Search

The increase in the prevalence of obesity and the concomitant rise in obesity-related illness have led to substantial pressure on health care systems throughout the world. While the combination of reduced exercise, increased sedentary time, poor diet, and genetic predisposition is undoubtedly pivotal in generating obesity and increasing disease risk, a large body of work indicates that the sympathetic nervous system (SNS) contributes to obesity-related disease development and progression. In obesity, sympathetic nervous activity is regionalized, with activity in some outflows being particularly sensitive to the obese state, whereas other outflows, or responses to stimuli, may be blunted, thereby making the assessment of sympathetic nervous activation in the clinical setting difficult. Isotope dilution methods and direct nerve recording techniques have been developed and utilized in clinical research, demonstrating that in obesity there is preferential activation of the muscle vasoconstrictor and renal sympathetic outflows. With weight loss, sympathetic activity is reduced. Importantly, sympathetic nervous activity is associated with end-organ dysfunction and changes in sympathetic activation that accompany weight loss are often reflected in an improvement of end-organ function. Whether targeting the SNS directly improves obesity-related illness remains unknown, but merits further attention., (© 2019 New York Academy of Sciences.)

Aims/hypothesis: Increasing brown adipose tissue (BAT) activity is a possible therapeutic strategy to increase energy expenditure and glucose and lipid clearance to ameliorate obesity and associated comorbidities. The thiazolidinedione (TZD) class of glucose-lowering drugs increase BAT browning in preclinical experimental models but whether these actions extend to humans in vivo is unknown. The aim of this study was to determine the effect of pioglitazone treatment on adipocyte browning and adaptive thermogenesis in humans., Methods: We first examined whether pioglitazone treatment of cultured human primary subacromioclavicular-derived adipocytes induced browning. Then, in a blinded, placebo-controlled, parallel trial, conducted within the Baker Institute clinical research laboratories, 14 lean male participants who were free of cardiometabolic disease were randomised to receive either placebo (lactose; n = 7, age 22 ± 1 years) or pioglitazone (45 mg/day, n = 7, age 21 ± 1 years) for 28 days. Participants were allocated to treatments by Alfred Hospital staff independent from the study via electronic generation of a random number sequence. Researchers conducting trials and analysing data were blind to treatment allocation. The change in cold-stimulated BAT activity, assessed before and after the intervention by [ 18 F]fluorodeoxyglucose uptake via positron emission tomography/computed tomography in upper thoracic and cervical adipose tissue, was the primary outcome measure. Energy expenditure, cardiovascular responses, core temperature, blood metabolites and hormones were measured in response to acute cold exposure along with body composition before and after the intervention., Results: Pioglitazone significantly increased in vitro browning and adipogenesis of adipocytes. In the clinical trial, cold-induced BAT maximum standardised uptake value was significantly reduced after pioglitazone compared with placebo (-57 ± 6% vs -12 ± 18%, respectively; p < 0.05). BAT total glucose uptake followed a similar but non-significant trend (-50 ± 10% vs -6 ± 24%, respectively; p = 0.097). Pioglitazone increased total and lean body mass compared with placebo (p < 0.05). No other changes between groups were detected., Conclusions/interpretation: The disparity in the actions of pioglitazone on BAT between preclinical experimental models and our in vivo human trial highlight the imperative to conduct human proof-of-concept studies as early as possible in BAT research programmes aimed at therapeutic development. Our clinical trial findings suggest that reduced BAT activity may contribute to weight gain associated with pioglitazone and other TZDs., Trial Registration: ClinicalTrials.gov NCT02236962 FUNDING: This work was supported by the Diabetes Australia Research Program and OIS scheme from the Victorian State Government.

Aims: Elevated serum uric acid (SUA) is often present in conditions associated with increased cardiovascular risk yet it is not recognized as a marker of risk. We evaluated whether SUA was associated with evidence of early markers of cardiovascular risk factor including subclinical early organ damage, sympathetic tone and metabolic profile in a healthy population with a high prevalence of obesity., Material and Methods: Data from 281 patients (175 women and 106 men, mean age: 35.5 ± 0.8 years, mean BMI: 33.2 ± 0.5 kg/m) were retrieved from a database. All participants were healthy, nonsmoker and free of medication. Available data included metabolic profile, muscle sympathetic nervous activity (MSNA, microneurography), endothelial function (pulse amplitude tonometry, augmentation index), estimated glomerular filtration rate (eGFR) and echocardiography., Results: With participants grouped into sex-adjusted tertiles of SUA, those in the third tertile of SUA had increased waist circumference, worse metabolic profile (fasting glucose, total cholesterol, triglycerides and HDL), elevated MSNA, decreased endothelial function, increased augmentation index and decreased eGFR compared with those in the first tertile of SUA. In multiple regression analysis adjusted for age, sex, BMI and ethnicity, SUA was independently associated with waist circumference, low-density lipoprotein, triglycerides, augmentation index, MSNA and eGFR, providing a combined adjusted R = 0.599 or 60% of the overall variance., Conclusion: In a healthy population with a high proportion of obesity, SUA is associated with measures of metabolic, end-organ damage and sympathetic tone indicating the potential value of SUA as a marker of early cardiovascular disease development.

