Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms.

This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk.

Are the metabolic benefits of resistance training in type 2 diabetes linked to improvements in adipose tissue microvascular blood flow?

The microcirculation in adipose tissue is markedly impaired in type 2 diabetes (T2D). Resistance training (RT) often increases muscle mass and promotes a favorable metabolic profile in people with T2D, even in the absence of fat loss. Whether the metabolic benefits of RT in T2D are linked to improvements in adipose tissue microvascular blood flow is unknown. Eighteen sedentary people with T2D (7 women/11 men, 52 ± 7 yr) completed 6 wk of RT. Before and after RT, overnight-fasted participants had blood sampled for clinical chemistries (glucose, insulin, lipids, HbA1c, and proinflammatory markers) and underwent an oral glucose challenge (OGC; 50 g glucose × 2 h) and a DEXA scan to assess body composition. Adipose tissue microvascular blood volume and flow were assessed at rest and 1 h post-OGC using contrast-enhanced ultrasound. RT significantly reduced fasting blood glucose ( P = 0.006), HbA1c ( P = 0.007), 2-h glucose area under the time curve post-OGC ( P = 0.014), and homeostatic model assessment of insulin resistance ( P = 0.005). This was accompanied by a small reduction in total body fat ( P = 0.002), trunk fat ( P = 0.023), and fasting triglyceride levels ( P = 0.029). Lean mass ( P = 0.003), circulating TNF-α ( P = 0.006), and soluble VCAM-1 ( P < 0.001) increased post-RT. There were no significant changes in adipose tissue microvascular blood volume or flow following RT; however those who did have a higher baseline microvascular blood flow post-RT also had lower fasting triglyceride levels ( r = -0.476, P = 0.045). The anthropometric, glycemic, and insulin-sensitizing benefits of 6 wk of RT in people with T2D are not associated with an improvement in adipose tissue microvascular responses; however, there may be an adipose tissue microvascular-linked benefit to fasting triglyceride levels.

Training the Next Generation of Latino Health Researchers: A Multilevel, Transdisciplinary, Community-Engaged Approach.

Reducing health disparities is a national public health priority. Latinos represent the largest racial/ethnic minority group in the United States and suffer disproportionately from poor health outcomes, including cardiovascular disease risk. Academic training programs are an opportunity for reducing health disparities, in part by increasing the diversity of the public health workforce and by incorporating training designed to develop a skill set to address health disparities. This article describes the Training and Career Development Program at the UCLA Center for Population Health and Health Disparities: a multilevel, transdisciplinary training program that uses a community-engaged approach to reduce cardiovascular disease risk in two urban Mexican American communities. Results suggest that this program is effective in enhancing the skill sets of traditionally underrepresented students to become health disparities researchers and practitioners.

Effects of varying doses of testosterone on atherogenic markers in healthy younger and older men.

Whether exogenous testosterone is proatherogenic remains controversial. We assessed the effects of graded doses of testosterone on serum markers of oxidative stress, chemotaxis, adhesion, and inflammation in healthy younger and older men. In a double-blind, randomized trial, 121 eugonadal men (n = 61, 18-35 years of age and n = 60, 60-75 years of age) were randomized to one of five groups to receive weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk, respectively, along with a long-acting gonadotropin-releasing hormone (GnRH) agonist. Energy and protein intakes were standardized and no resistance training was allowed. We measured plasma levels of the atherogenic biomarkers monocyte chemotactic protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1), 8-isoprostane-PGF(2α) (8-iso-PGF(2α)), and high-sensitivity C-reactive protein (hs-CRP) before and after the intervention. Administration of increasing doses of testosterone led to reduction in total 8-iso-PGF(2α) in the younger (p-trend(Younger) = 0.01), but not older (p-trend(Older) = 0.79) men. No significant linear associations were observed between testosterone dose and MCP-1, sICAM-1, or hs-CRP (all p-trend >0.20). In apparently healthy men, over a wide dose range, testosterone did not adversely affect atherogenic biomarkers. Long-term studies with larger sample sizes are warranted to determine whether testosterone supplementation affects atherosclerosis progression and cardiovascular risk.

