisms underlying this difference are largely unknown. One possible explanation involves enhanced metabolism of fatty acid stores in the skeletal muscle by moderate-intensity exercise, which may directly improve insulin sensitivity. Overall, new technologic and physiologic investigative tools are beginning to shed light on the biology. Further understanding of these mechanisms will lead to better understanding of the clinical implications of a healthy lifestyle and may ultimately offer new therapeutic targets for common medical conditions such as insulin resistance and diabetes.

Aims/hypothesis: Although the Diabetes Prevention Program (DPP) established lifestyle changes (diet, exercise and weight loss) as the 'gold standard' preventive therapy for diabetes, the relative contribution of exercise alone to the overall utility of the combined diet and exercise effect of DPP is unknown; furthermore, the optimal intensity of exercise for preventing progression to diabetes remains very controversial. To establish clinical efficacy, we undertook a study (2009 to 2013) to determine: how much of the effect on measures of glucose homeostasis of a 6 month programme modelled after the first 6 months of the DPP is due to exercise alone; whether moderate- or vigorous-intensity exercise is better for improving glucose homeostasis; and to what extent amount of exercise is a contributor to improving glucose control. The primary outcome was improvement in fasting plasma glucose, with improvement in plasma glucose AUC response to an OGTT as the major secondary outcome., Methods: The trial was a parallel clinical trial. Sedentary, non-smokers who were 45-75 year old adults (n = 237) with elevated fasting glucose (5.28-6.94 mmol/l) but without cardiovascular disease, uncontrolled hypertension, or diabetes, from the Durham area, were studied at Duke University. They were randomised into one of four 6 month interventions: (1) low amount (42 kJ kg body weight(-1) week(-1) [KKW])/moderate intensity: equivalent of expending 42 KKW (e.g. walking ∼16 km [8.6 miles] per week) with moderate-intensity (50% [Formula: see text]) exercise; (2) high amount (67 KKW)/moderate intensity: equivalent of expending 67 KKW (∼22.3 km [13.8 miles] per week) with moderate-intensity exercise; (3) high amount (67 KKW)/vigorous intensity: equivalent to group 2, but with vigorous-intensity exercise (75% [Formula: see text]); and (4) diet + 42 KKW moderate intensity: same as group 1 but with diet and weight loss (7%) to mimic the first 6 months of the DPP. Computer-generated randomisation lists were provided by our statistician (G. P. Samsa). The randomisation list was maintained by L. H. Willis and C. A. Slentz with no knowledge of or input into the scheduling, whereas all scheduling was done by L. A. Bateman, with no knowledge of the randomisation list. Subjects were automatically assigned to the next group listed on the randomisation sheet (with no ability to manipulate the list order) on the day that they came in for the OGTT, by L. H. Willis. All plasma analysis was done blinded by the individuals doing the measurements (i.e. lipids, glucose, insulin). Subjects and research staff (other than individuals analysing the blood) were not blinded to the group assignments., Results: Number randomised, completers and number analysed with complete OGTT data for each group were: low-amount/moderate-intensity (61, 43, 35); high-amount/moderate-intensity (61, 44, 40); high-amount/vigorous-intensity (61, 43, 38); diet/exercise (54, 45, 37), respectively. Only the diet and exercise group experienced a decrease in fasting glucose (p < 0.001). The means and 95% CIs for changes in fasting glucose (mmol/l) for each group were: high-amount/moderate-intensity -0.07 (-0.20, 0.06); high-amount/vigorous 0.06 (-0.07, 0.19); low-amount/moderate 0.05 (-0.05, 0.15); and diet/exercise -0.32 (-0.46, -0.18). The effects sizes for each group (in the same order) were: 0.17, 0.15, 0.18 and 0.71, respecively. For glucose tolerance (glucose AUC of OGTT), similar improvements were observed for the diet and exercise (8.2% improvement, effect size 0.73) and the 67 KKW moderate-intensity exercise (6.4% improvement, effect size 0.60) groups; moderate-intensity exercise was significantly more effective than the same amount of vigorous-intensity exercise (p < 0.0207). The equivalent amount of vigorous-intensity exercise alone did not significantly improve glucose tolerance (1.2% improvement, effect size 0.21). Changes in insulin AUC, fasting plasma glucose and insulin did not differ among the exercise groups and were numerically inferior to the diet and exercise group., Conclusions/interpretation: In the present clinical efficacy trial we found that a high amount of moderate-intensity exercise alone was very effective at improving oral glucose tolerance despite a relatively modest 2 kg change in body fat mass. These data, combined with numerous published observations of the strong independent relation between postprandial glucose concentrations and prediction of future diabetes, suggest that walking ∼18.2 km (22.3 km prescribed with 81.6% adherence in the 67 KKW moderate-intensity group) per week may be nearly as effective as a more intensive multicomponent approach involving diet, exercise and weight loss for preventing the progression to diabetes in prediabetic individuals. These findings have important implications for the choice of clinical intervention to prevent progression to type 2 diabetes for those at high risk., Trial Registration: ClinicalTrials.gov NCT00962962 FUNDING: The study was funded by National Institutes for Health National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NDDK) (R01DK081559)., Competing Interests: Duality of interest The authors declare that there is no duality of interest associated with this manuscript.