Background and Aims: Plasma sphingolipids including ceramides, and gangliosides are associated with insulin resistance (IR) through effects on insulin signalling and glucose metabolism. Our studies of subjects with metabolic syndrome (MetS) showed close relationships between IR and sympathetic nervous system (SNS) activity including arterial norepinephrine (NE). We have therefore investigated possible associations of IR and SNS activity with complex lipids that are involved in both insulin sensitivity and neurotransmission., Methods: We performed a cross-sectional assessment of 23 lipid classes/subclasses (total 339 lipid species) by tandem mass spectrometry in 94 overweight untreated subjects with IR (quantified by HOMA-IR, Matsuda index and plasma insulin)., Results: Independently of IR parameters, several circulating complex lipids associated significantly with arterial NE and NEFA (non-esterified fatty acids) and marginally with heart rate (HR). After accounting for BMI, HOMA-IR, systolic BP, age, gender, and correction for multiple comparisons, these associations were significant (p < 0.05): NE with ceramide, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine and free cholesterol; NEFA with mono- di- and trihexosylceramide, G M3 ganglioside, sphingomyelin, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine, phosphatidylinositol and free cholesterol; HR marginally (p = or <0.1>0.05) with ceramide, G M3 ganglioside, sphingomyelin, lysophosphatidylcholine, phosphatidylinositol, lysophosphatidylinositol and free cholesterol. Multiple subspecies of these lipids significantly associated with NE and NEFA. None of the IR biomarkers associated significantly with lipid classes/subclasses after correction for multiple comparisons., Conclusions: This is the first demonstration that arterial norepinephrine and NEFA, that reflect both SNS activity and IR, associate significantly with circulating complex lipids independently of IR, suggesting a role for such lipids in neural mechanisms operating in MetS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Prolonged sitting is increasingly recognized as a ubiquitous cardiometabolic risk factor, possibly distinct from lack of physical exercise. We examined whether interrupting prolonged sitting with brief bouts of light-intensity activity reduced blood pressure (BP) and plasma noradrenaline in type 2 diabetes (T2D)., Methods: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men; mean ± SD; 62 ± 6 years) consumed standardized meals during 3 × 8 h conditions: uninterrupted sitting (SIT); sitting + half-hourly bouts of walking (3.2 km/h for 3-min) (light-intensity walking); and sitting + half-hourly bouts of simple resistance activities for 3 min (SRAs), each separated by 6-14 days washout. Resting seated BP was measured hourly (mean of three recordings, ≥20-min postactivity). Plasma noradrenaline was measured at 30-min intervals for the first hour after meals and hourly thereafter., Results: Compared with SIT, mean resting SBP and DBP were significantly reduced (P < 0.001) for both light-intensity walking (mean ± SEM; -14 ± 1/-8 ± 1 mmHg) and SRA (-16 ± 1/-10 ± 1 mmHg), with a more pronounced effect for SRA (P < 0.05 versus light-intensity walking). Similarly, mean plasma noradrenaline was significantly reduced for both light-intensity walking (-0.3 ± 0.1 nmol/l) and SRA (-0.6 ± 0.1 nmol/l) versus SIT, with SRA lower than light-intensity walking (P < 0.05). Mean resting heart rate was lowered by light-intensity walking (-3 ± 1 bpm; P < 0.05), but not SRA (-1 ± 1 bpm)., Conclusion: Interrupting prolonged sitting with brief bouts of light-intensity walking or SRA reduces resting BP and plasma noradrenaline in adults with T2D, with SRA being more effective. Given the ubiquity of sedentary behaviors and poor adherence to structured exercise, this approach may have important implications for BP management in patients with T2D.

Objective: To determine whether interrupting prolonged sitting with brief bouts of light-intensity walking (LW) or simple resistance activities (SRA) improves postprandial cardiometabolic risk markers in adults with type 2 diabetes (T2D)., Research Design and Methods: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men 62 ± 6 years old) underwent the following 8-h conditions on three separate days (with 6-14 days washout): uninterrupted sitting (control) (SIT), sitting plus 3-min bouts of LW (3.2 km · h(-1)) every 30 min, and sitting plus 3-min bouts of SRA (half-squats, calf raises, gluteal contractions, and knee raises) every 30 min. Standardized meals were consumed during each condition. Incremental areas under the curve (iAUCs) for glucose, insulin, C-peptide, and triglycerides were compared between conditions., Results: Compared with SIT, both activity-break conditions significantly attenuated iAUCs for glucose (SIT mean 24.2 mmol · h · L(-1) [95% CI 20.4-28.0] vs. LW 14.8 [11.0-18.6] and SRA 14.7 [10.9-18.5]), insulin (SIT 3,293 pmol · h · L(-1) [2,887-3,700] vs. LW 2,104 [1,696-2,511] and SRA 2,066 [1,660-2,473]), and C-peptide (SIT 15,641 pmol · h · L(-1) [14,353-16,929] vs. LW 11,504 [10,209-12,799] and SRA 11,012 [9,723-12,301]) (all P < 0.001). The iAUC for triglycerides was significantly attenuated for SRA (P < 0.001) but not for LW (SIT 4.8 mmol · h · L(-1) [3.6-6.0] vs. LW 4.0 [2.8-5.1] and SRA 2.9 [1.7-4.1])., Conclusions: Interrupting prolonged sitting with brief bouts of LW or SRA attenuates acute postprandial glucose, insulin, C-peptide, and triglyceride responses in adults with T2D. With poor adherence to structured exercise, this approach is potentially beneficial and practical., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS., Participants and Methods: We examined multiunit and single-unit muscle SNS activity (by microneurography), HRV (time and frequency domain analysis) and endothelial function [ischaemic reactive hyperaemia index (RHI) using the EndoPAT device] in 19 overweight/obese women with PCOS (BMI: 31·3 ± 1·5 kg/m(2), age: 31·3 ± 1·6 years) and compared them with 21 control overweight/obese women (BMI: 33·0 ± 1·4 kg/m(2), age: 28·2 ± 1·6 years) presenting a similar metabolic profile (fasting total, HDL and LDL cholesterol, glucose, triglycerides, insulin sensitivity and blood pressure)., Results: Women with PCOS had elevated multiunit muscle SNS activity (41 ± 2 vs 33 ± 3 bursts per 100 heartbeats, P < 0·05). Single-unit analysis showed that vasoconstrictor neurons were characterized by elevated firing rate and probability and incidence of multiple spikes (P < 0·01 for all parameters). Women with PCOS also had impaired endothelial function (RHI: 1·77 ± 0·14 vs 2·18 ± 0·14, P < 0·05). HRV did not differ between the groups., Conclusion: Women with PCOS have increased sympathetic drive and impaired endothelial function independent of obesity and metabolic disturbances. Sympathetic activation and endothelial dysfunction may confer greater cardiovascular risk in women with PCOS., (© 2015 John Wiley & Sons Ltd.)

Background: The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program., Methods: Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m(2), underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry., Results: Weight loss averaged -8.3 ± 0.6% of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9%, P = 0.04) and exogenous insulin clearance (by 12 ± 5%, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by -12 ± 5%, whole-body norepinephrine spillover rate by -14 ± 8%, and MSNA by -9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = -0.63, P = 0.01) which explained 40% of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64% of the variance., Conclusions: Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850.

