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Context: The sympathetic nervous system is an important physiological modulator of basal and postprandial energy expenditure., Objective: Our objective was to investigate whether the variability of weight loss attained during hypocaloric dietary intervention is related to individual differences in baseline sympathetic drive and nutritional sympathetic nervous system responsiveness., Participants and Methods: Untreated obese subjects (n = 42; body mass index = 32.1 ± 0.5 kg/m(2)), aged 57 ± 1 yr, who fulfilled Adult Treatment Panel III metabolic syndrome criteria participated in a 12-wk weight loss program using a modified Dietary Approaches to Treat Hypertension (DASH) diet. Muscle sympathetic nerve activity (MSNA) was measured by microneurography at rest and in a subset of subjects during a standard 75-g oral glucose tolerance test., Results: Weight loss (6.7 ± 0.5 kg) was independently predicted by baseline resting MSNA burst incidence (r = 0.38; P = 0.019), which accounted for 14.3% of the variance after adjustment for age and baseline body weight. Weight loss-resistant subjects in the lower tertile of weight loss (4.4 ± 0.3%) had significantly blunted MSNA responses to oral glucose at baseline compared with successful weight losers (9.6 ± 0.8%). Absolute Δ MSNA averaged -7 ± 2, -6 ± 5, and -3 ± 3 bursts per 100 heartbeats at 30, 60, and 90 min after glucose in the weight loss-resistant group. Corresponding values in the successful weight loss group were 9 ± 3, 12 ± 3, and 15 ± 4 bursts per 100 heartbeats (time × group interaction, P = 0.004)., Conclusions: These findings indicate that baseline sympathetic drive and nutritional sympathetic responsiveness may be important prognostic biological markers for weight loss outcome.

Aim: Insulin resistance and visceral adiposity are predisposing factors for fatty liver disease. The main objectives of this study were (i) to compare the effects of caloric restriction (CR) alone or together with moderate-intensity aerobic exercise training (CR+EX) on liver enzymes, a surrogate marker of liver injury, in obese metabolic syndrome (MetS) subjects and (ii) to identify anthropometric, metabolic, cardiovascular and dietary predictors of changes in liver enzymes., Methods: Sedentary men and women (n = 63), aged 55 ± 6 (s.d.) years with body mass index 32.7 ± 4.1 kg/m(2) and confirmed MetS, were randomized to 12-week CR, CR+EX or no treatment (Control)., Results: Weight loss averaged 7.6% in the CR and 9.1% in the CR+EX group (time effect, p < 0.001; group effect, p = 0.11); insulin sensitivity improved by 49 and 45%, respectively (both p < 0.001). Fitness (maximal oxygen consumption) increased by 19% in the CR+EX group only (p < 0.001). Alanine aminotransferase (ALT) levels decreased by 20% in the CR and 24% in the CR+EX group (time effect, both p < 0.001; group effect, p = 0.68); corresponding values for γ-glutamyltransferase (GGT) were -28 and -33%, respectively (time effect, both p < 0.001; group effect, p = 0.28). Reduction in abdominal fat mass (measured by DXA from L1 to L4) independently predicted ΔALT (r = 0.42, p = 0.005) and ΔGGT (r = 0.55, p < 0.001), whereas change in dietary saturated fat intake was independently associated with ΔALT (r = 0.35, p = 0.03)., Conclusions: Reductions in central adiposity and saturated fat intake are key drivers of improvement in liver enzymes during lifestyle interventions. Exercise training did not confer significant incremental benefits in this study., (© 2011 Blackwell Publishing Ltd.)

Objective: Metabolic syndrome (MetS) obesity is an independent risk factor for chronic kidney disease. This study was conducted to examine the effects of lifestyle interventions on renal parameters and putative metabolic, neuroadrenergic and hemodynamic mediators of renal injury., Methods: Untreated men and women (mean age 55 ± 1 years; BMI 32.7 ± 0.6 kg/m) without pre-existing renal dysfunction, who fulfilled MetS criteria were randomized to dietary weight loss (WL, n = 13), weight loss combined with aerobic exercise (WL + EX, n = 13), or no treatment (control, n = 12). Estimated glomerular filtration rate (eGFR), 24 h urinary albumin excretion, plasma renin activity (PRA), muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), anthropometric, metabolic and fitness variables were measured at baseline and week 12., Results: Body weight decreased by -8.2 ± 0.8% in the WL and -10.7 ± 0.9% in the WL + EX groups (both P < 0.001). Fitness (maximal oxygen consumption) increased by 15 ± 5% and BRS by 5.5 ± 2.4 ms/mmHg in the WL + EX group only (P < 0.05). Serum creatinine decreased by -8.1 ± 4.8%, (WL, P = 0.016) and -14.9 ± 3.0% (WL + EX, P < 0.001). Estimated GFR increased commensurately but the increment was greater in the WL + EX group (P = 0.04). Albuminuria (P < 0.05) and MSNA (P < 0.001) decreased similarly in both groups, whereas PRA, high sensitivity C-reactive protein, uric acid and DBP decreased only in the WL + EX group (all P < 0.05)., Conclusion: Moderate weight loss in obese MetS patients is associated with a reduction in albuminuria and an improvement in eGFR which is augmented by exercise co-intervention.

