Comparison of aspartame- and sugar-sweetened soft drinks on postprandial metabolism.

Aim: We compared the impact of artificially- and sugar-sweetened beverages co-ingested with a mixed meal on postprandial fat and carbohydrate oxidation, blood glucose, and plasma insulin and triglyceride concentrations. Methods: Eight college-aged, healthy males completed three randomly assigned trials, which consisted of a mixed macronutrient meal test with 20oz of Diet-Coke (AS), Coca-Cola (NS), or water (CON). One week separated each trial and each participant served as his own control. Resting energy expenditure (REE) via indirect calorimetry, blood pressure, and blood samples were obtained immediately before, 5, 10, 30, 60, 120, and 180 min after meal and beverage ingestion. A two-way (treatment × time) repeated-measures ANOVA was conducted to assess REE, fat and carbohydrate oxidation rates, blood glucose, and plasma insulin and triglyceride concentrations. Results: There was a significant main effect of treatment on total fat oxidation (P = 0.006), fat oxidation was significantly higher after AS (P = 0.006) and CON (P = 0.001) compared to following NS. There was a significant main effect of treatment on total carbohydrate oxidation (P = 0.005), carbohydrate oxidation was significantly lower after AS (P = 0.014) and CON (P = 0.001) compared to following NS. Plasma insulin concentration AUC was significantly lower after AS (P = 0.019) and trended lower in CON (P = 0.054) compared to following NS. Conclusion: Ingestion of a mixed meal with an artificially-sweetened beverage does not impact postprandial metabolism, whereas a sugar-sweetened beverage suppresses fat oxidation and increases carbohydrate oxidation compared to artificially-sweetened beverage and water.

Effect of Prior Exercise on Postprandial Lipemia: An Updated Meta-Analysis and Systematic Review.

The purpose of this systematic review was to synthesize the results from current literature examining the effects of prior exercise on the postprandial triglyceride (TG) response to evaluate current literature and provide future direction. A quantitative review was performed using meta-analytic methods to quantify individual effect sizes. A moderator analysis was performed to investigate potential variables that could influence the effect of prior exercise on postprandial TG response. Two hundred and seventy-nine effects were retrieved from 165 studies for the total TG response and 142 effects from 87 studies for the incremental area under the curve TG response. There was a moderate effect of exercise on the total TG response (Cohen's d = -0.47; p < .0001). Moderator analysis revealed exercise energy expenditure significantly moderated the effect of prior exercise on the total TG response (p < .0001). Exercise modality (e.g., cardiovascular, resistance, combination of both cardiovascular and resistance, or standing), cardiovascular exercise type (e.g., continuous, interval, concurrent, or combined), and timing of exercise prior to meal administration significantly affected the total TG response (p < .001). Additionally, exercise had a moderate effect on the incremental area under the curve TG response (Cohen's d = -0.40; p < .0001). The current analysis reveals a more homogeneous data set than previously reported. The attenuation of postprandial TG appears largely dependent on exercise energy expenditure (∼2 MJ) and the timing of exercise. The effect of prior exercise on the postprandial TG response appears to be transient; therefore, exercise should be frequent to elicit an adaptation.

Tabata-style functional exercise increases resting and postprandial fat oxidation but does not reduce triglyceride concentrations.

NEW FINDINGS: What is the central question of this study? What are the metabolic impacts of high intensity functional Tabata exercise? What is the main finding and its importance? Tabata exercise with high intensity functional movements causes increases in fasted and postprandial fat oxidation the day after exercise without altering postprandial triglyceride concentrations. These results support the usage of a Tabata-style high intensity functional exercise to improve postprandial fat oxidation. ABSTRACT: We evaluated the effect of a high fat meal with and without prior high intensity functional exercise executed in a Tabata-style interval pattern on resting and postprandial substrate oxidation, as well as postprandial blood glucose and triglyceride concentrations. Eleven healthy males completed two trials (Tabata exercise (TE) and non-exercise control (CON)) in random order separated by 7 days. A two-day protocol was used in which TE or CON was performed on the first day and a high fat meal was administered ∼13 h later the following morning. Power output from the TE session was quantified using a kinematic approach by calculating external work performed per unit time for each of the four exercises (rowing, dumbbell thrusters, kettlebell swings and burpees). For the meal challenge, respiratory gases and blood samples were taken fasted and at 1, 2 and 3 h postprandial. Fat oxidation was significantly higher after TE compared to CON at all time points (P < 0.05). Carbohydrate oxidation was significantly lower after TE compared to CON at 1 h postprandial (P < 0.05). There were no significant effects of TE on fasting or postprandial glucose or triglyceride concentrations. Functional exercises performed in a high intensity TE pattern enhance fasting and postprandial fat oxidation on the following day with minimal influence on blood triglycerides or glucose levels.