A pilot validation of multi-echo based echo-planar correlated spectroscopic imaging in human calf muscles.

A current limitation of MR spectroscopic imaging of multiple skeletal muscles is prolonged scan duration. A significant reduction in the total scan duration using the echo-planar correlated spectroscopic imaging (EP-COSI) sequence was accomplished using two bipolar readout trains with different phase-encoded echoes for one of two spatial dimensions within a single repetition time (TR). The second bipolar readout was used for spatially encoding the outer k-space, whereas the first readout was used for the central k-space only. The performance of this novel sequence, called multi-echo based echo-planar correlated spectroscopic imaging (ME-EPCOSI), was demonstrated by localizing specific key features in calf muscles and bone marrow of 11 healthy volunteers and five subjects with type 2 diabetes (T2D). A 3 T MRI-MRS scanner equipped with a transmit-receive extremity coil was used. Localization of the ME-EPCOSI sequence was in good agreement with the earlier single-readout based EP-COSI sequence and the required scan time was reduced by a factor of two. In agreement with an earlier report using single-voxel based 2D MRS, significantly increased unsaturated pools of intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) and decreased IMCL and EMCL unsaturation indices (UIs) were observed in the soleus and tibialis anterior muscle regions of subjects with T2D compared with healthy controls. In addition, significantly decreased choline content was observed in the soleus of T2D subjects compared with healthy controls. Multi-voxel characterization of IMCL and EMCL ratios and UI in the calf muscle may be useful for the non-invasive assessment of altered lipid metabolism in the pathophysiology of T2D.

Effects of an intensive short-term diet and exercise intervention: comparison between normal-weight and obese children.

Lifestyle intervention programs currently emphasize weight loss secondary to obesity as the primary determinant of phenotypic changes. We examined whether the effects of a short-term lifestyle intervention program differ in normal-weight versus overweight/obese children. Nineteen overweight/obese (O; BMI = 33.6 ± 1.9 kg/m(2)) and 14 normal-weight (N; BMI = 19.9 ± 1.5 kg/m(2)) children participated in a 2-wk program consisting of an ad libitum high-fiber, low-fat diet and daily exercise (2-2.5 h). Fasting serum samples were taken pre- and postintervention for determination of lipids, glucose homeostasis, inflammatory cytokines, and adipokines. Only the O group lost weight (3.9%) but remained overweight/obese (32.3 ± 1.9 kg/m(2)). Both groups exhibited significant intervention-induced decreases (P < 0.05) in serum insulin (N: 52.5% vs. O: 28.1%; between groups, P = 0.38), homeostatic model assessment for insulin resistance (N: 53.1% vs. O: 28.4%, P = 0.43), leptin (N: 69.3% vs. O: 44.1%, P = 0.10), amylin (N: 28.7% vs. O: 26.1%, P = 0.80), resistin (N: 40.0% vs. O: 35.1%, P = 0.99), plasminogen activator-inhibitor-1 (N: 30.8% vs. O: 25.6%, P = 0.59), IL-6 (N: 58.8% vs. O: 48.5%, P = 0.78), IL-8 (N: 46.0% vs. O: 42.2%, P = 0.49), and TNFα (N: 45.8% vs. O: 40.8%, P = 0.99). No associations between indices of weight change and phenotypic changes were noted. A short-term, intensive lifestyle modification program is effective in ameliorating metabolic risk factors in N and O children. These results suggest that obesity per se was not the primary driver of the phenotypes noted and that dietary intake and physical inactivity induce the phenotypic abnormalities. These data may have implications for the weight loss-independent management of cardiometabolic risk in pediatric populations.

A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children.

