Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.     

Influence of abdominal obesity on vascular endothelial function in overweight/obese adult men

It has been suggested that body fat distribution may be an important determinant of the impact of adiposity on endothelial function. We tested the hypothesis that overweight/obese adults with abdominal adiposity exhibit worse endothelial vasodilator and fibrinolytic function than overweight/obese adults without abdominal adiposity. Sixty adult men were studied: 20 normal weight (BMI: 22.3 ± 0.7 kg/m2; waist circumference (WC): 84.9 ± 2.0 cm); 20 overweight/obese with WC <102 cm (29.2 ± 0.3 kg/m2; 98.1 ± 0.7 cm); and 20 overweight/obese with WC ≥102 cm (30.0 ± 0.4 kg/m2; 106.7 ± 1.0 cm). Forearm blood flow (FBF) responses to intra-arterial acetylcholine and sodium nitroprusside (SNP) were measured. Additionally, net endothelial release of tissue-type plasminogen activator (t-PA) was determined in response to bradykinin (BK) and SNP. Overweight/obese men demonstrated lower (~30%; P < 0.01) FBF responses to acetylcholine compared with normal weight controls. However, there were no differences in FBF responses to acetylcholine between overweight/obese men with (4.1 ± 0.3-10.8 ± 1.3 ml/100 ml tissue/min) and without (4.5 ± 0.3-11.6 ± 0.8 ml/100 ml tissue/min) abdominal adiposity. Similarly, endothelial t-PA release to BK was lower (~40%; P < 0.05) in the overweight/obese men compared with normal weight controls; however, t-PA release was not different between the overweight/obese men with (-0.7 ± 0.4-40.4 ± 6.2 ng/100 ml tissue/min) and without (-0.3 ± 0.6-48 ± 7.5 ng/100 ml tissue/min) abdominal adiposity. These results indicate that abdominal obesity is not associated with greater impairment in endothelial vasodilation and fibrinolytic capacity in overweight/obese men. Excess adiposity, regardless of anatomical distribution pattern, is associated with impaired endothelial function.     

Endothelial t-PA release is impaired in overweight and obese adults but can be improved with regular aerobic exercise

Endothelial release of tissue-type plasminogen activator (t-PA) regulates fibrinolysis and is considered to be a primary endogenous defense mechanism against thrombosis. Adiposity is associated with an increased risk of atherothrombotic events. We determined the influence of overweight and obesity on the capacity of the vascular endothelium to release t-PA and the effects of regular aerobic exercise on endothelial t-PA release in previously sedentary overweight and obese adults. First, we studied 66 sedentary adults: 28 normal-weight (BMI < 25 kg/m2); 22 overweight (BMI > or = 25 and < 30 kg/m2); and 16 obese (BMI > or = 30 kg/m2). Net endothelial t-PA release was determined in vivo in response to intrabrachial infusions of bradykinin (BK) and sodium nitroprusside. Second, we studied 17 overweight and obese adults who completed a 3-mo aerobic exercise intervention. Net release of t-PA in response to BK was approximately 45% lower (P < 0.01) in overweight (from 0.1 +/- 0.4 to 41.7 +/- 4.9 ng x 100 ml tissue(-1) x min(-1)) and obese (-0.1 +/- 0.6 to 47.7 +/- 5.2 ng x 100 ml tissue(-1) x min(-1)) compared with normal-weight (0.1 +/- 0.8 to 77.5 +/- 6.7 ng x 100 ml tissue(-1) x min(-1)) adults. There was no difference in t-PA release between the overweight and obese groups. Exercise training significantly increased t-PA release capacity in overweight and obese adults (from -0.3 +/- 0.5 to 37.1 +/- 4.9 ng x 100 ml tissue(-1) x min(-1) before training vs. 1.0 +/- 0.9 to 65.4 +/- 6.3 ng x 100 ml tissue(-1) x min(-1) after training) to levels comparable with those of their normal-weight peers. These results indicate that overweight and obesity are associated with profound endothelial fibrinolytic dysfunction. Importantly, however, regular aerobic exercise can increase the capacity of the endothelium to release t-PA in this at-risk population.     