The sympathetic nervous system (SNS) plays a key role in both cardiovascular and metabolic regulation; hence, disturbances in SNS regulation are likely to impact on both cardiovascular and metabolic health. With excess adiposity, in particular when visceral fat accumulation is present, sympathetic activation commonly occurs. Experimental investigations have shown that adipose tissue releases a large number of adipokines, cytokines, and bioactive mediators capable of stimulating the SNS. Activation of the SNS and its interaction with adipose tissue may lead to the development of hypertension and end-organ damage including vascular, cardiac, and renal impairment and in addition lead to metabolic abnormalities, especially insulin resistance. Lifestyle changes such as weight loss and exercise programs considerably improve the cardiovascular and metabolic profile of subjects with obesity and decrease their cardiovascular risk, but unfortunately weight loss is often difficult to achieve and sustain. Pharmacological and device-based approaches to directly or indirectly target the activation of the SNS may offer some benefit in reducing the cardiometabolic consequences of obesity. Preliminary evidence is encouraging, but more trials are needed to investigate whether sympathetic inhibition could be used in obesity to reverse or prevent cardiometabolic disease development. The purpose of this review article is to highlight the current knowledge of the role that SNS plays in obesity and its associated metabolic disorders and to review the potential benefits of sympathoinhibition on metabolic and cardiovascular functions., (Copyright © 2015 the American Physiological Society.)

Context: Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis., Objective: This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome., Methods: Un-medicated individuals (n=42, mean age 56±0.8 yrs, body mass index 34±0.6 kg/m(2)) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index., Results: PIO increased clamp derived glucose utilisation by 35% (P<0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P<0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all <0.05). The overall norepinephrine spillover response (AUC(0-120)) increased significantly in the PIO group (group × time interaction, P=0.04), with greatest increment at 30 minutes post-glucose (101±38 ng/min at baseline versus 241±48 ng/min post treatment, P=0.04) and correlated with percent improvement in M., Conclusions: PIO enhances the early postprandial SNS response to carbohydrate ingestion., (Copyright © 2015. Published by Elsevier Inc.)

Context: Impaired insulin clearance contributes to the hyperinsulinemia of obesity, yet relatively little is known concerning the pathophysiological determinants of insulin clearance in obese populations., Objective: To examine the cross-sectional relationship between insulin clearance and resting sympathetic nervous system activity in a cohort of obese subjects with metabolic syndrome., Participants and Methods: Unmedicated, nonsmoking subjects (31 male, 27 female; aged 56 ± 1 year; body mass index 33.7 ± 0.6 kg/m(2)) underwent euglycemic hyperinsulinemic clamp to determine insulin sensitivity (M) and insulin clearance, assessment of norepinephrine kinetics, peripheral arterial tonometry, Doppler echocardiography, and oral glucose tolerance test., Results: Univariate correlation analyses showed inverse associations between insulin clearance and arterial norepinephrine concentration (r = -0.44, P = .0006), calculated norepinephrine spillover rate (r = -0.33, P = .01), augmentation index (AI, r = -0.37, P = .005), and positive associations with M (r = 0.30, P = .02), Matsuda insulin sensitivity index (r = 0.27, P = .04), and cardiac output (r = 0.27, P = .04). Insulin clearance and sensitivity did not differ between genders, however females had higher AI compared to males (35 ± 3% versus 14 ± 2%, P < .001). In age and gender adjusted stepwise regression analyses, arterial norepinephrine concentration alone explained 19% of the variance in insulin clearance. When all significant variables were entered into the regression model, arterial norepinephrine, AI, gender, and M were independent predictors of insulin clearance, together explaining 41% of the variance., Conclusions: Arterial norepinephrine concentration is inversely and independently associated with whole-body insulin clearance rate in obese individuals with metabolic syndrome. Prospective studies are needed to determine the direction of causality and the chronology of interactions between insulin clearance and sympathetic neural activity.

Context: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk., Objective: The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake., Participants and Methods: A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography., Results: PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08)., Conclusions: Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

The underlying cause of predisposition to obesity is complex but one marker is cortisol responsiveness. Selection of sheep for high (HR) or low (LR) cortisol responses to adrenocorticotropin shows that HR are more likely to become obese. Increased propensity to obesity is associated with reduced skeletal muscle thermogenesis. We sought to determine whether metabolic or behavioral responses to stress also contribute to altered propensity to obesity in LR and HR. Animals (n=5-10/group) were exposed to 3 stressors and we measured food intake and thermogenesis (recorded with dataloggers implanted into muscle). Stressors were hypoglycaemia (0.125 units/kg insulin, IV), a barking dog and immune challenge (200 ng/kg lipopolysaccharide--LPS, IV). LR animals showed a greater catabolic state in response to both immune and psychosocial stressors. LPS reduced (P<0.01) food intake in both groups but LR showed a greater (P<0.05) reduction in food intake and a more substantial (P<0.05) rise in muscle temperature. Introduction of the barking dog reduced (P<0.05) food intake in LR only. These metabolic differences coincided with differences in cortisol responsiveness, where HR animals had increased (P<0.05) cortisol in response to both immune and psychosocial stressors. We also assessed behavior in the following paradigms: 1, isolation in the open field test; 2, response to a human intruder; and 3, food competition. LR had greater (P<0.05) activity, reduced fearfulness and displayed a proactive coping style of behavior. Thus we demonstrate that high cortisol responsiveness identifies animals with stress-induced metabolic and behavioral traits that may contribute to susceptibility to obesity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: To examine the emotional well-being of severely obese Australians with type 2 diabetes, along with markers of social and economic disadvantage, using the Diabetes MILES - Australia dataset., Methods: Diabetes MILES - Australia was a national survey of 3338 adults with diabetes that focused on psychosocial issues; 1795 had type 2 diabetes and reported BMI. We extracted data regarding depression (PHQ-9), anxiety (GAD-7), obesity- and diabetes-related comorbidities, and demographics. The severely obese group (SOG) (BMI ≥ 35; median BMI=41.6) constituted 530 (30%) of the type 2 diabetes respondents and was matched with 530 controls (CG) (BMI<35; median BMI=28.2). Within- and between-group trends were examined., Results: The SOG had higher depression scores (median (IQR) 6.0 (3-12)) than CG (5.0 (2-10)); p<0.001, and were more likely to report moderate-severe depressive symptoms (37% versus 27%; p<0.001). The groups did not differ on anxiety. The SOG, compared with the CG, were more likely to live alone (21% versus 17%), receive a disability pension (21% versus 15%), earn ≤$40.000/year (51% versus 41%; all p<0.05), and were less likely to be employed (46% versus 53%), university or higher educated (17% versus 26%), or have health insurance (50% versus 60%; all p ≤ 0.01). Moderate-severe depression was positively associated with cumulative stressors of severe obesity, socioeconomic disadvantage, and obesity- and diabetes-related comorbidity., Conclusions: Severely obese people living with type 2 diabetes have cumulative stressors related to health, disability, demographic and socioeconomic factors, and impaired emotional well-being., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Context: Altered cardiac structure and function have been reported in prediabetic and diabetic populations; however, the contribution of the sympathetic nervous system (SNS) to these changes has yet to be delineated., Objective: Our objective was to examine interrelationships between glucose metabolism, left ventricular mass and function, and SNS activity in obese metabolic syndrome subjects., Participants and Methods: Unmedicated impaired glucose tolerant (IGT) (n = 31) or treatment-naive type 2 diabetic (T2D) (n = 25) subjects, matched for age (mean 58 ± 1 years), gender, body mass index (32.2 ± 0.5 kg/m(2)), and blood pressure, participated. They underwent echocardiography and assessments of whole-body norepinephrine kinetics, muscle sympathetic nerve activity, and insulin sensitivity by euglycemic clamp (M value)., Results: T2D subjects had higher left ventricular mass index (LVMI) (93.6 ± 3.5 vs 77.2 ± 3.4 g/m(2), P = .002) and Doppler-derived isovolumetric relaxation and deceleration times (both P < .05) and lower early/late transmitral inflow velocities (E/A) (P = .02) compared with IGT. Total muscle sympathetic nerve activity and arterial norepinephrine concentration were higher in the T2D group (by 18% and 32%, respectively, both P ≤ .05), whereas plasma norepinephrine clearance was reduced (1.94 ± 0.11 vs 2.26 ± 0.10 L/min, P = .02). M value correlated inversely with left ventricular septal thickness (r = -0.46, P = .007). Whole-body noradrenaline spillover rate correlated with LVMI in the T2D subgroup (r = 0.47, P = .03). In the pooled cohort, LVMI was independently predicted by pulse pressure (r = 0.38, P = .004) and E/A ratio by 2-hour glucose (r = -0.38, P = .005)., Conclusions: Transition from IGT to T2D is associated with cardiac enlargement and diastolic dysfunction, which relate to metabolic, hemodynamic, and SNS alterations.