The present study was designed to examine the effects of short-term diet and exercise on markers of metabolic health, serum-stimulated production of inflammatory biomarkers from cultured monocytes and adipocytes, and serum lipomics. Twenty-one overweight/obese children (9 boys and 12 girls, age 13.0 ± 0.5 yr, BMI 33.0 ± 1.8 kg/m(2)) were placed on a 2-wk ad libitum, high-fiber, low-fat diet and daily exercise regimen. Fasting serum samples were taken pre- and postintervention for determination of cytokines, metabolic risk markers, and lipomics. Monocytes and adipocytes were incubated with pre- and postintervention serum to investigate changes in cytokine secretion. Correlative associations were calculated, followed by hierarchical clustering to determine relationships between fatty acid (FA) species and clinical biomarkers. Despite remaining overweight/obese, interleukin (IL)-6, IL-8, TNFα, PAI-1, resistin, amylin, leptin, insulin, and IL-1ra decreased and adiponectin increased. Culture studies indicated decreases in monocyte secretion of IL-6, TNFα, and IL-1ß and adipocyte secretion of IL-6. Lipomic analysis revealed a decrease in total lipids and decreases in saturated FAs and an increase in 18:1/18:0. In general, Pearson's correlations revealed that inflammatory markers are negatively associated with a cluster of polyunsaturated FAs and positively correlated with several saturated FAs. These results indicate significant modification of multiple indices of metabolic health with short-term rigorous lifestyle modification in overweight/obese children prior to obesity reversal.

Low aerobic fitness and obesity are associated with lower standardized test scores in children.

OBJECTIVE: To investigate whether aerobic fitness and obesity in school children are associated with standardized test performance. STUDY DESIGN: Ethnically diverse (n = 1989) 5th, 7th, and 9th graders attending California schools comprised the sample. Aerobic fitness was determined by a 1-mile run/walk test; body mass index (BMI) was obtained from state-mandated measurements. California standardized test scores were obtained from the school district. RESULTS: Students whose mile run/walk times exceeded California Fitnessgram standards or whose BMI exceeded Centers for Disease Control sex- and age-specific body weight standards scored lower on California standardized math, reading, and language tests than students with desirable BMI status or fitness level, even after controlling for parent education among other covariates. Ethnic differences in standardized test scores were consistent with ethnic differences in obesity status and aerobic fitness. BMI-for-age was no longer a significant multivariate predictor when covariates included fitness level. CONCLUSIONS: Low aerobic fitness is common among youth and varies among ethnic groups, and aerobic fitness level predicts performance on standardized tests across ethnic groups. More research is needed to uncover the physiological mechanisms by which aerobic fitness may contribute to performance on standardized academic tests.

Effects of Home-Based Exercise Training Systems, Combined with Diet, on Cardiometabolic Health.

The efficacy of exercise training systems designed to be used in the home on cardiometabolic outcomes remains largely unknown. This investigation included two studies. Study 1 tested the effects a multi-exercise pulley system (NordicTrack Fusion CST with video trainer) and Study 2 an incline trainer (NordicTrack X22i with video trainer), both combined with daily food provision, for 12-weeks on indices of cardiometabolic health. Study 1 enrolled 27 adults (11 men, 16 women, 33.8±4.4 years of age) and Study 2 enrolled 29 adults (11 men, 18 women, 40.8±12.5 years of age). Pre- and post-intervention measurements were performed for body weight, fat mass, lean tissue mass, and visceral fat by dual energy x-ray absorptiometry, blood pressure, aerobic fitness and body circumferences. For Study 1, there were significant decreases in body weight, fat mass, visceral fat, diastolic blood pressure (DBP), resting heart rate (RHR), and all circumference sites, while there was an increase in aerobic fitness (all p<0.001). Both males and females exhibited significant improvement in all these outcomes. For Study 2, there were significant decreases in body weight, fat mass, visceral fat, DBP, RHR, all circumference sites (all p<0.001), and lean tissue mass (LTM) (p=0.006), and an increase in aerobic fitness (p<0.001). Both males and females exhibited significant changes in all these outcomes, except LTM which did not change in females. Both studies exhibited high exercise session attendance and high dietary adherence. Overall these data indicate the potential efficacy of home-based training systems, when combined with diet, on selected cardiometabolic outcomes.

Rats Selectively Bred for High Voluntary Physical Activity Behavior are Not Protected from the Deleterious Metabolic Effects of a Western Diet When Sedentary.