Objective: The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts., Methods: Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group., Results: Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant increases in the concentration of large LDL-P and large HDL-P and mean LDL-P size. These changes remained significant in meta-analysis with adjustment for age, sex, race, baseline body mass index, and baseline trait value., Conclusions: Despite differences in exercise programs and study populations, regular exercise produced putatively beneficial changes in the lipoprotein subclass profile across 10 exercise interventions. Further research is needed to examine how exercise-induced changes in lipoprotein subclasses may be associated with (concomitant changes in) cardiovascular disease risk., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims/hypotheses: Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individuals during exercise intervention., Methods: Whole-body leucine turnover, IS by hyperinsulinaemic-euglycaemic clamp, and circulating and skeletal muscle amino acids, branched-chain α-keto acids and acylcarnitines were measured in ten healthy controls (Control) and nine OW, untrained, insulin-resistant individuals (OW-Untrained). OW-Untrained then underwent a 6 month aerobic and resistance exercise programme and repeated testing (OW-Trained)., Results: IS was higher in Control vs OW-Untrained and increased significantly following exercise. IS was lower in OW-Trained vs Control expressed relative to body mass, but was not different from Control when normalised to fat-free mass (FFM). Plasma BCAAs and leucine turnover (relative to FFM) were higher in OW-Untrained vs Control, but did not change on average with exercise. Despite this, within individuals, the decrease in molar sum of circulating BCAAs was the best metabolic predictor of improvement in IS. Circulating glycine levels were higher in Control and OW-Trained vs OW-Untrained, and urinary metabolic profiling suggests that exercise induces more efficient elimination of excess acyl groups derived from BCAA and aromatic amino acid (AA) metabolism via formation of urinary glycine adducts., Conclusions/interpretation: A mechanism involving more efficient elimination of excess acyl groups derived from BCAA and aromatic AA metabolism via glycine conjugation in the liver, rather than increased BCAA disposal through oxidation and turnover, may mediate interactions between exercise, BCAA metabolism and IS., Trial Registration: Clinicaltrials.gov NCT01786941.