Excess weight is established as a major risk factor for cardiovascular diseases, particularly in young individuals. To get a better understanding of the pathophysiology underlying increased cardiovascular disease risk, we evaluated early signs of organ damage and their possible relationship to sympathetic nervous activity. Eighteen lean (body mass index <25 kg/m(2)) and 25 overweight or obese (body mass index >25 kg/m(2)) healthy university students were included in the study. We comprehensively assessed subclinical target organ damage, including the following: (1) assessment of renal function; (2) left ventricular structure and systolic and diastolic function; and (3) endothelial function. Muscle sympathetic nervous activity was assessed by microneurography. Participants with excess weight had decreased endothelial function (P<0.01), elevated creatinine clearance (P<0.05), increased left ventricular mass index (P<0.05), increased left ventricular wall thickness (P<0.01), lower systolic and diastolic function (P<0.01), and elevated muscle sympathetic nervous activity (P<0.001) compared with lean individuals. In multiple regression analysis, endothelial function was inversely related to muscle sympathetic nervous activity (R(2)=0.244; P<0.05), whereas creatinine clearance and left ventricular mass index were positively related to muscle sympathetic nervous activity, after adjustment for body mass index, sex, and blood pressure (R(2)=0.318, P<0.01 and R(2)=0.312, P<0.05, respectively). Excess weight in young individuals is associated with subclinical alterations in renal and endothelial function, as well as in the structure of the heart, even in the absence of hypertension. Sympathetic activity is closely associated with cardiovascular and renal alterations observed in these subjects.

Objective: Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function., Research Design and Methods: Untreated men and women (mean age 55 +/- 1 year; BMI 32.3 +/- 0.5 kg/m(2)) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks., Results: Body weight decreased by -7.1 +/- 0.6 and -8.4 +/- 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 +/- 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by -96 +/- 30 and -101 +/- 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by -12 +/- 6 and -19 +/- 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups., Conclusions: The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.

Arterial hypertension represents a major cardiovascular epidemic in the developed and developing world. Projections out to 2025 suggest that up to 50% of the adult populations of Western countries will meet standard guideline definitions of hypertension and thus require therapeutic intervention both non-pharmacological or pharmacological. Hyper-tension is also a component of many other major comorbidities contributing to cardiovascular disease burden. These include obesity, the metabolic syndrome, hyperlipidaemia, diabetes, and chronic kidney disease (CKD). Downstream consequences initially presenting as target organ damage of various degrees include coronary artery disease, cerebrovascular disease, nephropathy and chronic heart failure. Although elevated blood pressure per se is undoubtedly the major factor contributing to hypertensive target organ damage there is clear evidence that other mediators are also crucially involved in the transition from a healthy to a diseased state of target organs in the clinical setting of elevated blood pressure. This has obvious consequences for a multifactorial approach aimed not only at achieving target blood pressure levels but also at preventing the development or the progression of target organ damage in order to optimally reduce the overall cardiovascular risk for patients. The epidemic we are currently facing in regards to obesity is closely associated with the expected increase in the prevalence of hypertension. A closer look into the role of obesity and associated factors for the rise in blood pressure and their role in target organ damage is therefore inevitable. This review will thus focus on the clinically important aspects of target organ damage associated with hypertension, particularly obesity related hypertension, and the evidence for the involvement of neurohormonal activation and inflammatory pathways.

Objective: The purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted., Research Design and Methods: Thirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 +/- 1 years (mean +/- SE) with BMI 31.6 +/- 0.6 kg/m2, who fulfilled the Adult Treatment Panel III criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program., Results: Body weight decreased by 8.1 +/- 0.9 and 8.4 +/- 1.1 kg and resting norepinephrine spillover by 94 +/- 31 and 166 +/- 58 ng/min (all P < or = 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged -3 +/- 25 versus 73 +/- 24 ng/min at 30 min (P = 0.039), 36 +/- 21 versus 115 +/- 28 ng/min at 60 min (P = 0.045), 9 +/- 21 versus 179 +/- 50 ng/min at 90 min (P < 0.001), and 40 +/- 48 versus 106 +/- 39 ng/min at 120 min (P = 0.24)., Conclusions: Weight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis.

Background: Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese., Objective: The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose., Design: Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load., Results: IR subjects had a higher insulin area under the curve from 0 to 120 min (AUC(0-120): 13,468 +/- 677 compared with 6399 +/- 612 mU/L . min; P < 0.001), glucose AUC(0-120) (P < 0.05), and resting MSNA (41 +/- 3 compared with 31 +/- 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 +/- 7% and 40 +/- 13%, respectively; P < or = 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC(0-120) were independent (inverse) predictors of the SNS response., Conclusions: IR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.