BACKGROUND: Physical activity and diet are well-established modifiable factors that influence chronic disease risk. We developed a selectively bred, polygenic model for high and low voluntary running (HVR and LVR, respectively) distances. After 8 generations, large differences in running distance were noted. Despite these inherent behavioral differences in physical activity levels, it is unknown whether HVR rats would be inherently protected from diet-induced metabolic dysfunction. OBJECTIVES: The aim of this study was to determine whether HVR rats without voluntary running wheels would be inherently protected from diet-induced metabolic dysfunction. METHODS: Young HVR, LVR, and a wild-type (WT) control group were housed with no running wheel access and fed either a normal diet (ND) or a high-sugar/fat Western diet (WD) for 8 wk. Body weight, percentage body fat (by dual-energy X-ray absorptiometry scan), blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs), nonesterified fatty acids], and hepatic TG content were measured, and indices of insulin sensitivity were determined via an intravenous glucose tolerance test. Additionally, weekly energy intake and feed efficiency were calculated. RESULTS: After 8 wk, significant differences in body weight and body fat percentage were noted in all WD animals compared with ND animals, with the LVR-WD exhibiting the greatest increase due, in part, to their enhanced feed efficiency. Lipid dysregulation was present in all WD rat lines compared with ND counterparts. Furthermore, LVR-WD rats had higher total cholesterol, HDL cholesterol, and TG concentrations, and higher areas under the curve (AUC) for insulin than HVR-WD and WT-WD, although HVR-WD animals had higher AUCglucose than both LVR-WD and WT-WD and higher LDL than WT-WD. CONCLUSIONS: In the absence of high voluntary running behavior, the genetic predisposition for high running in HVR did not largely protect them from the deleterious effects of a WD compared with LVR, suggesting genetic factors influencing physical activity levels may, in part, be independent from genes influencing metabolism.

Resistance-exercise training ameliorates LPS-induced cognitive impairment concurrent with molecular signaling changes in the rat dentate gyrus.

Effective treatments preventing brain neuroinflammatory diseases are lacking. Resistance-exercise training (RT) ameliorates mild cognitive impairment (MCI), a forerunner to neuroinflammatory diseases. However, few studies have addressed the molecular basis by which RT abates MCI. Thus experiments were performed to identify some molecular changes occurring in response to RT in young, female Wistar rats. To induce MCI, intraventricular lipopolysaccharide (LPS) injections were used to increase dentate gyrus inflammation, reflected by significantly increased TNF-α (~400%) and IL-1ß (~1,500%) mRNA (P < 0.0001) after 6 wk. Five days after LPS injections, half of LPS-injected rats performed RT by ladder climbing for 6 wk, 3 days/wk, whereas half remained without ladders. RT for 6 wk increased lean body mass percentage (P < 0.05), individual muscle masses (gastrocnemius and tibialis anterior) (P < 0.05), and maximum lifting capacity (P < 0.001). The RT group, compared with sedentary controls, had 1) ameliorated spatial learning deficits (P < 0.05), 2) increased dentate gyrus phosphorylation of IGF-1R, protein kinase B, and GSK-3ß proteins (P < 0.05), components of downstream IGF-1 signaling, and 3) increased dentate gyrus synaptic plasticity marker synapsin protein (P < 0.05). Two follow-up experiments (without LPS) characterized dentate gyrus signaling during short-term RT. Twenty-four hours following the third workout in a 1-wk training duration, phosphorylation of ERK1/2 and GSK-3ß proteins, as well as proliferation marker protein, PCNA, were significantly increased (P < 0.05). Similar changes did not occur in a separate group of rats following a single RT workout. Taken together, these data indicate that RT ameliorates LPS-induced MCI after RT, possibly mediated by increased IGF-1 signaling pathway components within the dentate gyrus. NEW & NOTEWORTHY The data suggest that resistance-exercise training restores cognitive deficits induced by lipopolysaccharides and can activate associated IGF-1 signaling in the dentate gyrus. Our data show, for the first time, that as few as three resistance-exercise workouts (spread over 1 wk) can activate IGF-1 downstream signaling and increase proliferation marker PCNA in the dentate gyrus.

Insulin-like growth factor-I is inversely related to adiposity in overweight Latino children.