Most health organizations recommend a combination of aerobic training (AT) and resistance training (RT), yet few studies have compared their acute (within 24 h of the last exercise bout) and sustained (after 14 days of no exercise training) effects alone and in combination on glucose metabolism. The present study (Studies Targeting Risk Reduction Interventions through Defined Exercise-Aerobic Training and/or Resistance Training) compared the effects of AT, RT, and the combination (AT/RT) on insulin action at both acute and sustained phases. Subjects (N = 196) were 18-70 yr old (mean age = 50 yr), overweight (mean body mass index = 30 kg/m2), sedentary with moderate dyslipidemia, and were randomized into one of three 8-mo exercise groups: 1) RT: 3 days/wk, 8 exercises, 3 sets/exercise, 8-12 repetitions/set; 2) AT: equivalent to ∼19.2 km/wk (12 miles/wk) at 75% peak O2 consumption; 3) AT/RT: the combination of AT and RT. One hundred forty-four subjects completed the intervention. Eighty-eight subjects completed all pre- and postintervention testing visits. Insulin sensitivity, glucose effectiveness, and disposition index were measured via a frequently sampled intravenous glucose tolerance test with subsequent minimal model analyses. AT/RT resulted in greater improvements in insulin sensitivity, β-cell function (disposition index), and glucose effectiveness than either AT or RT alone (all P < 0.05). Approximately 52% of the improvement in insulin sensitivity by AT/RT was retained 14 days after the last exercise training bout. Neither AT or RT led to acute or chronic improvement in sensitivity index. In summary, only AT/RT (which required twice as much time as either alone) led to significant acute and sustained benefits in insulin sensitivity

Recent guidelines on exercise for weight loss and weight maintenance include resistance training as part of the exercise prescription. Yet few studies have compared the effects of similar amounts of aerobic and resistance training on body mass and fat mass in overweight adults. STRRIDE AT/RT, a randomized trial, compared aerobic training, resistance training, and a combination of the two to determine the optimal mode of exercise for obesity reduction. Participants were 119 sedentary, overweight or obese adults who were randomized to one of three 8-mo exercise protocols: 1) RT: resistance training, 2) AT: aerobic training, and 3) AT/RT: aerobic and resistance training (combination of AT and RT). Primary outcomes included total body mass, fat mass, and lean body mass. The AT and AT/RT groups reduced total body mass and fat mass more than RT (P < 0.05), but they were not different from each other. RT and AT/RT increased lean body mass more than AT (P < 0.05). While requiring double the time commitment, a program of combined AT and RT did not result in significantly more fat mass or body mass reductions over AT alone. Balancing time commitments against health benefits, it appears that AT is the optimal mode of exercise for reducing fat mass and body mass, while a program including RT is needed for increasing lean mass in middle-aged, overweight/obese individuals.

Purpose: Our study characterizes food and energy intake responses to long-term aerobic training (AT) and resistance training (RT) during a controlled 8-month trial., Methods: In the STRRIDE-AT/RT trial, overweight/obese sedentary dyslipidemic men and women were randomized to AT (n = 39), RT (n = 38), or a combined treatment (AT/RT, n = 40) without any advice to change their food intakes. Quantitative food intake assessments and food frequency questionnaires were collected at baseline (before training) and after 8 months of training (end of training); body mass (BM) and fat-free mass (FFM) were also assessed., Results: In AT and AT/RT, respectively, meaningful decreases in reported energy intake (REI) (-217 and -202 kcal, P < 0.001) and in intakes of fat (-14.9 and -14.9 g, P < 0.001, P = 0.004), protein (-8.3 and -10.7 g, P = 0.002, P < 0.001), and carbohydrate (-28.1 and -14.7 g, P = 0.001, P = 0.030) were found by food frequency questionnaires. REI relative to FFM decreased (P < 0.001 and P = 0.002), as did intakes of fat (-0.2 and -0.3 g, P = 0.003 and P = 0.014) and protein (-0.1 and -0.2 g, P = 0.005 and P < 0.001) in AT and AT/RT and carbohydrate (-0.5 g, P < 0.003) in AT only. For RT, REI by quantitative daily dietary intake decreased (-3.0 kcal.kg(-1) FFM, P = 0.046), as did fat intake (-0.2 g, P = 0.033). BM decreased in AT (-1.3 kg, P = 0.006) and AT/RT (-1.5 kg, P = 0.001) but was unchanged (0.6 kg, P = 0.176) in RT., Conclusions: Previously sedentary subjects completing 8 months of AT or AT/RT reduced their intakes of calories and macronutrients and BM. In RT, fat intakes and REI (when expressed per FFM) decreased, BM was unchanged, and FFM increased.