Effect of exercise intensity on circulating microparticles in men and women.

NEW FINDINGS: What is the central question of this study? What is the effect of exercise intensity on circulating microparticle populations in young, healthy men and women? What is the main finding and its importance? Acute, moderate-intensity continuous exercise and high-intensity interval exercise altered distinct microparticle populations during and after exercise in addition to a sex-specific response in CD62E+ microparticles. The microparticles studied contribute to cardiovascular disease progression, regulate vascular function and facilitate new blood vessel formation. Thus, characterizing the impact of intensity on exercise-induced microparticle responses advances our understanding of potential mechanisms underlying the beneficial vascular adaptations to exercise. ABSTRACT: Circulating microparticles (MPs) are biological vectors of information within the cardiovascular system that elicit both deleterious and beneficial effects on the vasculature. Acute exercise has been shown to alter MP concentrations, probably through a shear stress-dependent mechanism, but evidence is limited. Therefore, we investigated the effect of exercise intensity on plasma levels of CD34+ and CD62E+ MPs in young, healthy men and women. Blood samples were collected before, during and after two energy-matched bouts of acute treadmill exercise: interval exercise (10 × 1 min intervals at ∼95% of maximal oxygen uptake V̇O2max) and continuous exercise (65% V̇O2max). Continuous exercise, but not interval exercise, reduced CD62E+ MP concentrations in men and women by 18% immediately after exercise (from 914.5 ± 589.6 to 754.4 ± 390.5 MPs µl-1 ; P < 0.05), suggesting that mechanisms underlying exercise-induced CD62E+ MP dynamics are intensity dependent. Furthermore, continuous exercise reduced CD62E+ MPs in women by 19% (from 1030.6 ± 688.1 to 829.9 ± 435.4 MPs µl-1 ; P < 0.05), but not in men. Although interval exercise did not alter CD62E+ MPs per se, the concentrations after interval exercise were higher than those observed after continuous exercise (P < 0.05). Conversely, CD34+ MPs did not fluctuate in response to short-duration acute continuous or interval exercise in men or women. Our results suggest that exercise-induced MP alterations are intensity dependent and sex specific and impact MP populations differentially.

Zinc Supplementation Does Not Alter Indicators of Insulin Secretion and Sensitivity in Black and White Female Adolescents.

Background: Zinc is a micronutrient involved in the production of, and peripheral sensitivity to, pancreatic ß cell-derived insulin. To our knowledge, the effect of zinc supplementation on insulin outcomes, and potential risk of diabetes, in otherwise healthy children in the United States has not been investigated.Objective: The objective of this study was to determine the influence of zinc supplementation on insulin outcomes in black and white girls in the early stages of adolescence. A secondary objective was to determine relations between baseline zinc concentrations and insulin outcomes.Methods: Healthy black and white girls aged 9-11 y were randomly assigned to daily supplementation of zinc (9 mg elemental Zn/d; n = 75; blacks: n = 35) or placebo (n = 72; blacks: n = 32) for 4 wk. Fasting serum insulin, glucose, and C-peptide were assessed at baseline and at 4 wk. C-peptide and glucose values were used to calculate the computer model-derived homeostatic model assessment of insulin resistance (HOMA2-IR). Changes in outcome measures were compared by using repeated-measures, mixed-model ANOVA.Results: Baseline plasma zinc was not correlated with C-peptide (r = -0.07), insulin (r = -0.06), or HOMA2-IR (r = -0.09) (all P > 0.05) after controlling for race and age. Treatment × time interactions for C-peptide and HOMA2-IR were not significant (both P > 0.05). Although the treatment × race × time interactions for C-peptide and HOMA2-IR were not significant (both P = 0.08), black girls who received the placebo experienced slight increases in C-peptide (15.7%) and HOMA2-IR (17.7%) (P = 0.06).Conclusions: Four weeks of zinc supplementation had no effect on insulin outcomes in healthy black and white early-adolescent girls, although C-peptide and HOMA2-IR tended to increase in black girls who received placebo. Additional trials that are appropriately powered should further explore the effect of zinc on markers of diabetes risk, and whether race affects this relation. This trial was registered at clinicaltrials.gov as NCT01892098.