The purpose of this study was to examine interrelationships between IGF-I, IGF binding proteins (IGFBPs) and adiposity in 178 overweight Hispanic adolescents (11.2 +/- 1.7 yr; body mass index: 28.2 +/- 5.4 kg/m2). Immunoradiometric assays were used to measure IGF-I, IGFBP-1 and IGFBP-3. Total fat and lean tissue mass were measured by DEXA and visceral and subcutaneous adipose tissue by MRI. IGF-I and IGFBP-3 remained inversely correlated with total body fat mass (r = -0.52, p < 0.001 and r = -0.25, p < 0.01, respectively) after controlling for covariates. IGFBP-1 was inversely correlated to total fat mass (r = -0.55, p < 0.001) in simple correlations; however, this relationship was eliminated after controlling for covariates (r = 0.02, p = 0.85). Correlations with visceral and subcutaneous adipose tissue yielded similar results. These results demonstrate that IGF-I, IGFBP-1 and IGFBP-3 are all inversely related to adiposity in Hispanic children.

Adiponectin independently predicts metabolic syndrome in overweight Latino youth.

CONTEXT: Adiponectin may be important in the pathogenesis of insulin resistance and the metabolic syndrome in youth. OBJECTIVE: The objective of the study was to determine the unique effect of adiponectin on the metabolic syndrome in overweight Latino youth. PARTICIPANTS: Participants included 175 overweight children (aged 11.1 +/- 1.7 yr, body mass index percentile 97.3 +/- 2.9) with a family history of type 2 diabetes. METHODS: Metabolic syndrome was defined according to a pediatric adaptation of the Adult Treatment Panel III report and included dyslipidemia, abdominal obesity, elevated blood pressure, and prediabetes (impaired fasting glucose or impaired glucose tolerance from a 2-h oral glucose tolerance test). Body composition was estimated via dual-energy x-ray absorptiometry, insulin sensitivity was quantified by the frequently sampled iv glucose tolerance test, visceral fat was measured using magnetic resonance imaging, and adiponectin was determined in fasting serum. RESULTS: In simple linear regression, adiponectin was significantly and inversely related to systolic blood pressure (P < 0.05), waist circumference (P < 0.001), triglycerides (P < 0.001), and 2-h glucose levels (P < 0.05) and positively related to high-density lipoprotein-cholesterol (P < 0.001). In multiple linear regression, adiponectin was significantly related to triglycerides (P < 0.01) and high-density lipoprotein-cholesterol (P < 0.01) independent of age, gender, Tanner stage, body composition, and insulin sensitivity. Analyses of covariance established that adiponectin levels were approximately 25% higher in healthy overweight youth, compared with those with the metabolic syndrome (12.5 +/- 3.5 vs. 9.4 +/- 2.8 microg/ml; P < 0.05). In multiple logistic regression, adiponectin was a significant independent predictor of the metabolic syndrome, even after adjustment for confounders including insulin sensitivity and visceral fat. CONCLUSIONS: Hypoadiponectinemia is an independent biomarker of the metabolic syndrome, and thus, adiponectin may play a role in the pathophysiology of the disorder in overweight youth.

Effect of a short-term diet and exercise intervention in youth on atherosclerotic risk factors.

Early stages of atherosclerosis are commonly noted in youth. The present study was designed to examine the effects of lifestyle modification in 19 overweight children (age 8-17) who were placed on a high-fiber, low-fat diet in a 2-week residential program where food was provided ad libitum and daily exercise (2-2.5h) was performed. In each subject, pre- and post-intervention fasting blood was drawn to measure serum lipids, oxidative stress marker 8-isoprostaglandin F2alpha (8-iso-PGF2alpha) and generating enzyme myeloperoxidase (MPO), soluble intracellular adhesion molecule (sICAM)-1 and sE-selectin as indicators of endothelial activation, the inflammatory protein C-reactive protein (CRP) and total matrix metalloproteinase-9 (MMP-9). Using subject sera and human aortic endothelial cell (HAEC) culture systems, monocyte chemotactic protein-1 (MCP-1) production, as well as nitric oxide (NO), superoxide and hydrogen peroxide production were measured in vitro by fluorometric detection. After 2 weeks, significant reductions (p<0.05) in all serum lipids (except HDL cholesterol), 8-iso-PGF2alpha, MPO, sICAM-1, sE-selectin, CRP, MMP-9, and cellular MCP-1 production were noted. Additionally, there was a significant decrease in cultured, serum-stimulated HAEC production of superoxide and hydrogen peroxide, and a concomitant increase in NO production (all p<0.01), These results indicate amelioration of several traditional as well as novel factors associated with atherosclerosis after lifestyle modification, even in youth without documented disease.