Background: Individuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed., Methodology/principal Findings: An adverse response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors., Conclusions/significance: Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.

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.

Randomized clinical trials of exercise training regimens in sedentary individuals have provided a mechanistic understanding of the long-term health benefits and consequences of physical activity and inactivity. The sedentary control periods from these trials have provided evidence of the progressive metabolic deterioration that results from as little as 4-6 mo of continuing a physically inactive lifestyle. These clinical trials have also demonstrated that only a modest amount of physical activity is required to prevent this metabolic deterioration, and this amount of physical activity is consistent with current physical activity recommendations (150 min/wk of moderate intensity physical activity). These recommendations have been issued to the general population for a vast array of health benefits. While greater adherence to these recommendations should result in substantial improvements in the health of the population, these recommendations still remain inadequate for many individuals. An individual's physical activity requirements are influenced by such factors as an individual's diet, nonexercise physical activity patterns, genetic profile, and medications. Improving the understanding of how these factors influence an individual's physical activity requirements will help advance the field and help move the field toward the development of more personalized physical activity recommendations.

Aerobic training (AT) improves the metabolic syndrome (MS) and its component risk factors; however, to our knowledge, no randomized clinical studies have addressed whether resistance training (RT) improves the MS when performed alone or combined with AT. Sedentary, overweight dyslipidemic men and women, aged 18 to 70 years completed a 4-month inactive run-in period and were randomized to 1 of 3 eight-month exercise programs (n = 196). The exercise programs were (1) RT (3 days/week, 3 sets/day of 8 to 12 repetitions of 8 different exercises targeting all major muscle groups); (2) AT (∼120 minutes/week at 75% of the maximum oxygen uptake), and (3) AT and RT combined (AT/RT) (exact combination of AT and RT). Of the 196 randomized patients, 144 completed 1 of the 3 exercise programs. The 86 participants with complete data for all 5 MS criteria were used in the present analysis, and a continuous MS z score was calculated. Eight months of RT did not change the MS score. AT improved the MS score (p <0.07) and showed a trend toward significance compared to RT (p <0.10). AT/RT significantly decreased the MS score and was significantly different from RT alone. In conclusion, RT was not effective at improving the MS score; however, AT was effective. Combined AT and RT was similarly effective but not different from AT alone. When weighing the time commitment versus health benefit, the data suggest that AT alone was the most efficient mode of exercise for improving cardiometabolic health., (Published by Elsevier Inc.)

Purpose: An active lifestyle is widely recognized as having a beneficial effect on cardiovascular health. However, no clear consensus exists as to whether exercise training increases overall physical activity energy expenditure (PAEE) or whether individuals participating in regular exercise compensate by reducing their off-exercise physical activity. The purpose of this study was to evaluate changes in PAEE in response to aerobic training (AT), resistance training (RT), or combined aerobic and resistance training (AT/RT)., Methods: Data are from 82 participants in the Studies of Targeted Risk Reduction Interventions through Defined Exercise-Aerobic Training versus Resistance Training study, a randomized trial of overweight (body mass index = 25-35 kg·m(-2)) adults, in which participants were randomized to receive 8 months of AT, RT, or AT/RT. All subjects completed a 4-month control period before randomization. PAEE was measured using triaxial RT3 accelerometers, which subjects wore for a 5- to 7-d period before and after the exercise intervention. Data reduction was performed with a previously published computer-based algorithm., Results: There was no significant change in off-exercise PAEE in any of the exercise training groups. We observed a significant increase in total PAEE that included the exercise training, in both AT and AT/RT but not in RT., Conclusions: Eight months of exercise training was not associated with a compensatory reduction in off-exercise physical activity, regardless of exercise modality. The absence of compensation is particularly notable for AT/RT subjects, who performed a larger volume of exercise than did AT or RT subjects. We believe that the extended duration of our exercise training program was the key factor in allowing subjects to reach a new steady-state level of physical activity within their daily lives.