Basal Endothelial Nitric Oxide Release Is Preserved in Overweight and Obese Adults

Objective: Impaired basal nitric oxide release is associated with a number of cardiovascular disorders including hypertension, arterial spasm, and myocardial infarction. We determined whether basal endothelial nitric oxide release is reduced in otherwise healthy overweight and obese adult humans. Research Methods and Procedures: Seventy sedentary adults were studied: 32 normal weight (BMI <25 kg/m²), 24 overweight (BMI ≥ 25 < 30 kg/m²), and 14 obese (BMI ≥ 30 kg/m²). Forearm blood flow (FBF) responses to intra‐arterial infusions of N^g‐monomethyl‐l ‐arginine (5 mg/min), a nitric oxide synthase inhibitor, were used as an index of basal nitric oxide release. Results: N^g‐monomethyl‐l ‐arginine elicited significant reductions in FBF in the normal weight (from 4.1 ± 0.2 to 2.7 ± 0.2 mL/100 mL tissue/min), overweight (4.1 ± 0.1 to 2.8 ± 0.2 mL/100 mL tissue/min), and obese (3.9 ± 0.3 to 2.7 ± 0.2 mL/100 mL tissue/min) subjects. Importantly, the magnitude of reduction in FBF (～30%) was similar among the groups. Discussion: These results indicate that the capacity of the endothelium to release nitric oxide under basal conditions is not compromised in overweight and obese adults.     

Enhanced endothelin-1 system activity with overweight and obesity

Endothelin (ET)-1-mediated vasoconstrictor tone contributes to the development and progression of several adiposity-related conditions, including hypertension and atherosclerotic vascular disease. The aims of the present study were to determine 1) whether endogenous ET-1 vasoconstrictor activity is elevated in overweight and obese adults, and, if so, 2) whether increased ET-1-mediated vasoconstriction contributes to the adiposity-related impairment in endothelium-dependent vasodilation. Seventy-nine adults were studied: 34 normal weight [body mass index (BMI) < 25 kg/m(2)], 22 overweight (BMI ≥ 25 and < 30 kg/m(2)), and 23 obese (BMI ≥ 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusion of ET-1 (5 pmol/min for 20 min) and selective ET-1 receptor blockade (BQ-123, 100 nmol/min for 60 min) were determined. In a subset of the study population, FBF responses to ACh (4.0, 8.0, and 16.0 μg·100 ml tissue(-1)·min(-1)) were measured in the absence and presence of selective ET-1 receptor blockade. The vasoconstrictor response to ET-1 was significantly blunted in overweight and obese adults (～ 70%) compared with normal weight adults. Selective ET-1 receptor blockade elicited a significant vasodilator response (～ 20%) in overweight and obese adults but did not alter FBF in normal weight adults. Coinfusion of BQ-123 did not affect FBF responses to ACh in normal weight adults but resulted in an ～ 20% increase (P < 0.05) in ACh-induced vasodilation in overweight and obese adults. These results demonstrate that overweight and obesity are associated with enhanced ET-1-mediated vasoconstriction that contributes to endothelial vasodilator dysfunction and may play a role in the increased prevalence of hypertension with increased adiposity.     

Seven days of aerobic exercise training improves conduit artery blood flow following glucose ingestion in patients with type 2 diabetes