Excess adiposity is associated with increased incidence of cardiovascular disease (CVD). Importantly, CVD mortality associated with obesity is more prevalent in young individuals. Elevated sympathetic nervous system (SNS) activity is present in obesity, even in individuals who are young and otherwise healthy. Baseline SNS overactivity, as well as blunted sympathetically mediated thermogenic response to a meal may play a critical role in the development and progression of CVD which is likely to develop as a result of multiple factors. Recent data indicate that SNS activity to the skeletal muscle is directly related to the degree of renal, endothelial and cardiac dysfunction in young individuals. Targeting the SNS may be an attractive and important avenue for the pharmacological treatment of obesity-related disturbances.

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m(2)), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = -0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = -0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.

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.

The present study compared the effectiveness of a mild calorie-restricted diet (D) alone, exercise (EX) alone and a combination of D+EX on weight loss-induced blood pressure (BP) reduction over 24 weeks. We focussed especially on the relationship between sympathetic nervous activity, as indicated from measures of plasma norepinephrine (NE), and insulin resistance (homeostasis model of insulin resistance, HOMA-IR). The three groups each comprised 30 obese, hypertensive men. Body mass index (BMI), fat mass, waist-to-hip ratio, BP, plasma NE and HOMA-IR were measured every 2 weeks during the first 4 weeks and subsequently every 4 weeks for the next 20 weeks. All basal parameters were similar among the three groups. At 24 weeks, the combination group with D+EX comprised a significantly higher prevalence of normotensive subjects than the D alone or EX alone group (P<0.05). In the D alone group, plasma NE was decreased significantly at 2 weeks, reductions in BMI, fat mass and BP were observed at 8 weeks, and waist-to-hip ratios and HOMA-IR were decreased at 12 weeks. In comparison, in the EX alone group, significant reductions of fat mass and HOMA-IR were observed at 4 weeks. Plasma NE and HOMA-IR were reduced at 8 weeks while decreases in BP were detected at 12 weeks. In the D+EX group, significant reductions in plasma NE were observed at 2 weeks followed by significant decreases in BMI, fat mass, waist-to-hip ratio, BP levels and HOMA-IR at 4 weeks. The magnitudes of reductions of all parameters were greatest in the D+EX group. These results demonstrate that D+EX exerts a stronger ameliorative effect on weight loss, weight loss-induced BP reduction, normalization of BP, sympathetic activation and insulin resistance compared with D or EX alone. D and EX might, perhaps, exert different mechanisms on weight loss and weight loss-induced BP reduction; however, a combination of caloric restriction and exercise is preferred to control BP levels in obese hypertensive patients.

Bariatric surgery, through its efficacy and improved safety, is emerging as an important and broadly available treatment for people with severe and complex obesity that has not responded adequately to other therapy. Established procedures, such as Roux-en-Y gastric bypass and adjustable gastric banding, account for more than 80% of bariatric surgical procedures globally. Sleeve gastrectomy has emerged as a stand-alone procedure. Truly malabsoptive procedures, such as biliopancreatic diversion and its duodenal switch variant, have a diminishing role as primary procedures, but remain an option for patients who do not respond adequately to less disruptive procedures. The procedures vary considerably in their postoperative morbidity and mortality; pattern and extent of weight loss; nature and severity of long-term complications; and nutritional requirements and risks. There is no perfect procedure--an informed risk and benefit assessment should be made by each patient. Gastroenterologists also need to be familiar with the risks and benefits of current and emerging procedures as they are likely to be increasingly involved in the integrated care of these patients.

Stress in several guises is evident in individuals with hypertension and in those with the metabolic syndrome and may account, at least in part, for the extent and pattern of sympathetic nervous activation. Importantly, elevated activity of the sympathetic nervous system is related to the development of obesity-related illnesses including hypertension, insulin resistance, and renal, cardiac, and vascular impairment. Notably, evidence of subclinical organ damage is evident even in young, normotensive, overweight persons, thereby reinforcing the need to develop and implement effective early intervention.

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.