Objective: To understand relationships between exercise training-mediated improvements in insulin sensitivity (S(I)) and changes in circulating concentrations of metabolic intermediates, hormones, and inflammatory mediators., Research Design and Methods: Targeted mass spectrometry and enzyme-linked immunosorbent assays were used to quantify metabolic intermediates, hormones, and inflammatory markers at baseline, after 6 months of exercise training, and 2 weeks after exercise training cessation (n = 53). A principal components analysis (PCA) strategy was used to relate changes in these intermediates to changes in S(I)., Results: PCA reduced the number of intermediates from 90 to 24 factors composed of biologically related components. With exercise training, improvements in S(I) were associated with reductions in by-products of fatty acid oxidation and increases in glycine and proline (P < 0.05, R² = 0.59); these relationships were retained 15 days after cessation of exercise training (P < 0.05, R² = 0.34)., Conclusions: These observations support prior observations in animal models that exercise training promotes more efficient mitochondrial β-oxidation and challenges current hypotheses regarding exercise training and glycine metabolism.

The obese are at increased risk for cardiovascular disease and type 2 diabetes. However, some who are obese have no metabolic abnormalities. So, it is not adipose tissue per se, but perhaps where it is located that is important for determining metabolic consequences. Regular exercise is known to reduce risk for metabolic disease through numerous mechanisms. The purpose of this report is to highlight some of the efficacy-based data on the effects of exercise (and also a sedentary lifestyle) on abdominal obesity, visceral fat, and metabolic risk. We also discuss how impaired fatty acid oxidation (FAO) in skeletal muscle may be related to both insulin resistance and a contributor to weight gain. In summary, it is evident that exercise in sufficient amounts can lead to substantial decreases in body weight, total body fat, and visceral fat. Additionally, evidence now supports the conclusion that there is a dose-response relationship between exercise amount and these changes, i.e., more exercise leads to additional benefits. Additionally, there are a number of important cardiometabolic risk factors that were most favorably effected by moderate-intensity compared to vigorous-intensity exercise. Unfortunately, it is also apparent that in sedentary middle-aged men and women, short periods of physical inactivity lead to significant weight gain, substantial increases in visceral fat, and further metabolic deterioration. Finally, favorable modulation of mitochondrial oxidative capacity in skeletal muscle by exercise training may reduce a block for complete oxidation of fatty acids in muscle and thereby relieve a block to effective insulin signaling.

Lipids are a strong mediator of coronary artery disease and cardiovascular risk. Although the effects of exercise to improve high-density lipoprotein (HDL) cholesterol and serum triglycerides (TGs) have been known for some time, the effects of different amounts and intensities of exercise on fasting and postprandial serum lipids are little understood. Normal lipid physiology is perturbed in insulin resistant states, where inhibition of lipolysis is impaired, particularly in the postprandial period when excursions in insulin and serum TGs are particularly high. In our STRRIDE (Studies of a Targeted Risk Reduction Intervention through Defined Exercise) study, three important metabolic cardiovascular risk-related variables were improved more by moderate intensity than vigorous-intensity exercise. Moderate-intensity exercise was significantly more effective at lowering TGs and improving insulin sensitivity than was vigorous exercise. Additionally, a composite score for metabolic syndrome improved significantly with low-amount/moderate, but did not with low-amount/vigorous-intensity exercise. That all three of these strong, independent, cardiovascular risk factors were significantly affected by moderate-intensity exercise suggests that regular walking exercise might be as effective, if not more so, than more vigorous exercise in favorably modifying cardiovascular risk. Despite the impressive effects of regular exercise on fasting lipids and atherogenic dyslipidemia, they are more impressive when compared with the trajectory of changes that occur in individuals that remain inactive, without regular exposure to regular exercise. A scientific priority for future investigations should be to study the independent and combined effects of exercise intensity and amount on exercise responses through a direct comparison between two groups matched on amount but differing in intensity.