The vasodilatory effects of insulin account for up to 40% of insulin-mediated glucose disposal; however, insulin-stimulated vasodilation is impaired in individuals with type 2 diabetes, limiting perfusion and delivery of glucose and insulin to target tissues. To determine whether exercise training improves conduit artery blood flow following glucose ingestion, a stimulus for increasing circulating insulin, we assessed femoral blood flow (FBF; Doppler ultrasound) during an oral glucose tolerance test (OGTT; 75 g glucose) in 11 overweight or obese (body mass index, 34 ± 1 kg/m2), sedentary (peak oxygen consumption, 23 ± 1 ml·kg?1·min?1) individuals (53 ± 2 yr) with non-insulin-dependent type 2 diabetes (HbA1c, 6.63 ± 0.18%) before and after 7 days of supervised treadmill and cycling exercise (60 min/day, 60-75% heart rate reserve). Fasting glucose, insulin, and FBF were not significantly different after 7 days of exercise, nor were glucose or insulin responses to the OGTT. However, estimates of whole body insulin sensitivity (Matsuda insulin sensitivity index) increased (P < 0.05). Before exercise training, FBF did not change significantly during the OGTT (1 ± 7, -7 ± 5, 0 ± 6, and 0 ± 5% of fasting FBF at 75, 90, 105, and 120 min, respectively). In contrast, after exercise training, FBF increased by 33 ± 9, 39 ± 14, 34 ± 7, and 48 ± 18% above fasting levels at 75, 90, 105, and 120 min, respectively (P < 0.05 vs. corresponding preexercise time points). Additionally, postprandial glucose responses to a standardized breakfast meal consumed under "free-living" conditions decreased during the final 3 days of exercise (P < 0.05). In conclusion, 7 days of aerobic exercise training improves conduit artery blood flow during an OGTT in individuals with type 2 diabetes.     

Endothelial Progenitor Cell Function,Apoptosis, and Telomere Length in Overweight/Obese Humans

Excess adiposity is associated with increased cardiovascular morbidity and mortality. Endothelial progenitor cells (EPCs) play an important role in vascular repair. We tested the hypothesis that increased adiposity is associated with EPC dysfunction, characterized by diminished capacity to release angiogenic cytokines, increased apoptotic susceptibility, reduced cell migration, and shorter telomere length. A total of 67 middle‐aged and older adults (42–67 years) were studied: 25 normal weight (normal weight; BMI: 18.5–24.9 kg/m²) and 42 overweight/obese (overweight/obese; BMI: 25.0–34.9 kg/m²). Cells with phenotypic EPC characteristics were isolated from peripheral blood. EPC release of vascular endothelial growth factor (VEGF) and granulocyte colony–stimulating factor (G‐CSF) was determined in the absence and presence of phytohemagglutinin (10 µg/ml). Intracellular active caspase‐3 and cytochrome c concentrations were determined by immunoassay. Migratory activity of EPCs in response to VEGF (2 ng/ml) and stromal cell–derived factor‐1α (SDF‐1α; 10 ng/ml) was determined by Boyden chamber. Telomere length was assessed by Southern hybridization. Phytohemagglutinin‐stimulated release of VEGF (90.6 ± 7.6 vs. 127.2 ± 11.6 pg/ml) and G‐CSF (896.1 ± 77.4 vs. 1,176.3 ± 126.3 pg/ml) was ～25% lower (P < 0.05) in EPCs from overweight/obese vs. normal weight subjects. Staurosporine induced a ～30% greater (P < 0.05) increase in active caspase‐3 in EPCs from overweight/obese (2.8 ± 0.2 ng/ml) compared with normal weight (2.2 ± 0.2) subjects. There were no significant differences in EPC migration to either VEGF or SDF‐1α. Telomere length did not differ between groups. These results indicate that increased adiposity adversely affects the ability of EPCs to release proangiogenic cytokines and resist apoptosis, potentially compromising their reparative potential.     

Effect of aerobic and resistance exercise training on vascular function in heart failure

Exercise training of a muscle group improves local vascular function in subjects with chronic heart failure (CHF). We studied forearm resistance vessel function in 12 patients with CHF in response to an 8-wk exercise program, which specifically excluded forearm exercise, using a crossover design. Forearm blood flow (FBF) was measured using strain-gauge plethysmography. Responses to three dose levels of intra-arterial acetylcholine were significantly augmented after exercise training when analyzed in terms of absolute flows (7.0 +/- 1.8 to 10.9 +/- 2.1 ml x 100 ml(-1) x min(-1) for the highest dose, P < 0.05 by ANOVA), forearm vascular resistance (21.5 +/- 5.0 to 15.3 +/- 3.9 ml x 100 ml forearm(-1) x min(-1), P < 0.01), or FBF ratios (P < 0.01, ANOVA). FBF ratio responses to sodium nitroprusside were also significantly increased after training (P < 0.05, ANOVA). Reactive hyperemic flow significantly increased in both upper limbs after training (27.9 +/- 2.7 to 33.5 +/- 3.1 ml x 100 ml(-1) x min(-1), infused limb; P < 0.05 by paired t-test). Exercise training improves endothelium-dependent and -independent vascular function and peak vasodilator capacity in patients with CHF. These effects on the vasculature are generalized, as they were evident in a vascular bed not directly involved in the exercise stimulus.     

