Weight Loss and Exercise Alter the High-Density Lipoprotein Lipidome and Improve High-Density Lipoprotein Functionality in Metabolic Syndrome.

OBJECTIVE: High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. APPROACH AND RESULTS: Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. CONCLUSIONS: WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943.

Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.

Interrupting prolonged sitting in type 2 diabetes: nocturnal persistence of improved glycaemic control.

AIMS/HYPOTHESIS: We aimed to examine the effect of interrupting 7 h prolonged sitting with brief bouts of walking or resistance activities on 22 h glucose homeostasis (including nocturnal-to-following morning hyperglycaemia) in adults with type 2 diabetes. METHODS: This study is an extension of a previously published randomised crossover trial, which included 24 inactive overweight/obese adults with type 2 diabetes (14 men; 62 ± 6 years) who completed three 7 h laboratory conditions, separated by 6-14 day washout periods: SIT: (1) prolonged sitting (control); (2) light-intensity walking (LW): sitting plus 3 min bouts of light-intensity walking at 3.2 km/h every 30 min; (3) simple resistance activities (SRA): sitting plus 3 min bouts of simple resistance activities (alternating half-squats, calf raises, brief gluteal contractions and knee raises) every 30 min. In the present study, continuous glucose monitoring was performed for 22 h, encompassing the 7 h laboratory trial, the evening free-living period after leaving the laboratory and sleeping periods. Meals and meal times were standardised across conditions for all participants. RESULTS: Compared with SIT, both LW and SRA reduced 22 h glucose [SIT: 11.6 ± 0.3 mmol/l, LW: 8.9 ± 0.3 mmol/l, SRA: 8.7 ± 0.3 mmol/l; p < 0.001] and nocturnal mean glucose concentrations [SIT: 10.6 ± 0.4 mmol/l, LW: 8.1 ± 0.4 mmol/l, SRA: 8.3 ± 0.4 mmol/l; p < 0.001]. Furthermore, mean glucose concentrations were sustained nocturnally at a lower level until the morning following the intervention for both LW and SRA (waking glucose both -2.7 ± 0.4 mmol/l compared with SIT; p < 0.001). CONCLUSIONS/INTERPRETATION: Interrupting 7 h prolonged sitting time with either LW or SRA reduced 22 h hyperglycaemia. The glycaemic improvements persisted after these laboratory conditions and nocturnally, until waking the following morning. These findings may have implications for adults with relatively well-controlled type 2 diabetes who engage in prolonged periods of sitting, for example, highly desk-bound workers. TRIAL REGISTRATION: anzctr.org.au ACTRN12613000576729 FUNDING: : This research was supported by a National Health and Medical Research Council (NHMRC) project grant (no. 1081734) and the Victorian Government Operational Infrastructure Support scheme.

Should the sympathetic nervous system be a target to improve cardiometabolic risk in obesity?

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.

Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance.

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.

Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss.

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.

Advanced glycation end products (AGEs) are cross-sectionally associated with insulin secretion in healthy subjects.

It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6-31.0 kg/m(2)). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43; p < 0.05) and lower 2-h glucose concentrations during OGTT (r = -0.31; p < 0.05). In addition, fasting (r = -0.36; p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = -0.39; p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure.