Objective: To determine whether circulating metabolic intermediates are related to insulin resistance and beta-cell dysfunction in individuals at risk for type 2 diabetes., Research Design and Methods: In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids, and conventional metabolites were measured with a targeted, mass spectrometry-based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates., Results: The 75 metabolic intermediates clustered into 19 factors comprising biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (S(I)) (R(2) = 0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R(2) = 0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI) (R(2) = 0.39). Sex differences were found for metabolic predictors of S(I) and DI., Conclusions: In addition to the well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids were independently associated with insulin resistance. Fatty acids were inversely related to the pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play a role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert sex-specific effects on insulin action.

Introduction: We examined the effects of three exercise training interventions on total physical activity energy expenditure (PAEE) or nonexercise PAEE in a randomized controlled trial where sedentary, overweight, and obese men and women were assigned to inactive control, low-amount/moderate-intensity, low-amount/vigorous-intensity, or high-amount/vigorous-intensity aerobic exercise., Methods: To measure PAEE, triaxial RT3 accelerometers were worn by subjects for 7 d at the beginning and end of an 8-month exercise intervention. In total, 50 subjects (control, n = 8; two low-amount groups, n = 28; high-amount group, n = 14) had usable PAEE data collected at both time points., Results: At baseline, subjects had an average age of 53.2 yr, had a body mass index of 29.7 kg x m(-2), and a relative peak VO2 of 28.7 mL x kg(-1) x min(-1). There were no significant differences between groups at baseline. After the intervention, average change in total PAEE was 8.4 +/- 20.9 kJ x h(-1) for controls, 58.6 +/- 20.9 kJ x h(-1) for the two low-amount groups, and 138.1 +/- 33.5 kJ x h(-1) for the high-amount group (means +/- SE). The high-amount group experienced a significantly greater increase in total PAEE compared with the controls (P = 0.02). As expected, total PAEE increased with increasing exercise volume. Average change in nonexercise PAEE was 8.4 +/- 20.9 kJ x h(-1) for control, 25.1 +/- 20.9 kJ x h(-1) for the low-amount groups combined, and 62.8 +/- 29.3 kJ x h(-1) for the high-amount group. There was no statistically significant difference in change of nonexercise PAEE among groups., Conclusions: We conclude that in middle-aged overweight or obese subjects participating in an extended exercise intervention, total PAEE increased, and there was no compensatory decrease in nonexercise PAEE.

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.

Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Small LDL and HDL particle size are characteristic of a proatherogenic lipoprotein profile. Aerobic exercise increases these particle sizes. Although visceral adipose tissue (VAT) has been strongly linked with dyslipidemia, the importance of intermuscular adipose tissue (IMAT) to dyslipidemia and exercise responses is less well understood. We measured exercise-associated changes in thigh IMAT and VAT and examined their relationships with changes in LDL and HDL particle size. Sedentary, dyslipidemic, overweight subjects (n = 73) completed 8-9 mo of aerobic training. Linear regression models were used to compare the power of IMAT change and VAT change to predict lipoprotein size changes. In men alone (n = 40), IMAT change correlated inversely with both HDL size change (r = -0.42, P = 0.007) and LDL size change (r = -0.52, P < 0.001). That is, reduction of IMAT was associated with a shift toward larger, less atherogenic lipoprotein particles. No significant correlations were observed in women. After adding VAT change to the model, IMAT change was the only significant predictor of either HDL size change (P = 0.034 for IMAT vs. 0.162 for VAT) or LDL size change (P = 0.004 for IMAT vs. 0.189 for VAT) in men. In conclusion, in overweight dyslipidemic men, exercise-associated change in thigh IMAT was inversely correlated with both HDL and LDL size change and was more predictive of these lipoprotein changes than was change in VAT. Reducing IMAT through aerobic exercise may be functionally related to some improvements in atherogenic dyslipidemia in men.