Aerobic exercise and snoring in overweight children: a randomized controlled trial

Objective: To determine whether regular aerobic exercise improves symptoms of sleep‐disordered breathing in overweight children, as has been shown in adults. Research Methods and Procedures: Healthy but overweight (BMI ≥85th percentile) 7‐ to 11‐year‐old children were recruited from public schools for a randomized controlled trial of exercise effects on diabetes risk. One hundred children (53% black, 41% male) were randomly assigned to a control group (n = 27), a low‐dose exercise group (n = 36), or a high‐dose exercise group (n = 37). Exercise groups underwent a 13 ± 1.5 week after‐school program that provided 20 or 40 minutes per day of aerobic exercise (average heart rate = 164 beats per minute). Group changes were compared on BMI z‐score and four Pediatric Sleep Questionnaire scales: Snoring, Sleepiness, Behavior, and a summary scale, Sleep‐Related Breathing Disorders. Analyses were adjusted for age. Results: Both the high‐dose and low‐dose exercise groups improved more than the control group on the Snoring scale. The high‐dose exercise group improved more than the low‐dose exercise and control groups on the summary scale. No group differences were found for changes on Sleepiness, Behavior, or BMI z‐score. At baseline, 25% screened positive for sleep‐disordered breathing; half improved to a negative screen after intervention. Discussion: Regular vigorous exercise can improve snoring, a symptom of sleep‐disordered breathing, in overweight children. Aerobic exercise programs may be valuable for prevention and treatment of sleep‐disordered breathing in overweight children.     

A 12‐Week Aerobic Exercise Program Reduces Hepatic Fat Accumulation and Insulin Resistance in Obese,Hispanic Adolescents

The rise in obesity‐related morbidity in children and adolescents requires urgent prevention and treatment strategies. Currently, only limited data are available on the effects of exercise programs on insulin resistance, and visceral, hepatic, and intramyocellular fat accumulation. We hypothesized that a 12‐week controlled aerobic exercise program without weight loss reduces visceral, hepatic, and intramyocellular fat content and decreases insulin resistance in sedentary Hispanic adolescents. Twenty‐nine postpubertal (Tanner stage IV and V), Hispanic adolescents, 15 obese (7 boys, 8 girls; 15.6 ± 0.4 years; 33.7 ± 1.1 kg/m²; 38.3 ± 1.5% body fat) and 14 lean (10 boys, 4 girls; 15.1 ± 0.3 years; 20.6 ± 0.8 kg/m²; 18.9 ± 1.5% body fat), completed a 12‐week aerobic exercise program (4 × 30 min/week at ≥70% of peak oxygen consumption (VO₂peak)). Measurements of cardiovascular fitness, visceral, hepatic, and intramyocellular fat content (magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS)), and insulin resistance were obtained at baseline and postexercise. In both groups, fitness increased (obese: 13 ± 2%, lean: 16 ± 4%; both P < 0.01). In obese participants, intramyocellular fat remained unchanged, whereas hepatic fat content decreased from 8.9 ± 3.2 to 5.6 ± 1.8%; P < 0.05 and visceral fat content from 54.7 ± 6.0 to 49.6 ± 5.5 cm²; P < 0.05. Insulin resistance decreased indicated by decreased fasting insulin (21.8 ± 2.7 to 18.2 ± 2.4 µU/ml; P < 0.01) and homeostasis model assessment of insulin resistance (HOMA_IR) (4.9 ± 0.7 to 4.1 ± 0.6; P < 0.01). The decrease in visceral fat correlated with the decrease in fasting insulin (R² = 0.40; P < 0.05). No significant changes were observed in any parameter in lean participants except a small increase in lean body mass (LBM). Thus, a controlled aerobic exercise program, without weight loss, reduced hepatic and visceral fat accumulation, and decreased insulin resistance in obese adolescents.     