Skeletal Muscle Microvascular-Linked Improvements in Glycemic Control From Resistance Training in Individuals With Type 2 Diabetes.

OBJECTIVE: Insulin increases glucose disposal in part by enhancing microvascular blood flow (MBF) and substrate delivery to myocytes. Insulin's microvascular action is impaired with insulin resistance and type 2 diabetes. Resistance training (RT) improves glycemic control and insulin sensitivity, but whether this improvement is linked to augmented skeletal muscle microvascular responses in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS: Seventeen (11 male and 6 female; 52 ± 2 years old) sedentary patients with type 2 diabetes underwent 6 weeks of whole-body RT. Before and after RT, participants who fasted overnight had clinical chemistries measured (lipids, glucose, HbA1c, insulin, and advanced glycation end products) and underwent an oral glucose challenge (OGC) (50 g × 2 h). Forearm muscle MBF was assessed by contrast-enhanced ultrasound, skin MBF by laser Doppler flowmetry, and brachial artery flow by Doppler ultrasound at baseline and 60 min post-OGC. A whole-body DEXA scan before and after RT assessed body composition. RESULTS: After RT, muscle MBF response to the OGC increased, while skin microvascular responses were unchanged. These microvascular adaptations were accompanied by improved glycemic control (fasting blood glucose, HbA1c, and glucose area under the curve [AUC] during OGC) and increased lean body mass and reductions in fasting plasma triglyceride, total cholesterol, advanced glycation end products, and total body fat. Changes in muscle MBF response after RT significantly correlated with reductions in fasting blood glucose, HbA1c, and OGC AUC with adjustment for age, sex, % body fat, and % lean mass. CONCLUSIONS: RT improves OGC-stimulated muscle MBF and glycemic control concomitantly, suggesting that MBF plays a role in improved glycemic control from RT.

Expression of catalase and glutathione peroxidase in renal insufficiency.

Chronic renal failure (CRF) is associated with oxidative stress, the precise mechanism of which is yet to be elucidated. The present study was undertaken to investigate in renal insufficiency the expression of catalase and glutathione peroxidase, which play a critical role in antioxidant defense system by catalyzing detoxification of hydrogen peroxide (H2O2) and organic hydroperoxides. Rats were randomly assigned to the CRF (5/6 nephrectomized) and sham-operated control groups and observed for 6 weeks. Renal and thoracic aortic catalase and glutathione peroxidase protein abundance was measured by Western blotting. The enzyme activities in the renal and aortic extracts, hepatic glutathione levels, blood pressure and urinary nitric oxide metabolites (NO(x)) excretion were also measured. Blood pressure and urinary nitric oxide metabolite (NO(x)) excretion were also measured. The CRF group showed a significant down-regulation of both immunodetectable catalase and glutathione peroxidase proteins in the remnant kidney. Catalase activity was also significantly decreased in the remnant kidney whereas glutathione peroxidase activity was not significantly affected. Furthermore, the protein abundance of catalase was unchanged whereas the enzyme activity was significantly decreased in the thoracic aorta of CRF animals compared to the sham-operated controls. By contrast, both the protein abundance and the enzyme activity of glutathione peroxidase were not significantly affected in the aorta of CRF animals compared to the sham-operated controls. This was coupled with marked arterial hypertension, significant reduction of hepatic glutathione levels and urinary NO(x) excretion pointing to increased inactivation and sequestration of NO by superoxide. These events point to the role of impaired antioxidant defense system in the pathogenesis of oxidative stress in CRF.