Sympathetic nervous system hyperactivity is observed in patients with renal injury, renovascular hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD). Elevated sympathetic activity is of prognostic relevance in that plasma norepinephrine concentrations predict survival and the incidence of cardiovascular events in patients with ESRD, as well as future renal injury in normotensive healthy subjects with renal function in the normal range. Renal injury, CKD and ESRD are often associated with obesity, and its common sequelae hypertension and diabetes. In fact, hypertension and diabetes mellitus are the main causes of ESRD in western societies and together account for approximately more than 50% of ESRD incidence in the United States and Japan. Obesity also leads to increases in the incidence of cardiovascular diseases. Several clinical and epidemiological studies have clearly documented that heightened sympathetic nervous activity has an important role in the onset and maintenance of obesity and hypertension. Elevated sympathetic nervous activity may actually represent an important mechanism contributing to the onset and maintenance of renal injury at least in part through its concomitant adverse effects on obesity and hypertension. Understanding the contribution of sympathetic nervous hyperactivity to the onset and maintenance of renal injury might aid in the prevention and treatment of renal injury, CKD and ESRD. Very recently, renal sympathetic denervation was shown to be a potentially novel therapeutic strategy in resistant hypertension. In addition, renin-angiotensin system inhibitors are recommended as the initial therapy because of their renal protective effect, especially in hypertensive patients with type 2 diabetes or with proteinuria. The purpose of this review is to provide an overview of our current knowledge on the relationships between sympathetic nerve activity and renal function to further our understanding of the precise roles of sympathetic nerve activity in renal injury, particularly in the context of obesity and hypertension. These insights may be useful to improve prevention and treatment of renal injury in these patients.

The world wide prevalence of obesity and the metabolic syndrome is escalating. Contrary to earlier experimental evidence, human obesity is characterised by sympathetic nervous activation, with the outflows to both the kidney and skeletal muscle being activated. While the mechanisms responsible for initiating the sympathetic activation remain to be unequivocally elucidated, hyperinsulinemia, obstructive sleep apnoea, increased circulating adipokines, stress and beta adrenergic receptor polymorphisms are implicated. The pattern of sympathetic activation may be the pathophysiological mechanism underpinning much obesity-related illnesses with the consequences including, amongst others, the development of hypertension, insulin resistance, diastolic dysfunction and renal impairment. While diet and exercise are the first line therapy for the treatment of obesity and the metabolic syndrome, pharmacological interventions targeting the sympathetic nervous system, either directly or indirectly are also likely to be of benefit. Importantly, the benefit may not necessarily be weight related but may be associated with a reduction in end organ damage., (Copyright 2010 Elsevier Inc. All rights reserved.)

Overweight and obesity is a growing "world-wide epidemic problem". Because as many as, two-thirds of the adult population and a growing number of children are overweight. The prevalence of diabetes, especially type 2 diabetes and hypertension have significantly increased with the prevalence of obesity. Obesity accompanying type 2 diabetes and hypertension are known to be closely linked with insulin resistance and elevated sympathetic nervous activity. It has been well documented that obesity, hypertension, and diabetes are high risk factors for subsequent cardiovascular and renal complications. Many patients are both diabetic and hypertensive, while they are obese, but not all diabetic patients have hypertension, indicating that insulin resistance is not only a mechanism for blood pressure elevation in diabetic-hypertensive patients. Several investigators have reported that sympathetic nervous activation relates to cardiovascular complications in patients with hypertension, diabetes, and obesity, and that sympathetic nerve activity accompanying insulin resistance is closely linked with left ventricular hypertrophy in healthy subjects. In addition, sympathetic nerve activation may predict future renal injury in healthy normotensive subjects. These findings suggest that elevated sympathetic nerve activity associated with insulin resistance may contribute to the onset and maintenance of cardiovascular and renal complications in diabetes, and hypertension in obesity. Further, genetic polymorphisms of the beta2- and beta3-adrenoceptor gene have been associated with type-2 diabetes and insulin resistance in many epidemiological studies and might be another factor responsible for the close relationship between insulin resistance and heightened sympathetic nerve activity. Thus, focusing on the interactions between insulin resistance, sympathetic nervous activity and beta-adrenoceptor polymorphisms might help in understanding the precise relationships between insulin resistance and sympathetic nerve activity in type 2 diabetes and obesity-related hypertension. The purpose of this article is to provide a synthesis of the current findings on the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, diabetes and hypertension. A better understanding of the relationships of sympathetic nervous system activity and insulin resistance might help with the clinical treatment of diabetes and hypertension in obesity. Further, to clarify the pathogenesis and mechanisms of the association between obesity, diabetes, and hypertension may lead to reductions in cardiovascular and renal risk.

Purpose of Review: The prevalence of obesity is rising to epidemic proportions worldwide, and in tandem so is that of type 2 diabetes. Neuroadrenergic abnormalities, comprising increased resting sympathetic nervous system activity and blunted sympathetic neural responsiveness are recognized features of metabolic syndrome obesity, which contribute importantly to both the pathophysiology and adverse clinical prognosis of this high-risk population. Weight loss is recommended as first-line treatment for obesity. This review examines the effects of nonpharmacological weight loss on sympathetic nervous system function under basal and stimulated conditions., Recent Findings: Human weight loss trials show that even moderate weight reduction is accompanied by significant attenuation in resting whole-body norepinephrine spillover rate and muscle sympathetic nerve activity, an improvement in cardiac autonomic modulation, and a reversal of blunted sympathetic responsiveness at both peripheral and central nervous system levels. Recent findings underscore the relevance of insulin resistance in mediating blunted sympathetic responsiveness to endogenous hyperinsulinemia induced by glucose ingestion. Impaired insulin transport across the blood-brain barrier may be one mechanism mediating these effects. Weight loss reverses blunted sympathetic responsiveness to glucose, which has implications for postprandial energy expenditure and body weight homeostasis., Summary: The autonomic dysfunction of obesity is reversible with weight loss, highlighting the importance of lifestyle intervention as a key therapeutic modality.

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.

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.