Mitochondria-specific antioxidant supplementation does not influence endurance exercise training-induced adaptations in circulating angiogenic cells, skeletal muscle oxidative capacity or maximal oxygen uptake.

KEY POINTS: Reducing excessive oxidative stress, through chronic exercise or antioxidants, can decrease the negative effects induced by excessive amounts of oxidative stress. Transient increases in oxidative stress produced during acute exercise facilitate beneficial vascular training adaptations, but the effects of non-specific antioxidants on exercise training-induced vascular adaptations remain elusive. Circulating angiogenic cells (CACs) are an exercise-inducible subset of white blood cells that maintain vascular integrity. We investigated whether mitochondria-specific antioxidant (MitoQ) supplementation would affect the response to 3 weeks of endurance exercise training in CACs, muscle mitochondrial capacity and maximal oxygen uptake in young healthy men. We show that endurance exercise training increases multiple CAC types, an adaptation that is not altered by MitoQ supplementation. Additionally, MitoQ does not affect skeletal muscle or whole-body aerobic adaptations to exercise training. These results indicate that MitoQ supplementation neither enhances nor attenuates endurance training adaptations in young healthy men. ABSTRACT: Antioxidants have been shown to improve endothelial function and cardiovascular outcomes. However, the effects of antioxidants on exercise training-induced vascular adaptations remain elusive. General acting antioxidants combined with exercise have not impacted circulating angiogenic cells (CACs). We investigated whether mitochondria-specific antioxidant (MitoQ) supplementation would affect the response to 3 weeks of endurance exercise training on CD3+ , CD3+ /CD31+ , CD14+ /CD31+ , CD31+ , CD34+ /VEGFR2+ and CD62E+ peripheral blood mononuclear cells (PBMCs), muscle mitochondrial capacity, and maximal oxygen uptake (VO2 max ) in healthy men aged 22.1 ± 0.7 years, with a body mass index of 26.9 ± 0.9 kg m-2 , and 24.8 ± 1.3% body fat. Analysis of main effects revealed that training induced 33, 105 and 285% increases in CD14+ /CD31+ , CD62E+ and CD34+ /VEGFR2+ CACs, respectively, and reduced CD3+ /CD31- PBMCs by 14%. There was no effect of MitoQ on CAC levels. Also independent of MitoQ supplementation, exercise training significantly increased quadriceps muscle mitochondrial capacity by 24% and VO2 max by roughly 7%. In conclusion, endurance exercise training induced increases in multiple CAC types, and this adaptation is not modified by MitoQ supplementation. Furthermore, we demonstrate that a mitochondrial-targeted antioxidant does not influence skeletal muscle or whole-body aerobic adaptations to exercise training.

Endothelial and inflammatory responses to acute exercise in perimenopausal and late postmenopausal women.

Endothelial dysfunction and inflammation are characteristics of subclinical atherosclerosis and may increase through progressive menopausal stages. Evaluating endothelial responses to acute exercise can reveal underlying dysfunction not apparent in resting conditions. The purpose of this study was to investigate markers of endothelial function and inflammation before and after acute exercise in healthy low-active perimenopausal (PERI) and late postmenopausal (POST) women. Flow-mediated dilation (FMD), CD31+/CD42b- and CD62E+ endothelial microparticles (EMPs), and the circulating inflammatory factors monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8), and tumor necrosis factor-α (TNF-α) were measured before and 30 min after acute exercise. Before exercise, FMD was not different between groups (PERI: 6.4 ± 0.9% vs. POST: 6.5 ± 0.8%, P = 0.97); however, after acute exercise PERI tended to improve FMD (8.5 ± 0.9%, P = 0.09), whereas POST did not (6.2 ± 0.8%, P = 0.77). Independent of exercise, we observed transient endothelial dysfunction in POST with repeated FMD measures. There was a group × exercise interaction for CD31+/CD42b- EMPs (P = 0.04), where CD31+/CD42b- EMPs were similar before exercise (PERI: 57.0 ± 6.7 EMPs/µl vs. POST: 58.5 ± 5.3 EMPs/µl, P = 0.86) but were higher in POST following exercise (PERI: 48.2 ± 6.7 EMPs/µl vs. POST: 69.4 ± 5.3 EMPs/µl, P = 0.023). CD62E+ EMPs were lower in PERI compared with POST before exercise (P < 0.001) and increased in PERI (P = 0.04) but did not change in POST (P = 0.68) in response to acute exercise. After acute exercise, MCP-1 (P = 0.055), TNF-α (P = 0.02), and IL-8 (P < 0.001) were lower in PERI but only IL-8 decreased in POST (P < 0.001). Overall, these data suggest that perimenopausal and late postmenopausal women display different endothelial and inflammatory responses to acute exercise.