Systemic alpha-adrenergic and nitric oxide inhibition on basal limb blood flow: effects of endurance training in middle-aged and older adults

Endurance training improves endothelium-dependent vasodilation, yet it does not increase basal blood flow in the legs. We determined the effects of a 3-mo aerobic exercise intervention on basal leg blood flow and alpha-adrenergic vasoconstriction and nitric oxide (NO) release in seven apparently healthy middle-aged and older adults (60 +/- 3 yr). Basal femoral artery blood flow (via Doppler ultrasound) (pretraining: 354 +/- 29; posttraining: 335 +/- 34 ml/min) and vascular conductance did not change significantly with the exercise training. Before the exercise intervention, femoral artery blood flow increased 32 +/- 16% with systemic alpha-adrenergic blockade (with phentolamine) (P < 0.05), and the addition of nitric oxide synthase (NOS) inhibition using N(G)-monomethyl-L-arginine (L-NMMA) did not affect femoral artery blood flow. After training was completed, femoral artery blood flow increased 47 +/- 7% with alpha-adrenergic blockade (P < 0.01) and then decreased 18 +/- 7% with the subsequent administration of L-NMMA (P < 0.05). Leg vascular conductance showed a greater alpha-adrenergic blockade-induced vasodilation (+1.7 +/- 0.5 to +3.0 +/- 0.5 units, P < 0.05) as well as NOS inhibition-induced vasoconstriction (-0.8 +/- 0.4 to -2.7 +/- 0.7 units, P < 0.05) after the exercise intervention. Resting plasma norepinephrine concentration significantly increased after the training. These results suggest that regular aerobic exercise training enhances NO bioavailability in middle-aged and older adults and that basal limb blood flow does not change with exercise training because of the contrasting influences of sympathetic nervous system activity and endothelium-derived vasodilation on the vasculature.     

Evaluation of a multisensor armband in estimating energy expenditure in obese individuals

Objective: To examine the reliability and validity of the SenseWear Pro 2 Armband (SWA; Body Media, Pittsburgh, PA) during rest and exercise compared with indirect calorimetry (IC) in obese individuals. Research Methods and Procedures: Energy expenditure was assessed during rest with the SWA and IC in 142 obese adults (37 men and 105 women, BMI = 42.3 ± 7.0) and in 25 lean and overweight adults (BMI = 25.3 ± 3.2) who were used as a comparison group. Twenty‐nine of the obese adults also participated in three separate short exercise sessions including cycle ergometry, stair stepping, and treadmill walking. Results: The repeatability of SWA estimates in obese subjects was high (r = 0.88, p < 0.001). The SWA generally underestimated the resting energy expenditure (REE) (1811 ± 346 vs. 1880 ± 382 kcal/d) and highly overestimated the energy expenditure during the exercise sessions in obese individuals. REE estimations by SWA were significantly correlated with fat‐free mass (r = 0.88, p < 0.001). Bland‐Altman plots based statistical analysis for the estimated REE, and measured IC showed a low agreement (Total Error > 20% but Systematic Error < 5%) between the two methods in obese subjects, although they showed a high correlation and a very good agreement in lean and overweight patients. Discussion: The SWA is an easy to handle, practical, new portable device for measuring energy expenditure. The accuracy of the SWA appeared to be poor in the obese subjects we examined, especially those with high REE both in rest and exercise. We believe that it is necessary to incorporate new, obesity‐specific algorithms in the relative software.     