Leptin plays a key role in the regulation of body weight through the sympathetic nervous system; however, the contributions of leptin-receptor polymorphisms to obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between leptin-receptor polymorphisms, plasma leptin and whole-body norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.4-39.5 kg/m(2)), we measured leptin-receptor polymorphisms (Gln223Arg, Lys656Asn, and Lys109Arg), plasma leptin levels, whole-body NE spillover, whole-body NE clearance, BMI and blood pressure (BP) levels in the supine position after overnight fasting. Overweight-obese (BMI>or=25 kg/m(2)) subjects had significantly greater BMI, BP levels, plasma leptin and whole-body NE spillover compared to lean (BMI<25 kg/m(2)) subjects, but the NE clearance was similar. Overweight-obese subjects had significantly higher frequencies of the Arg223 allele and the Arg223 homozygous allele of Gln223Arg and the Asn656 allele of Lys656Asn compared to lean subjects. Subjects carrying the Arg223 homozygous or the Asn656 allele had higher levels of plasma leptin, BMI, waist circumference, and waist-to-hip ratio, but significantly less whole-body NE spillover, especially when they were also overweight-obese. BP levels and whole-body NE clearance were similar between subjects with and without the Arg223 homozygous or Asn656 allele. No differences were found in the distributions of the Arg109 allele of Lys109Arg polymorphism between nonobese and overweight-obese subjects. In addition, BMI, BP, plasma leptin levels, whole-body NE spillover and whole-body NE clearance were similar between those with and without the Arg109 allele. Together, these findings demonstrate that leptin-receptor polymorphisms were related to the incidence of obesity in a Caucasian male population. These polymorphisms were accompanied by high plasma leptin levels (leptin resistance) and lower whole-body plasma NE spillover (blunted sympathetic nerve activity). We therefore hypothesize that leptin-receptor play a role in the development of obesity through leptin resistance and blunted leptin-mediated sympathetic nerve activity.

Efforts to limit the impact of the coronavirus disease (COVID‐19) pandemic led to the implementation of public health measures and reallocation of health resources. To investigate trends in blood pressure (BP), hypertension and BMI in the Australian population during the COVID‐19 pandemic, data from publicly accessible health stations were analyzed. Average BP and BMI measured by the SiSU Health Station network in Australia in over 1.6 million health screenings were compared between the years 2018 and 2021. Additionally, paired trajectories for BP and BMI development before and during the COVID‐19 pandemic were calculated. Comparisons between pre‐COVID years and post‐COVID years of 2018 versus 2020, 2019 versus 2020, 2018 versus 2021, and 2019 versus 2021 showed increases in average adjusted systolic BP of 2.0, 1.7, 2.6, and 2.3 mmHg, respectively. Paired analysis of longitudinal data showed an overall increase in the trajectory of systolic BP of 3.2 mmHg between pre‐ and post‐COVID years. The prevalence of hypertension in users of the health stations increased by approximately 25% in the years 2020–2021. Similar trends were seen for BMI. Data from public Australian health stations indicated a strong trend toward higher BP during the COVID‐19 pandemic. At the population level, BP increments have been shown to markedly increase cardiovascular disease risk. Anti‐pandemic measures need to be carefully evaluated in terms of secondary public health effects and health support systems extended to effectively target cardiovascular risk. [ABSTRACT FROM AUTHOR]

Stress produces many physiological changes, some of which may contribute to the development of cardiovascular disease (CVD). Individuals with intellectual disability (ID) are exposed to multiple and stressful challenges everyday which may put them at increased cardiovascular risk. This current study aimed to establish whether adults with ID experience higher levels of subjective stress and encounter different stressors (including social isolation) than the general population, and whether there is a relationship between stress and cardiometabolic profile in this population. Adults with ID (n = 35) aged 18–45 years completed the Subjective Stress Survey, and underwent a physiological assessment to measure blood pressure, metabolic profile and subclinical CVD risk factors, and were compared to a control group (n = 29). Multiple regression was used to investigate whether cardiometabolic parameters were predicative of SSS scores. Findings showed adults with ID have higher perceived stress levels (total score ID: 21.3 ± 11.4 vs control: 13.9 ± 9.0, p = 0.006), which is elicited by unique stressors, when compared to people without ID. Stress was strongly associated with increased social isolation (r = −0.38, p = 0.002) and with obesity in females with mild ID (r = 0.72). Regression showed that arterial stiffness was predictive of total SSS score (p = 0.038). Adults with ID aged 18–45 years report higher levels of perceived stress when compared to people without ID. Reducing stress in this young population may prevent development of arterial stiffness, and consequently lower the risk of cardiometabolic morbidity and mortality. There are unique targets for stress management in young adults with intellectual disability, including supporting decision-making and improving self-efficacy. Improving community integration and reducing social isolation may decrease perceived stress in young adults with intellectual disability. [ABSTRACT FROM AUTHOR]

Introduction: To determine whether combined exercise training with an energy-restricted diet leads to improved physical fitness and body composition when compared to energy restriction alone in free-living premenopausal women with clinically severe obesity. Methods: Sixty premenopausal women (BMI of 40.4 ± 6.7) were randomised to energy restriction only (ER) or to exercise plus energy restriction (EXER) for 12 months. Body composition and fitness were measured at baseline, 3, 6 and 12 months. Results: VO2 peak improved more for EXER compared to ER at 3 (mean difference ± SEM 2.5 ± 0.9 mL ∙ kg–1 ∙ min–1, p = 0.006) and 6 (3.1 ± 1.2 mL ∙ kg–1 ∙ min–1, p = 0.007) but not 12 months (2.3 ± 1.6 mL ∙ kg–1 ∙ min–1, p = 0.15). Muscle strength improved more for EXER compared to ER at all time points. No differences between groups for lean mass were observed at 12 months. Conclusion: Combining exercise training with an energy-restricted diet did not lead to greater aerobic power, total body mass, fat mass or limit lean body mass loss at 12 months when compared to energy restriction alone for premenopausal women with clinically severe obesity in free-living situations. Future research should aim to determine an effective lifestyle approach which can be applied in the community setting for this high-risk group. [ABSTRACT FROM AUTHOR]

Summary: Objective: Polycystic ovary syndrome (PCOS) is associated with increased obesity with a greater propensity to weight gain and a lack of sustainable lifestyle interventions. Altered brown adipose tissue (BAT) thermogenesis is a potential contributor to obesity in PCOS. BAT activity and modulation have not been studied in PCOS. This observational study explored BAT thermogenesis and its associations in women with and without PCOS. Participants and methods: Cutaneous temperature was recorded from supraclavicular (indicator of BAT activity) and upper arm regions using dataloggers (SubCue, Calgary, Canada) in a cross‐sectional substudy, nested within a randomized control trial, of community‐recruited premenopausal women with (n = 47, Rotterdam diagnostic criteria) and without (n = 11) PCOS. Results: Complete temperature data were available in 44 PCOS (mean age: 30.0 ± 6.2, mean BMI: 29.3 ± 5.5) and 11 non‐PCOS (mean age: 33.0 ± 7.0, mean BMI: 25 ± 3) women. Women with PCOS had lower supraclavicular skin temperature compared to controls overall (33.9 ± 0.7 vs 34.5 ± 1, P < 0.05) and during sleep (34.5 ± 0.6 vs 35.2 ± 0.9, P < 0.001). In the PCOS group, supraclavicular skin temperature overall and over sleep and waking hours correlated inversely with testosterone (r = −0.41 P < 0.05, r = −0.485 P < 0.01 and r = −0.450 P < 0.01 respectively). Testosterone levels explained approximately 15%, 30% and 20% of the variability in supraclavicular skin temperature overall and over sleep and waking hours in women with PCOS, respectively. Conclusion: Women with PCOS have lower BAT activity compared to controls. BAT thermogenesis is negatively associated with androgen levels in PCOS. [ABSTRACT FROM AUTHOR]

Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity. Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH). Methods: Fifty seven patients with RH undergoing RDN program have been included in this study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m2, mean ± SEM). Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs. 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs. 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs. 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs. 0.47 ± 0.04 mEq/l, p < 0.001). Adiponectin concentration was significantly higher after RDN (5,654 ± 800 vs. 6,644 ± 967 ng/ml, p = 0.024). Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways. [ABSTRACT FROM AUTHOR]

Background: Neck circumference (NC) is a predictor of cardiometabolic risk. The objective of this study was to explore the relationship of NC to muscle sympathetic nerve activity (MSNA) within an overweight and obese population. Methods: The study design was a retrospective cross-sectional analysis. Un-medicated persons (72 men, 53 postmenopausal women) aged 56 ± 1 years (mean ± SEM) with body mass index (BMI) 32.8 ± 0.4 kg/m2, were studied. NC was measured together with traditional anthropometric measures, supine blood pressure, fasting blood lipids, insulin, and glucose. Insulin sensitivity was assessed by homeostasis model (HOMA-IR) and Matsuda Insulin Sensitivity Index (ISI) derived from 75-g oral glucose tolerance test. Resting multiunit MSNA was recorded by microneurography in the peroneal nerve and expressed as burst frequency and burst incidence. Results: Men within the highest tertile of NC had significantly higher fasting and post-glucose plasma insulin levels (insulin AUC0-120), HOMA-IR, non-esterified fatty acids, MSNA (45 ± 2 vs. 36 ± 2 bursts per min; 69 ± 3 vs. 58 ± 3 bursts per 100 hb) and heart rate, and lower Matsuda ISI compared to men in the lowest tertile (P all <0.05). In stepwise regression analyses, NC alone explained 12%, and together with insulin AUC0-120 it accounted for 22%, of the variance in MSNA in men. In women, NC was associated with anthropometric measures but not with MSNA or metabolic indices. Conclusions: Among overweight and obese men, NC was independently associated with elevated MSNA and hyperinsulinemia, and thus may be relevant to cardiometabolic risk prediction. The biological basis of gender differences merits further elucidation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Elevated sympathetic nervous system (SNS) activity is a characteristic of obesity and type 2 diabetes (T2D) that contributes to target organ damage and cardiovascular risk. In this study we examined whether baseline metabolic status influences the degree of sympathoinhibition attained following equivalent dietary weight loss. Methods: Un-medicated obese individuals categorized as normal glucose tolerant (NGT, n = 15), impaired glucose tolerant (IGT, n = 24), and newly-diagnosed T2D (n = 15) consumed a hypocaloric diet (29% fat, 23% protein, 45% carbohydrate) for 4-months. The three groups were matched for baseline age (56 ± 1 years), body mass index (BMI, 32.9 ± 0.7 kg/m²), and gender. Clinical measurements included whole-body norepinephrine kinetics, muscle sympathetic nerve activity (MSNA, by microneurography), spontaneous cardiac baroreflex sensitivity (BRS), and oral glucose tolerance test. Results: Weight loss averaged -7.5 ± 0.8, -8.1 ± 0.5, and -8.0 ± 0.9% of body weight in NGT, IGT, and T2D groups, respectively. T2D subjects had significantly greater reductions in fasting glucose, 2-h glucose and glucose area under the curve (AUC0-120) compared to NGT and IGT (group effect, P < 0.001). Insulinogenic index decreased in IGT and NGT groups and increased in T2D (group x time, P = 0.04). The magnitude of reduction in MSNA (-7 ± 3, -8 ± 4, -15 ± 4 burst/100 hb, respectively) and whole-body norepinephrine spillover rate (-28 ± 8, -18 ± 6, and -25 ± 7%, respectively), time effect both P < 0.001, did not differ between groups. After adjustment for age and change in body weight, Δ insulin AUC0-120 was independently associated with reduction in arterial norepinephrine concentration, whilst Δ LDL-cholesterol and improvement in BRS were independently associated with decrease in MSNA. Conclusions: Equivalent weight loss through hypocaloric diet is accompanied by similar sympathoinhibition in matched obese subjects with different baseline glucose tolerance. Attenuation of hyperinsulinemia and hyperlipidemia, rather than glycemic indices, is associated with reduction in SNS activity following weight loss intervention. [ABSTRACT FROM AUTHOR]

Background Bioelectrical impedance analysis (BIA) is well tolerated, inexpensive, and readily available, but can it be used to detect with clinical precision aberrant changes in the proportion of fat mass to fat-free mass during weight loss? Objectives To assess the variance in percentage body fat mass explained by the readily available inputs and assess residual variance provided by leg-to-leg BIA scales. Methods Using cross-sectional data from a cohort of 665 patients of Indian ethnicity presenting for bariatric surgery, we examine the determinants of percentage body fat as provided by leg-to-leg output from Tanita SC-330 BIA scales. Results Four input factors—sex, weight, height, and age—contributed to provide 92% and 95% explanation in output variance for percentage fat mass (%FM) and actual fat mass, respectively, in 665 patients. Body mass index alone explained 89% and 81% of variance in %FM output for women and men, respectively. Neither weight distribution, as indicated by waist and hip circumference or waist to hip ratio, nor plasma lipids or markers of glucose metabolism contributed additional variance in %FM when controlled for the 4 key inputs. Conclusions Simple, known input variables dominate the leg-to-leg BIA output of %FM, and this may compromise the detection of aberrant changes in %FM and fat-free mass with substantial weight loss. For clinical research, validated methods not largely dependent on known inputs should be used for evaluating changes in body composition after substantial weight loss. [ABSTRACT FROM AUTHOR]