Effect of acute exercise on circulating angiogenic cell and microparticle populations.

Subpopulations of peripheral blood mononuclear cells (PMBCs), known as circulating angiogenic cells (CACs), have been implicated in endothelial repair, angiogenesis and vascular homeostasis. Conversely, microparticles released from endothelial cells, platelets and leucocytes in response to injury or apoptosis are elevated in chronic diseases. We investigated the effect of acute exercise on CAC subpopulations, specifically CD34(+)/VEGFR2(+), CD3(+)/CD31(+), CD14(+)/CD31(+) and CD62E(+) PBMCs and CD62E(+), CD31(+)/CD42b(-) and CD34(+) MPs in men and women. Additionally, we examined angiogenesis-related gene expression in CD34(+), CD31(+) and CD62E(+) PBMCs at baseline and after exercise. Finally, we examined whether acute exercise modulates CD62E(+) PBMC paracrine actions on cultured endothelial cells. Blood samples for CAC and MP analyses were obtained before and after cycling exercise at 70% peak oxygen uptake that elicited an energy expenditure of 600 kcal. Exercise produced a decrease in CD14(+)/CD31(+) PBMCs, whereas CD62E expression on PBMCs increased with exercise. CD34(+)/VEGFR2(+) and CD3(+)/CD31(+) PBMC levels were not altered with exercise. Gene expression analysis revealed a more proangiogenic phenotype in CD62E(+) cells at baseline compared with CD31(+) and CD34(+) cells. Conditioned media from CD62E(+) PBMCs obtained after exercise exerted a proangiogenic influence on human umbilical vein endothelial cells, with increases in genes encoding receptors for growth factors (KDR, FGFR1 and EGFR) and inflammatory mediators (TLR4 and TNFR1). Finally, exercise increased CD62E(+) endothelial MPs in men and increased CD34(+) MPs in women. Our work highlights the potential role of CD62E(+) cells as a novel, exercise-responsive proangiogenic cell population and demonstrates sex-specific exercise-induced changes in circulating MPs.

Chronic NOS inhibition accelerates NAFLD progression in an obese rat model.

The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via N(ω)-nitro-L-arginine methyl ester (L-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or L-NAME (65-70 mg·kg(-1)·day(-1))-containing drinking water for 4 wk. L-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, L-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where L-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, L-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1ß (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by L-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity.

Chronic endurance exercise affects paracrine action of CD31+ and CD34+ cells on endothelial tube formation.

We aimed to determine if chronic endurance-exercise habits affected redox status and paracrine function of CD34(+) and CD34(-)/CD31(+) circulating angiogenic cells (CACs). Subjects were healthy, nonsmoking men and women aged 18-35 yr and categorized by chronic physical activity habits. Blood was drawn from each subject for isolation and culture of CD34(+) and CD34(-)/CD31(+) CACs. No differences in redox status were found in any group across either cell type. Conditioned media (CM) was generated from the cultured CACs and used in an in vitro human umbilical vein endothelial cell-based tube assay. CM from CD34(+) cells from inactive individuals resulted in tube structures that were 29% shorter in length (P < 0.05) and 45% less complex (P < 0.05) than the endurance-trained group. CD34(-)/CD31(+) CM from inactive subjects resulted in tube structures that were 26% shorter in length (P < 0.05) and 42% less complex (P < 0.05) than endurance-trained individuals. Proteomics analyses identified S100A8 and S100A9 in the CM. S100A9 levels were 103% higher (P < 0.05) and S100A8 was 97% higher in the CD34(-)/CD31(+) CM of inactive subjects compared with their endurance-trained counterparts with no significant differences in either protein in the CM of CD34(+) CACs as a function of training status. Recombinant S100A8/A9 treatment at concentrations detected in inactive subjects' CD34(-)/CD31(+) CAC CM also reduced tube formation (P < 0.05). These findings are the first, to our knowledge, to demonstrate a differential paracrine role in CD34(+) and CD34(-)/CD31(+) CACs on tube formation as a function of chronic physical activity habits and identifies a differential secretion of S100A9 by CD34(-)/CD31(+) CACs due to habitual exercise.

Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction.

Ovariectomized rodents model human menopause in that they rapidly gain weight, reduce spontaneous physical activity (SPA), and develop metabolic dysfunction, including insulin resistance. How contrasting aerobic fitness levels impacts ovariectomy (OVX)-associated metabolic dysfunction is not known. Female rats selectively bred for high and low intrinsic aerobic fitness [high-capacity runners (HCR) and low-capacity runners (LCR), respectively] were maintained under sedentary conditions for 39 wk. Midway through the observation period, OVX or sham (SHM) operations were performed providing HCR-SHM, HCR-OVX, LCR-SHM, and LCR-OVX groups. Glucose tolerance, energy expenditure, and SPA were measured before and 4 wk after surgery, while body composition via dual-energy X-ray absorptiometry and adipose tissue distribution, brown adipose tissue (BAT), and skeletal muscle phenotype, hepatic lipid content, insulin resistance via homeostatic assessment model of insulin resistance and AdipoIR, and blood lipids were assessed at death. Remarkably, HCR were protected from OVX-associated increases in adiposity and insulin resistance, observed only in LCR. HCR rats were ∼30% smaller, had ∼70% greater spontaneous physical activity (SPA), consumed ∼10% more relative energy, had greater skeletal muscle proliferator-activated receptor coactivator 1-alpha, and ∼40% more BAT. OVX did not increase energy intake and reduced SPA to the same extent in both HCR and LCR. LCR were particularly affected by an OVX-associated reduction in resting energy expenditure and experienced a reduction in relative BAT; resting energy expenditure correlated positively with BAT across all animals (r = 0.6; P < 0.001). In conclusion, despite reduced SPA following OVX, high intrinsic aerobic fitness protects against OVX-associated increases in adiposity and insulin resistance. The mechanism may involve preservation of resting energy expenditure.

Measurement of intramuscular fat by muscle echo intensity.

INTRODUCTION: The aim of this study was to compare ultrasound echo intensity (EI) with high-resolution T1 -weighted MRI and to establish calibration equations to estimate percent intramuscular fat from EI. METHODS: Thirty-one participants underwent both ultrasound and MRI testing of 4 muscles: rectus femoris (RF); biceps femoris (BF); tibialis anterior (TA); and medial gastrocnemius (MG). RESULTS: Strong correlations were found between MRI percent fat and muscle EI after correcting for subcutaneous fat thickness (r = 0.91 in RF, r = 0.80 in BF, r = 0.80 in TA, r = 0.76 in MG). Three types of calibration equations were established. CONCLUSIONS: Muscle ultrasound is a practical and reproducible method that can be used as an imaging technique for examination of percent intramuscular fat. Future ultrasound studies are needed to establish equations for other muscle groups to enhance its use in both research and clinical settings.

Identification of genes whose expression is altered by obesity throughout the arterial tree.

We used next-generation RNA sequencing (RNA-Seq) technology on the whole transcriptome to identify genes whose expression is consistently affected by obesity across multiple arteries. Specifically, we examined transcriptional profiles of the iliac artery as well as the feed artery, first, second, and third branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles from obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats. Within the gastrocnemius and soleus muscles, the number of genes differentially expressed with obesity tended to increase with increasing branch order arteriole number (i.e., decreasing size of the artery). This trend was opposite in the diaphragm. We found a total of 15 genes that were consistently upregulated with obesity (MIS18A, CTRB1, FAM151B, FOLR2, PXMP4, OAS1B, SREBF2, KLRA17, SLC25A44, SNX10, SLFN3, MEF2BNB, IRF7, RAD23A, LGALS3BP) and five genes that were consistently downregulated with obesity (C2, GOLGA7, RIN3, PCP4, CYP2E1). A small fraction (∼9%) of the genes affected by obesity was modulated across all arteries examined. In conclusion, the present study identifies a select number of genes (i.e., 20 genes) whose expression is consistently altered throughout the arterial network in response to obesity and provides further insight into the heterogeneous vascular effects of obesity. Although there is no known direct function of the majority of 20 genes related to vascular health, the obesity-associated upregulation of SREBF2, LGALS3BP, IRF7, and FOLR2 across all arteries is suggestive of an unfavorable vascular phenotypic alteration with obesity. These data may serve as an important resource for identifying novel therapeutic targets against obesity-related vascular complications.