Effect of a short-term diet and exercise intervention on metabolic syndrome in overweight children.

Overweight and the metabolic syndrome are increasing radically in children. The present study was designed to examine the effects of lifestyle modification in 16 children who were placed on a high-fiber, low-fat diet in a 2-week residential program where food was provided ad libitum and daily aerobic exercise was performed. In each subject, pre- and postintervention fasting blood was drawn. Insulin (27.2 +/- 3.5 vs 18.3 +/- 1.7 microU/mL, P < .01), homeostasis model assessment for insulin resistance (5.79 +/- 0.81 vs 4.13 +/- 0.38, P < .05), and body weight (92.0 +/- 7.0 vs 88.0 +/- 6.8 kg, P < .01) were reduced significantly. Total cholesterol (165 +/- 7.8 vs 127 +/- 7.4 mg/dL, P < .01), low-density lipoprotein (94.1 +/- 8.2 vs 68.5 +/- 6.7 mg/dL, P < .01), triglycerides (146 +/- 16.2 vs 88.1 +/- 8.1 mg/dL, P < .01), and total cholesterol-high-density lipoprotein (4.16 +/- 0.30 vs 3.34 +/- 0.30, P < .01) and low-density lipoprotein-high-density lipoprotein ratios (2.41 +/- 0.3 vs 1.86 +/- 0.2, P < .01) were reduced, with no change in high-density lipoprotein observed (42.3 +/- 2.4 vs 40.8 +/- 3.0 mg/dL). Systolic blood pressure (130 +/- 3.1 vs 117 +/- 1.8 mm Hg, P < .001) and diastolic blood pressure (74.3 +/- 3.0 vs 67.2 +/- 2.3 mm Hg, P = .01) also decreased. Most notably, before the intervention, 7 of the 16 subjects were classified with metabolic syndrome. After the 2-week intervention, despite remaining overweight, reversal of metabolic syndrome was noted in all 7 subjects. All of these changes occurred despite only modest improvements in the percentage of body fat (37.5% +/- 1.1% vs 36.4% +/- 1.2%, P < .01) and body mass index (33.2 +/- 1.9 vs 31.8 +/- 1.9 kg/m(2), P < .01). These results indicate that a short-term rigorous diet and exercise regimen can reverse metabolic syndrome, even in youth without documented atherosclerosis.

Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome.

Previously, we have demonstrated that chronic consumption of a high-fat, high-refined sugar (HFS) diet results in metabolic syndrome which is marked by obesity, insulin resistance, hyperlipidemia, and hypertension in Fischer rats. Metabolic syndrome in this model is associated with oxidative stress, avid nitric oxide (NO) inactivation by reactive oxygen species (ROS), diminished NO bioavailability, and dysregulation of NO synthase isotypes. Although occurrence of oxidative stress and its impact on NO metabolism are well established, the molecular source(s) of ROS in this model is unknown. In an attempt to explore this issue, we measured protein expressions of the key ROS-producing enzyme, NAD(P)H oxidase, and the main antioxidant enzymes, superoxide dismutase (CuZn SOD and Mn SOD), catalase, glutathione peroxidase (GPX), and heme oxygenase-2 (HO-2), in the kidney and aorta of Fischer rats fed an HFS or low-fat, complex-carbohydrate diet for 7 months. In addition, plasma lipid peroxidation product (malondialdehyde) as well as endothelium-dependent and -independent vasorelaxation (aorta rings) was determined. The results showed a significant upregulation of gp91(phox) subunit of NAD(P)H oxidase and downregulations of SOD isoforms, GPX, and HO-2 in the kidney and aorta of the HFS-fed animals. This was associated with increased plasma malondialdehyde concentration and impaired vasodilatory response to acetylcholine, but not the NO donor, Na nitroprusside. The latter findings confirm the presence of oxidative stress and endothelial dysfunction in the HFS-fed rats. Oxidative stress and endothelial dysfunction in the diet-induced metabolic syndrome are accompanied by upregulation of NAD(P)H oxidase, pointing to increased ROS production capacity, and downregulation of SOD isoforms, GPX, and HO-2, the key enzymes in the antioxidant defense system.