Background: Depression and obesity, the two common ailments of modern society, are associated with increased risk of coronary artery disease and raised C-reactive protein (CRP) levels. Are the effects of depression and obesity related or do they influence CRP levels independently?, Objective: In 493 consecutive patients presenting for obesity surgery, we explored the relationship between symptoms of depression and raised CRP levels after controlling for confounding factors., Methods and Procedures: Depression was measured using the Beck Depression Inventory (BDI). Confounding variables were age, gender, BMI, waist and hip measures, smoking and alcohol habits, medications, biochemical measures of the metabolic syndrome, and indirect measures of insulin resistance. General linear regression sought variables independently associated with CRP levels., Results: These patients had a BMI range from 31 to 91 kg/m2, participants age ranged from 14 to 71 years, and 76% were women. The median CRP concentration was 7.7mg/l (interquartile range: 3.9-14), 40% had an abnormally raised concentration (> 10mg/l). The mean BDI score was 17.0 +/- 9.0, indicating symptoms of moderate depression. We found five independent factors associated with raised CRP levels. In order of strength of association, these were: higher BMI (beta = 0.36, P < 0.001), female gender (beta = -0.19, P < 0.001), estrogen therapy (beta = 0.18, P < 0.001), higher BDI score (beta = 0.11, P = 0.01), and insulin resistance index (beta = 0.11, P = 0.01), and with a combined R2 = 0.24, (P < 0.001)., Discussion: In obese patients, symptoms of depression were associated with raised CRP levels after controlling for confounding variables. Obese women on estrogen therapy are at risk of high CRP levels.

Hypertension in normal-weight and obese individuals is characterized by activation of the sympathetic nervous system. Measurement of spillover of the sympathetic transmitter, norepinephrine, to plasma indicates that the regional pattern of sympathetic activation in the 2 "variants" of essential hypertension differs, excluding the heart in obesity-related hypertension. Whether sympathetic nerve firing characteristics also differ is unknown. We studied multiunit and single fiber sympathetic nerve firing properties in patients with normal-weight hypertension and obesity-related hypertension, comparing these with nerve characteristics in normal-weight and obese people with normal blood pressure. Both normal-weight hypertensive (n=10) and obese hypertensive (n=14) patients had increased total multiunit muscle sympathetic nerve activity compared with the normal-weight (n=11) and obese (n=11) people with normal blood pressure (65+/-4 versus 47+/-6 bursts per 100 heartbeats, P<0.01 in the normal-weight groups and 68+/-4 versus 53+/-3 bursts per 100 beats, P<0.01 in the obese groups). Sympathetic activation in normal-weight hypertension was characterized by increased firing rate of single vasoconstrictor fibers (70+/-8 versus 28+/-3 spikes per 100 beats; P<0.001), increased firing probability per heartbeat (39+/-3% versus 20+/-3%; P<0.001), and higher incidence of multiple spikes per heartbeat (30+/-4% versus 17+/-4%; P<0.05). Sympathetic activation in obesity-related hypertension differed, involving recruitment of previously silent fibers, which fired at a normal rate. The pattern of sympathetic activation in normal-weight and obesity-related hypertension differs in terms of both the firing characteristics of individual sympathetic fibers and the sympathetic outflows involved. The underlying central nervous system mechanism and the adverse consequences of the 2 modes of sympathetic activation may differ.

Background: Obesity and high blood pressure (BP) commonly coexist in patients, and both conditions are associated with elevated sympathetic nervous activity. We tested whether the sympathetic nervous system was differently affected in men and women by the body mass index (BMI), BP, leptin and weight loss., Methods: We measured muscle sympathetic nerve activity (MSNA, microneurography), BP and plasma leptin concentrations in 167 age-matched normotensive and hypertensive men and women divided into three subgroups: lean, BMI < 25 kg/m; overweight, BMI > or = 25 and < 30 kg/m; and obese, BMI > or = 30 kg/m. These measurements were repeated in a subgroup of 19 obese subjects who underwent a 12-week diet., Results: Women with hypertension had increased MSNA compared with their normotensive counterparts (37 +/- 2 versus 25 +/- 2 bursts/min, analysis of variance, P < 0.001) and MSNA was significantly related to BP (P < 0.05, r = 0.236) but not to BMI. MSNA in men with hypertension was no different from that in normotensive subjects (33 +/- 2 versus 30 +/- 2 bursts/min), but MSNA was significantly related to BMI (P < 0.05, r = 0.249). Diet resulted in the same degree of weight loss in men and women, but induced a decrease in MSNA only in men (43 +/- 3 to 34 +/- 3 bursts/min, P < 0.01). The plasma leptin concentration was higher in women than in men, and for both groups it was related to BMI not BP (r = 0.497, P < 0.001 in women and r = 0.483, P < 0.001 in men)., Conclusion: These data demonstrate a gender difference in the regulation of the sympathetic nervous system, in which MSNA mainly relates to BP in women and to BMI in men.