Unique transcriptomic signature of omental adipose tissue in Ossabaw swine: a model of childhood obesity.

To better understand the impact of childhood obesity on intra-abdominal adipose tissue phenotype, a complete transcriptomic analysis using deep RNA-sequencing (RNA-seq) was performed on omental adipose tissue (OMAT) obtained from lean and Western diet-induced obese juvenile Ossabaw swine. Obese animals had 88% greater body mass, 49% greater body fat content, and a 60% increase in OMAT adipocyte area (all P < 0.05) compared with lean pigs. RNA-seq revealed a 37% increase in the total transcript number in the OMAT of obese pigs. Ingenuity Pathway Analysis showed transcripts in obese OMAT were primarily enriched in the following categories: 1) development, 2) cellular function and maintenance, and 3) connective tissue development and function, while transcripts associated with RNA posttranslational modification, lipid metabolism, and small molecule biochemistry were reduced. DAVID and Gene Ontology analyses showed that many of the classically recognized gene pathways associated with adipose tissue dysfunction in obese adults including hypoxia, inflammation, angiogenesis were not altered in OMAT in our model. The current study indicates that obesity in juvenile Ossabaw swine is characterized by increases in overall OMAT transcript number and provides novel data describing early transcriptomic alterations that occur in response to excess caloric intake in visceral adipose tissue in a pig model of childhood obesity.

Adipose tissue and vascular phenotypic modulation by voluntary physical activity and dietary restriction in obese insulin-resistant OLETF rats.

Adipose tissue (AT)-derived cytokines are proposed to contribute to obesity-associated vascular insulin resistance. We tested the hypothesis that voluntary physical activity and diet restriction-induced maintenance of body weight would both result in decreased AT inflammation and concomitant improvements in insulin-stimulated vascular relaxation in the hyperphagic, obese Otsuka Long-Evans Tokushima fatty (OLETF) rat. Rats (aged 12 wk) were randomly assigned to sedentary (SED; n = 10), wheel running (WR; n = 10), or diet restriction (DR; n = 10; fed 70% of SED) for 8 wk. WR and DR rats exhibited markedly lower adiposity (7.1 ± 0.4 and 15.7 ± 1.1% body fat, respectively) relative to SED (27 ± 1.2% body fat), as well as improved blood lipid profiles and systemic markers of insulin resistance. Reduced adiposity in both WR and DR was associated with decreased AT mRNA expression of inflammatory genes (e.g., MCP-1, TNF-α, and IL-6) and markers of immune cell infiltration (e.g., CD8, CD11c, and F4/80). The extent of these effects were most pronounced in visceral AT compared with subcutaneous and periaortic AT. Markers of inflammation in brown AT were upregulated with WR but not DR. In periaortic AT, WR- and DR-induced reductions in expression and secretion of cytokines were accompanied with a more atheroprotective gene expression profile in the adjacent aortic wall. WR, but not DR, resulted in greater insulin-stimulated relaxation in the aorta; an effect that was, in part, mediated by a decrease in insulin-induced endothelin-1 activation in WR aorta. Collectively, we show in OLETF rats that lower adiposity leads to less AT and aortic inflammation, as well as an exercise-specific improvement in insulin-stimulated vasorelaxation.

Exercise training and vascular cell phenotype in a swine model of familial hypercholesterolaemia: conduit arteries and veins.