BACKGROUND Obesity is associated with elevated cardiovascular mortality, which may be attributed, in part, to sympathetic nervous system (SNS) activation and an associated poor metabolic profile. We examined the effects of laparoscopic adjustable gastric band (LAGB) on SNS activity and cardiovascular profile when the initial weight loss of 10%, corresponding to the recommendation of clinical guidelines, was reached. METHODS Direct muscle sympathetic nerve activity (MSNA, microneurography), baroreflex function, and cardiovascular profile were examined before and after a predetermined weight loss of 10% in 23 severely obese nondiabetic individuals. RESULTS The 10% weight loss was achieved at an average of 7.3±1.4 months (range = 1.3–23.3 months). This was associated with significant improvement in office systolic and diastolic blood pressure (BP) (−12mm Hg and −5mm Hg, respectively), a decrease in MSNA (33±3 to 22±3 bursts per minute), improvement in cardiac (16±3 to 31±4ms/mm Hg) and sympathetic (−2.23±0.39 to −4.30±0.96 bursts/100 heartbeats/mm Hg) baroreflex function, total cholesterol (5.33±0.13 to 4.97±0.16 mmol/L), fasting insulin (29.3±2.4 to 19.6±1.1 mmol/L), and creatinine clearance (172±11 to 142±8ml/min). None of the cardiovascular risk improvement related to the rate of weight loss. The change in systolic and diastolic BP correlated with change in waist circumference (r = 0.46, P = 0.04; r = 0.50, P = 0.02, respectively). CONCLUSIONS The initial 10% weight loss induced by LAGB was associated with substantial hemodynamic, metabolic, SNS, and renal function improvements. Changes in waist circumference appear to be an important factor contributing to BP adaptation after LAGB surgery. [ABSTRACT FROM AUTHOR]

This article provides a detailed review of the association of major depression with coronary heart disease (CHD), examines the biological variables underpinning the linkage and discusses the clinical implications for treatment. When considering the co-morbidity between major depressive disorder (MDD) and CHD it is important to differentiate between (i) the prevalence and impact of MDD in those with existing CHD and (ii) MDD as a risk factor for the development of CHD. Whether the same biological mechanisms are at play in these two instances remains unknown. Depression is common in patients with CHD. Importantly, depression in these patients increases mortality. There is also consistent evidence that MDD is a risk factor for the development of CHD. The relative risk of developing CHD is proportional to the severity of depression and is independent of smoking, obesity, hypercholesterolaemia, diabetes mellitus and hypertension. There is a clear need to identify the underlying neurochemical mechanisms responsible for MDD and their linkage to the heart and vascular system. Of particular interest are activation of stress pathways, including both the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, and inflammatory-mediated atherogenesis. Elevated sympathetic activity, reduced heart rate variability and increased plasma cortisol levels have been documented in patients with MDD. In addition to direct effects on the heart and vasculature, activation of stress pathways may also be associated with increased release of inflammatory cytokines such as interleukin-6 and tumour necrosis factor-α. Elevated levels of C-reactive protein are commonly observed in patients with MDD. The majority of investigations examining treatment of depression following myocardial infarction have focused on safety and efficacy; there is little evidence to indicate that treating depression in these patients improves survival. Given that strategies for preventive therapy remain incompletely formulated, future research should focus on generating a better understanding of the neurobiology of MDD and heart disease as a basis for rational and effective therapy. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species—in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify individual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. Individually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins. [ABSTRACT FROM AUTHOR]

Objectives: It is well demonstrated that there is a higher prevalence of hypertension (HT) in patients with type 2 diabetes (T2DM) than non-DM individuals as well as higher prevalence of DM in HT than normotensives (NT). However, it has not been clarified which of DM or HT leads to other, and what mechanisms may play a major role. Methods: In the present study, we compared neurohormonal parameters in the following 4 groups in weight loss (WL) program with a mild calorie restriction and exercise over 12 weeks; 53 obese NT without DM, 44 NT with T2DM, 68 HT without DM, and 43 HT with T2DM. HT and T2DM were all diagnosed in the last 3 months and none had medications. At entry period, the 4 groups were strictly matched in BMI and in BP. They were measured BMI, total body fat-mass, waist/hip ratio (W/H), BP, PR, HbA1c, fasting glucose, insulin (HOMA-IR), norepinephrine (NE) and leptin (LEP) at entry, 4 and 12 weeks. Results: At entry, fat-mass was greater in subjects with T2DM than non-DM in both NT and HT and HT had slightly greater fat-mass than NT, although BMI were strictly matched in the 4 study groups. HbA1c in T2DM was greater than non-DM, and slightly greater in HT than NT. Fasting insulin was greater in HT and T2DM than NT or non-DM, and HOMA-IR was slightly greater in HT than NT and significantly greater in T2DM than non-DM. LEP was similar between NT and HT, but it was greater in T2DM than non-DM. (HbA1c, HT with T2DM>NT with T2DM>>HT without DM>NT without DM; Insulin, HT with T2DM>NT with T2DM>>HT without DM>NT without DM; NE, HT with T2DM>>HT without DM=NT with T2DM>>NT without DM; LEP, HT with T2DM?NT with T2DM>>HT without DM>NT without DM). WL over 12 wks in HT and T2DM were smaller than those in NT or non-DM. At 12 weeks, in HT groups regardless of T2DM, percent (%) decreases in plasma NE and BP, and reductions in HbA1c were smaller than those in NT groups, although reductions in fat-mass and leptin were similar. In T2DM groups regardless of BP levels at entry, reductions in BMI, BP, HbA1c, HOMA-IR and NE were smaller than those in non-DM group. In the 4 groups, reductions in plasma NE was observed at first followed by reductions in HOMA-IR, HbA1c, BMI and BP over 12 weeks. Conclusions: These findings demonstrate that insulin resistance (IR) may play an important role on the onset of T2DM and high plasma NE appears to cause HT. HT had resistance to normalized high plasma NE and %reductions in NE, and T2DM had resistance to normalize IR and sympathetic overactivity. We previously reported that high plasma NE could predict future weight gain and BP elevation, and high NE preceded IR in non-obese subjects. Taken together, sympathetic overactivity observed in high NE may cause obesity and HT, and then IR seems to start with weight gain leading T2DM, suggesting that HT may lead to T2DM with this mechanisms. [ABSTRACT FROM AUTHOR]