Effects of Obesity on Substrate Utilization during Exercise

Objective: The capacity for lipid and carbohydrate (CHO) oxidation during exercise is important for energy partitioning and storage. This study examined the effects of obesity on lipid and CHO oxidation during exercise. Research Methods and Procedures: Seven obese and seven lean [body mass index (BMI), 33 ± 0.8 and 23.7 ± 1.2 kg/m², respectively] sedentary, middle‐aged men matched for aerobic capacity performed 60 minutes of cycle exercise at similar relative (50% Vo _2max) and absolute exercise intensities. Results: Obese men derived a greater proportion of their energy from fatty‐acid oxidation than lean men (43 ± 5% 31 ± 2%; p = 0.02). Plasma fatty‐acid oxidation determined from recovery of infused [0.15 μmol/kg fat‐free mass (FFM) per minute] [1‐¹³C]‐palmitate in breath CO₂ was similar for obese and lean men (8.4 ± 1.1 and 29 ± 15 μmol/kg FFM per minute). Nonplasma fatty‐acid oxidation, presumably, from intramuscular sources, was 50% higher in obese men than in lean men (10.0 ± 0.6 versus 6.6 ± 0.8 μmol/kg FFM per minute; p < 0.05). Systemic glucose disposal was similar in lean and obese groups (33 ± 8 and 29 ± 15 μmol/kg FFM per minute). However, the estimated rate of glycogen‐oxidation was 50% lower in obese than in lean men (61 ± 12 versus 90 ± 6 μmol/kg FFM per minute; p < 0.05). Discussion: During moderate exercise, obese sedentary men have increased rates of fatty‐acid oxidation from nonplasma sources and reduced rates of CHO oxidation, particularly muscle glycogen, compared with lean sedentary men.     

Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults

Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 μg·100 ml tissue(-1)·min(-1)) were measured before and after endothelial NO synthase inhibition with N(G)-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh - FBF baseline) - (FBF ACh(L-NMMA) - FBF baseline(L-NMMA))]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue(-1)·min(-1) for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue(-1)·min(-1) for the women (P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.     

Leptin, superoxide dismutase, and weight loss: initial leptin predicts weight loss

Objective: Our goal was to study how plasma leptin concentration, superoxide dismutase (SOD) activity, and weight loss are related in obese adults. Research Methods and Procedures: Serum leptin concentration, SOD activities, general biochemical data, and body composition measurements were obtained for 62 overweight and obese subjects before and after an 8‐week body weight reduction (BWR) regimen. The subjects were on dietary control, performed moderate aerobic and strength training exercises, and attended educational lectures. Results: The measurement results indicated that the following criteria were significantly reduced: body weight [84.4 ± 17.0 vs. 79.3 ± 16.1 (standard error) kg, p < 0.001]; BMI (31.5 ± 4.3 vs. 29.4 ± 4.2 kg/m², p < 0.001), and fat mass (33.3 ± 10.0 vs. 29.8 ± 10.4 kg, p < 0.001). Plasma leptin levels also significantly decreased from 31.5 ± 17.6 to 26.5 ± 17.2 ng/mL (p < 0.001). Additionally, SOD activity was significantly increased from 261.4 ± 66.0 to 302.7 ± 30.9 U/mL (p < 0.001). Based on linear regression analysis results, a 3.78‐ to 8.13‐kg reduction in weight can be expected after the 8‐week BWR regimen when initial leptin concentration was 5 to 30 ng/mL. Discussion: We found that an 8‐week exercise and diet program was effective in reducing weight and fat mass and, notably, had further beneficial effects on leptin resistance and SOD activity. Additionally, this study demonstrated that initial plasma leptin concentration may be used as a predictor for weight loss outcome.     