NEW FINDINGS: What is the central question of this study? Does endurance exercise training cause anti-atherogenic effects on the endothelium in a swine model of familial hypercholesterolaemia (FH), and how are these effects distributed across veins, arteries and multiple vascular territories within each system? What is the main finding and its importance? Coronary artery endothelium-dependent vasomotor function was depressed in sedentary FH pigs compared with sedentary control animals, and exercise training did not change vasomotor function within FH. In systemic conduit arteries and veins, few effects of FH on endothelial cell protein expression were noted, including both pro- and anti-atherogenic changes. These findings suggest that exercise training does not produce a consistently improved endothelial cell phenotype in either coronary or systemic conduit vessels in this swine model of FH. Exercise training has emerged as an intervention for the primary and secondary prevention of coronary artery disease, but the mechanisms through which training reduces relative risk are not completely understood. The goal of this study was to investigate the impact of endurance exercise training on vasomotor function and vascular cell phenotype in coronary arteries and systemic conduit arteries and veins against a background of advanced atherosclerosis. We tested the hypothesis that exercise training restores endothelial vasomotor function and produces an anti-atherogenic endothelial and smooth muscle cell phenotype in familial hypercholesterolaemic (FH) swine. The study included 30 FH (15 exercised and 15 sedentary) and 13 non-FH control male castrated swine. The exercise-training intervention consisted of treadmill running 5 days per week for 16-20 weeks. Tissues sampled at sacrifice included vascular rings from the coronary circulation for vasomotor function experiments (dose-dependent bradykinin-induced vasorelaxation) and endothelial cells (ECs) from isolated segments of the thoracic aorta, the carotid, brachial, femoral and renal arteries, as well as each corresponding regionally associated vein, and from the abdominal vena cava, the right coronary and internal mammary arteries. Smooth muscle cells were sampled from the right coronary artery only. Vascular cell phenotype was assessed by immunoblotting for a host of both pro- and anti-atherogenic markers [e.g. endothelial nitric oxide synthase, p67phox, superoxide dismutase 1 (SOD1)]. Coronary artery endothelium-dependent vasomotor function was depressed in sedentary FH pigs compared with sedentary control pigs, and exercise training did not change vasomotor function within FH. In contrast, only scattered effects of FH on EC phenotype were noted across the vasculature, which included both pro- and anti-atherogenic changes in EC protein expression (e.g. increased endothelial nitric oxide synthase in carotid artery ECs, decreased p67phox in brachial artery ECs, but decreased expression of the antioxidant protein SOD1 in thoracic vena cava; all P < 0.05). In thoracic vena cava ECs, this deficit was corrected by exercise training, while no other effects of exercise were observed in conduit vessel EC phenotype. Thus, while exercise training abrogated the adverse effect of hypercholesterolaemia on thoracic vena cava SOD1 expression, it appears that exercise training does not produce a consistently improved EC phenotype in either coronary or systemic conduit vessels in this FH swine model.

Differential vasomotor effects of insulin on gastrocnemius and soleus feed arteries in the OLETF rat model: role of endothelin-1.

The vascular actions of insulin are complex, because it can stimulate both nitric oxide-mediated dilatation and endothelin (ET)-1-mediated constriction. We examined vasoreactivity to insulin in isolated feed arteries of the gastrocnemius (GFA) and soleus muscles (SFA) of 32-week-old Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima fatty (OLETF) rats, a hyperphagic rodent model of obesity and insulin resistance. The insulin-induced vasoreactivity of SFA and GFA was similar in LETO (healthy) and OLETF (obese/insulin-resistant) rats. However, examination of between-vessel effects revealed a number of novel insights into the heterogeneous vascular effects of insulin. Soleus feed arteries dilated more than GFA in LETO at 100 and 1000 µIU ml(-1) insulin (23 versus 6 and 28 versus 0%, respectively; P < 0.05 for between-vessel differences). Likewise, in OLETF rats there was significantly greater dilatation in SFA than GFA at 10, 100 and 1000 µIU ml(-1) insulin (28 versus 3, 30 versus 0 and 34 versus 0%, respectively; all P < 0.05). In the presence of 3 µm tezosentan, a non-specific endothelin-1 receptor blocker, insulin-induced dilatation of the GFA was enhanced such that differences between vessels were largely abolished in both groups. Furthermore, acetylecholine-induced dilatation was significantly greater in SFA than GFA within each group, whereas sodium nitroprusside-induced dilatory responses were greater in the GFA compared with the SFA. Overall, our findings indicate that the insulin/endothelin-1 vasoconstrictor pathway is more active in GFA than in SFA, independent of obesity in the OLETF rat model.

Blood pressure regulation VIII: resistance vessel tone and implications for a pro-atherogenic conduit artery endothelial cell phenotype.