BACKGROUND: High levels of circulating advanced glycation end products (AGEs) can initiate chronic low-grade activation of the immune system (CLAIS) with each of these factors independently associated with cardiovascular (CV) morbidity and mortality. Therefore, our objective was to characterize the relationship between serum AGEs, CLAIS and other risk factors for CV disease in normotensive non-diabetic individuals. METHODS: We measured body mass index (BMI), waist-to-hip ratio (WHR), blood pressure, lipid and glucose profile in 44 non-diabetic volunteers (17 female, 27 males). Carboxymethyl-lysine (CML) was measured by ELISA as a marker for circulating AGEs and NF-κB p65 activity as an inflammatory marker by DNA-binding in peripheral blood mononuclear cells lysates (PBMC). RESULTS: Plasma CML concentrations were related to diastolic blood pressure (r=-0.51, p<0.01) independently of age, sex, BMI and WHR (p<0.05). Diastolic blood pressure was also related to NF-κB activity in PBMC (r=0.47, p<0.01) before and after adjustment for age, sex, BMI and WHR (p<0.05). Plasma CML concentrations were related to the pulse pressure before (r=0.42; p<0.05) and after adjustment for age, sex, BMI and waist (p<0.05). Neither CML nor NF-κB activity were related to systolic blood pressure (both p=ns). Plasma CML concentrations were not associated with plasma lipid or glucose concentrations (all p=ns). CONCLUSIONS: Plasma AGE levels and NF-κB activity in PBMC were independent determinants of diastolic and pulse pressure in healthy normotensive individuals. This association suggests a role for AGEs in the etiology of hypertension, possibly via the initiation of CLAIS and aortic stiffening.

A sympathetic view of human obesity.

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 dysfunction in obesity: an overview of the effects of weight loss.

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.

Plasma lipocalin-2/NGAL is stable over 12 weeks and is not modulated by exercise or dieting.

Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18-55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention (r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise.

Comparison of endothelial function and sympathetic nervous system activity along the glucose continuum in individuals with differing metabolic risk profiles and low dietary sodium intake.

OBJECTIVE: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and SNS activity in individuals with low sodium intake and differing categories of metabolic risk along the glucose continuum. We hypothesized that low sodium intake is associated with (1) impairment of endothelial function and (2) higher SNS activity in individuals with higher metabolic risk. RESEARCH DESIGN AND METHODS: In this prospective observational study, participants (n=54) with low sodium intake (single 24 hours urine sodium excretion <150 mmol/24 hours) were categorized based on oral glucose tolerance testing as: normal glucose tolerance (NGT, n=10), impaired glucose tolerance (IGT, n=15), treatment naive type 2 diabetes (T2D-) (n=12) or treated type 2 diabetes (T2D+) (n=17). We assessed endothelial function using pulse amplitude tonometry (PAT) derived reactive hyperemic index and PAT ratio; arterial stiffness via augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; glycosylated hemoglobin A1c (HbA1c) and lipid profile. RESULTS: Mean (SD) sodium excretion was 110.6 (26) mmol/24 hours. Compared with NGT, IGT and T2D-, the T2D+ group had lower MSNA (p=0.005), PAT ratio (p=0.04) and baroreflex sensitivity (p=0.0002) and an augmented heart rate (p=0.02). The T2D+ group had appropriate mean (SD) glycemic (HbA1c 7.2 (1.72)%), total cholesterol (4.2 (1.0) mmol/L), low-density lipoprotein (2.2 (1.0) mmol/L) and blood pressure (systolic 136 (13), diastolic 78 (12)) (mm Hg) control. CONCLUSIONS: Individuals with T2D+ have impaired endothelial and baroreflex function, despite low sodium intake, appropriately managed cardiometabolic risk factors and lower SNS activity, compared with others along the glucose continuum. Whether low sodium intake is associated with modulation of the sympathovascular profile in T2D requires further investigation.

Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population.

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.

Mediators of sympathetic activation in metabolic syndrome obesity.

The metabolic syndrome represents a major public health burden because of its high prevalence in the general population and its association with cardiovascular disease and type 2 diabetes. Accumulated evidence based on biochemical, neurophysiologic, and indirect measurements of autonomic activity indicate that visceral obesity and the metabolic syndrome are associated with enhanced sympathetic neural drive and vagal impairment. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not completely understood, and cause-effect relationships need further clarification from prospective trials. Components of the metabolic syndrome that may directly or indirectly enhance sympathetic drive include hyperinsulinemia, leptin, nonesterified fatty acids, proinflammatory cytokines, angiotensinogen, baroreflex impairment, and obstructive sleep apnea. beta-Adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic activity. Because chronic sympathetic activation contributes to hypertension and its target-organ damage, sympathoinhibition remains an important goal in the therapeutic management of the metabolic syndrome.