Postprandial Vascular Reactivity in Obese and Normal Weight Young Adults

As humans spend a significant amount of time in the postprandial state, we examined whether vascular reactivity (a key indicator of cardiovascular health) was different after a high‐fat meal in 11 obese (median BMI 46.4, age 32.1 ± 6.3 years, 7 men) and 11 normal weight (median BMI 22.6) age‐ and sex‐matched controls. At baseline and 1 and 3 h postmeal, blood pressure (BP), heart rate (HR), reactive hyperemia peripheral artery tonometry (RH‐PAT) index, radial augmentation index adjusted for HR (AIx75), brachial pulse wave velocity (PWV_b), glucose, insulin, total and high‐density lipoprotein (HDL) cholesterol, and triglycerides were measured. Brachial flow‐mediated dilatation (FMD) and, by venous plethysmography, resting and hyperemic forearm blood flows (FBFs) were measured at baseline and 3 h. At baseline, obese subjects had higher systolic BP, HR, resting FBF, insulin and equivalent FMD, RH‐PAT, hyperemic FBF, AIx75, PWV_b, glucose, total cholesterol, triglycerides, and lower HDL cholesterol. In obese and lean subjects, FMD at baseline and 3 h was not significantly different (6.2 ± 1.7 to 5.8 ± 4.3% for obese and 4.7 ± 4.1 to 4.3 ± 3.9% for normal weight, P = 0.975 for group × time). The meal did not produce significant changes in RH‐PAT, hyperemic FBF, and PWV_b in either group (P > 0.1 for the effect of time and for group × time interactions). In conclusion, the vascular responses to a high‐fat meal are similar in obese and normal weight young adults. An exaggerated alteration in postprandial vascular reactivity is thus unlikely to contribute importantly to the increased cardiovascular risk of obesity.     

Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis

Objective: Physical function and body composition in older obese adults with knee osteoarthritis (OA) were examined after intensive weight loss. Research Methods and Procedures: Older obese adults (n = 87; ≥60 years; BMI ≥ 30.0 kg/m²) with symptomatic knee OA and difficulty with daily activities were recruited for a 6‐month trial. Participants were randomized into either a weight stable (WS) or weight loss (WL) program. Participants in WL (10% weight loss goal) were prescribed a 1000 kcal/d energy deficit diet with exercise 3 d/wk. WS participants attended health information sessions. Body composition and physical function (Western Ontario and McMaster University Osteoarthritis Index, 6‐minute walking distance, and stair climb time) were assessed at baseline and 6 months. Statistical analysis included univariate analysis of covariance on 6‐month measurements using baseline values as covariates. Associations between physical function and body composition were performed. Results: Body weight decreased 8.7 ± 0.8% in WL and 0.0 ± 0.7% in WS. Body fat and fat‐free mass were lower for WL than WS at 6 months (estimated means: fat = 38.1 ± 0.4% vs. 40.9 ± 0.4%, respectively; fat‐free mass = 56.7 ± 0.4 vs. 58.8 ± 0.4 kg, respectively). WL had better function than WS, with lower Western Ontario and McMaster University Osteoarthritis Index scores, greater 6‐minute walk distance, and faster stair climb time (p < 0.05). Changes in function were associated with weight loss in the entire cohort. Discussion: An intensive weight loss intervention incorporating energy deficit diet and exercise training improves physical function in older obese adults with knee OA. Greater improvements in function were observed in those with the most weight loss.     

Long‐term Successful Weight Loss Improves Vascular Endothelial Function in Severely Obese Individuals

Obesity is associated with increased cardiovascular risk. Although short‐term weight loss improves vascular endothelial function, longer term outcomes have not been widely investigated. We examined brachial artery endothelium‐dependent vasodilation and metabolic parameters in 29 severely obese subjects who lost ≥10% body weight (age 45 ± 13 years; BMI 48 ± 9 kg/m²) at baseline and after 12 months of dietary and/or surgical intervention. We compared these parameters to 14 obese individuals (age 49 ± 11 years; BMI 39 ± 7 kg/m²) who failed to lose weight. For the entire group, mean brachial artery flow‐mediated dilation (FMD) was impaired at 6.7 ± 4.1%. Following sustained weight loss, FMD increased significantly from 6.8 ± 4.2 to 10.0 ± 4.7%, but remained blunted in patients without weight decline from 6.5 ± 4.0 to 5.7 ± 4.1%, P = 0.013 by ANOVA. Endothelium‐independent, nitroglycerin‐mediated dilation (NMD) was unaltered. BMI fell by 13 ± 7 kg/m² following successful weight intervention and was associated with reduced total and low‐density lipoprotein cholesterol, glucose, hemoglobin A_1c, and high‐sensitivity C‐reactive protein (CRP). Vascular improvement correlated most strongly with glucose levels (r = ?0.51, P = 0.002) and was independent of weight change. In this cohort of severely obese subjects, sustained weight loss at 1 year improved vascular function and metabolic parameters. The findings suggest that reversal of endothelial dysfunction and restoration of arterial homeostasis could potentially reduce cardiovascular risk. The results also demonstrate that metabolic changes in association with weight loss are stronger determinants of vascular phenotype than degree of weight reduction.     