Dysfunction of the endothelium is proposed as the primary initiator of atherosclerotic peripheral artery disease, which occurs mainly in medium- to large-sized conduit arteries of the lower extremities (e.g., iliac, femoral, popliteal arteries). In this review article, we propose the novel concept that conduit artery endothelial cell phenotype is determined, in part, by microvascular tone in skeletal muscle resistance arteries through both changes in arterial blood pressure as well as upstream conduit artery shear stress patterns. First, we summarize the literature supporting the involvement of sympathetic nerve activity (SNA) and nitric oxide (NO) in the modulation of microvascular tone and arterial blood pressure. We then focus on the role of elevated blood pressure and shear stress profiles in modulating conduit artery endothelial cell phenotype. Last, we discuss findings from classic and emerging studies indicating that increased vascular resistance, as it occurs in the context of increased SNA and/or reduced NO bioavailability, is associated with greater oscillatory shear stress (e.g., increased retrograde shear) in upstream conduit arteries. The ideas put forth in this review set the stage for a new paradigm concerning the mechanistic link between increased microvascular tone and development of conduit artery endothelial dysfunction and thus increased risk for peripheral artery disease. Indeed, a vast amount of evidence supports the notion that excessive blood pressure and oscillatory shear stress are potent pro-atherogenic signals to the endothelium.

Circulating angiogenic and inflammatory cytokine responses to acute aerobic exercise in trained and sedentary young men.

PURPOSE: Endurance exercise training can ameliorate many cardiovascular and metabolic disorders and attenuate responses to inflammatory stimuli. The purpose of this study was to determine whether the angiogenic and pro-inflammatory cytokine response to acute endurance exercise differs between endurance-trained and sedentary young men. METHODS: Ten endurance-trained and ten sedentary healthy young men performed 30 min of treadmill running at 75 % VO2max with blood sampling before and after exercise. Plasma concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-8, IL-6, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble VEGF receptor-1 (sFlt-1) were measured by multiplex ELISA. RESULTS: Acute exercise increased IL-6 by 165 % (P < 0.05), IL-8 by 32 % (P < 0.05), PlGF by ~16 % (P < 0.05), sFlt-1 by 36 % (P < 0.001), and tended to increase bFGF by ~25 % (P = 0.06) in main effects analyses. TNF-α and VEGF did not change significantly with exercise in either group. Contrary to our hypothesis, there were no significant differences in TNF-α, IL-6, VEGF, bFGF, PlGF, or sFlt-1 between groups before or after acute exercise; however, there was a tendency for IL-8 concentrations to be higher in endurance-trained subjects compared to sedentary subjects (P = 0.06). CONCLUSIONS: These results indicate that 30 min of treadmill running at 75 % VO2max produces a systemic angiogenic and inflammatory reaction, but endurance exercise training does not appear to significantly alter these responses in healthy young men.

Impact of aerobic fitness status, menstrual cycle phase, and oral contraceptive use on exercise substrate oxidation and metabolic flexibility in females.

The influence of menstrual cycle phase and fitness status on metabolism during high-intensity interval exercise (HIIE) was assessed. Twenty-five females (24.4 (3.6) years) were categorized by normal menstrual cycle (n = 14) vs. oral contraceptive (OC) use (n = 11) and by aerobic fitness, high-fitness females (HFF; n = 13) vs. low-fitness females (LFF; n = 12). HIIE was four sets of four repetitions with a 3 min rest between intervals on a cycle ergometer at a power output halfway between the ventilatory threshold and V̇O2peak and performed during follicular (FOL: days 2-7 or inactive pills) and luteal phases (LUT: day ∼21 or 3rd week of active pills). Substrate oxidation was assessed via indirect calorimetry, blood lactate via finger stick, and recovery of skeletal muscle oxidative metabolism (mV̇O2) via continuous-wave near-infrared spectroscopy. HFF oxidized more fat (g·kg-1) during the full session (FOL: p = 0.050, LUT: p = 0.001), high intervals (FOL: p = 0.048, LUT: p = 0.001), low intervals (FOL: p = 0.032, LUT: p = 0.024), and LUT recovery (p = 0.033). Carbohydrate oxidation area under the curve was greater in HFF during FOL (FOL: p = 0.049, LUT: p = 0.124). Blood lactate was lower in LFF in FOL (p ≤ 0.05) but not in LUT. Metabolic flexibility (Δ fat oxidation g·kg-1·min-1) was greater in HFF than LFF during intervals 2-3 in FOL and 1-4 in LUT (p ≤ 0.05). Fitness status more positively influences exercise metabolic flexibility during HIIE than cycle phase or OC use.