Serum uric acid and the relationship with subclinical organ damage in adults.

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 ±â€Š0.8 years, mean BMI: 33.2 ±â€Š0.5 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.

Markers of sympathetic nervous system activity associate with complex plasma lipids in metabolic syndrome subjects.

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, GM3 ganglioside, sphingomyelin, phosphatidylcholine, alkyl- and alkenylphosphatidylcholine, phosphatidylinositol and free cholesterol; HR marginally (p = or <0.1>0.05) with ceramide, GM3 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.

Effects of Moxonidine and Low-Calorie Diet: Cardiometabolic Benefits from Combination of Both Therapies.

OBJECTIVE: Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both. METHODS: Young (18-30 years) male subjects with overweight (BMI > 25 kg/m2 ) were allocated to a WL program (n = 10), a moxonidine treatment course (M; n = 10, 0.4 mg/d), a combination of both (WL + M; n = 11), or to a control (C) group (n = 6) for 6 months. Muscle sympathetic nerve activity (MSNA), endothelial function, renal function (Cockcroft-Gault formula), and the metabolic profile were assessed before and after intervention. RESULTS: WL occurred in the WL and WL + M groups (-7.6 ± 1.9 kg, P < 0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL + M groups (by ∼10 bursts/min, P < 0.001, and by ∼9 mm Hg, P < 0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL + M group, decreased total cholesterol (-0.78 ± 0.23 mmol/L, P < 0.001), decreased low-density lipoprotein cholesterol (-0.49 ± 0.16 mmol/L, P < 0.01), decreased insulin (-6.5 ± 2.8 mmol/L, P < 0.05), and attenuated glomerular hyperfiltration (-19 ± 5 mL/min, P < 0.01) occurred. CONCLUSIONS: The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight.

Neck Circumference Is Associated with Muscle Sympathetic Nerve Activity in Overweight and Obese Men but Not Women.

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.

Muscle Sympathetic Nerve Activity Is Associated With Elements of the Plasma Lipidomic Profile in Young Asian Adults.

Background: Asian subjects are at increased cardio-metabolic risk at comparatively lower body mass index (BMI) compared with white subjects. Sympathetic nervous system activation and dyslipidemia, both characteristics of increased adiposity, appear to be related. We therefore analyzed the association of muscle sympathetic nerve activity (MSNA) with the plasma lipidomic profile in young adult Asian and white subjects. Methods: Blood samples were collected from 101 participants of either Asian or white background (age, 18 to 30 years; BMI, 28.1 ± 5.9 kg/m2). Lipids were extracted from plasma and analyzed using electrospray ionization-tandem mass spectrometry. MSNA was quantified using microneurography. The association of MSNA and obesity with lipid species was examined using linear regression analysis. Results: The plasma concentrations of total dihydroceramide, ceramide, GM3 ganglioside, lysoalkylphosphatidylcholine, alkenylphosphatidylethanolamine, and lysophosphatidylinositol were elevated in the Asian subjects relative to the white subjects. After adjustment for confounders, diacylglycerols and triacylglycerols, cholesterol esters, phosphatidylinositols, phosphatidylethanolamines, and phosphatidylglycerols bore significant associations with MSNA but only in the Asian subjects. These associations remained significant after further adjustment for the participants' degree of insulin resistance and appeared not to be related to differences in diet macronutrient content between groups. Conclusions: The lipidomic profile differs between Asian and white subjects. There exists a strong relationship between certain lipid species and MSNA. The association is stronger in Asian subjects, despite their lower BMI. This study demonstrates an association between circulating lipids and central sympathetic outflow. Whether the stronger association between the lipid profile and sympathetic activation underpins the apparent greater risk posed by increased adiposity in Asian individuals merits further attention.