Forearm vascular control during acute hyperglycemia in healthy humans

The vascular endothelium is a site of pathological changes in patients with diabetes mellitus that may be related to severe chronic hyperglycemia. However, it is unclear whether transient hyperglycemia alters vascular function in an otherwise healthy human forearm. To test the hypothesis that acute, moderate hyperglycemia impairs endothelium-dependent forearm vasodilation, we measured vasodilator responses in 25 healthy volunteers (11 F, 14 M) assigned to one of three protocols. In protocol 1, glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance. Protocol 2 involved 6 h of mild hyperglycemia (approximately 7 mmol/l). Protocol 3 involved 6 h of euglycemia. Glucose concentration was maintained with a variable systemic glucose infusion. Insulin concentrations were maintained at approximately 65 pmol/l by means of a somatostatin and "basal" insulin infusion. Glucagon and growth hormone were replaced at basal concentrations. Forearm blood flow (FBF) was calculated from Doppler ultrasound measurements at the brachial artery. In each protocol, FBF dose responses to intrabrachial acetylcholine (ACh) and sodium nitroprusside (NTP) were assessed at baseline and at 60, 180, and 360 min of glucose infusion. Peak endothelium-dependent vasodilator responses to ACh were not diminished by hyperglycemia in any trial. For example, peak responses to ACh during protocol 2 were 307 +/- 47 ml/min at euglycemic baseline and 325 +/- 52, 353 +/- 65, and 370 +/- 70 ml/min during three subsequent hyperglycemic trials (P = 0.46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm.     

Direct effect of ethanol on human vascular function

Epidemiological studies indicate that moderate ethanol consumption reduces cardiovascular mortality. Cellular and animal data suggest that ethanol confers beneficial effects on the vascular endothelium and increases the bioavailability of nitric oxide. The purpose of this study was to assess the effect of ethanol on endothelium-dependent, nitric oxide-mediated vasodilation in healthy human subjects. Forearm blood flow (FBF) was determined by venous occlusion plethysmography in healthy human subjects during intra-arterial infusions of either methacholine (0.3, 1.0, 3.0, and 10.0 mcg/min, n = 9), nitroprusside (0.3, 1.0, 3.0, and 10.0 mcg/min, n = 9), or verapamil (10, 30, 100, and 300 mcg/min, n = 8) before and during the concomitant intra-arterial infusions of ethanol (10% ethanol in 5% dextrose). Additionally, a time control experiment was conducted, during which the methacholine dose-response curve was measured twice during vehicle infusions (n = 5). During ethanol infusion, mean forearm and systemic alcohol levels were 227 +/- 30 and 6 +/- 0 mg/dl, respectively. Ethanol infusion alone reduced FBF (2.5 +/- 0.1 to 1.9 +/- 0.1 ml.dl(-1).min(-1), P < 0.05). Despite initial vasoconstriction, ethanol augmented the FBF dose-response curves to methacholine, nitroprusside, and verapamil (P < 0.01 by ANOVA for each). To determine whether this augmented FBF response was related to shear-stress-induced release of nitric oxide, FBF was measured during the coinfusion of ethanol and N(G)-nitro-L-arginine (L-NAME; n = 8) at rest and during verapamil-induced vasodilation. The addition of L-NAME did not block the ability of ethanol to augment verapamil-induced vasodilation. Ethanol has complex direct vascular effects, which include basal vasoconstriction as well as potentiation of both endothelium-dependent and -independent vasodilation. None of these effects appear to be mediated by an increase in nitric oxide bioavailability, thus disputing findings from preclinical models.