The Effects of Weight Loss Versus Weight Loss Maintenance on ...

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The Effects of Weight Loss Versus Weight Loss Maintenance on Sympathetic Nervous System Activity and Metabolic Syndrome Components Nora E. Straznicky, Mariee T. Grima, Nina Eikelis, Paul J. Nestel, Tye Dawood, Markus P. Schlaich, Reena Chopra, Kazuko Masuo, Murray D. Esler, Carolina I. Sari, Gavin W. Lambert, and Elisabeth A. Lambert Laboratories of Human Neurotransmitters (N.E.S., M.T.G., G.W.L., T.D., R.C., K.M., M.D.E., C.I.S., E.A.L.), Neurovascular Hypertension and Kidney Disease (N.E., M.P.S.), and Cardiovascular Nutrition (P.J.N.), Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 8008, Australia; and Faculty of Medicine, Nursing, and Health Sciences (G.W.L., M.P.S.), and the Department of Physiology (E.A.L., M.D.E.), Monash University, Melbourne, Victoria 3800, Australia

Context: Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity. Objective: We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components. Methods: Untreated subjects (14 males, four females; mean age, 53 ⫾ 1 yr; body mass index, 30.9 ⫾ 0.9 kg/m2) who fulfilled Adult Treatment Panel III criteria were randomized to 12-wk hypocaloric diet alone (n ⫽ 8) or together with aerobic exercise training (n ⫽ 10). This was followed by a 4-month weight maintenance period. Measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics, substrate oxidation by indirect calorimetry, baroreflex sensitivity, plasma renin activity (PRA), and MetS components were performed. Results: Body weight decreased by 9.3 ⫾ 0.8% at wk 12 (P ⬍ 0.001), and this was maintained. During active weight loss, norepinephrine spillover rate decreased by 23 ⫾ 16% (P ⫽ 0.004), MSNA by 25 ⫾ 3 bursts per 100 heartbeats (P ⬍ 0.001), and PRA by 0.25 ⫾ 0.09 ng/ml 䡠 h (P ⫽ 0.007), whereas baroreflex sensitivity increased by 5.2 ⫾ 2.2 msec/mm Hg (P ⫽ 0.005). After weight maintenance, beneficial effects of weight loss on norepinephrine spillover rate were preserved, whereas PRA and MSNA rebounded (by 0.24 ⫾ 0.11 ng/ml 䡠 h, P ⫽ 0.02; and 20 ⫾ 5 bursts/100 heartbeats, P ⫽ 0.0003), and baroreflex sensitivity was attenuated. Conclusions: Divergent effects of successful weight loss maintenance on whole-body norepinephrine spillover rate and MSNA suggest organ-specific differentiation in SNS adaptation to weight loss under conditions of negative vs. stable energy balance. (J Clin Endocrinol Metab 96: E503–E508, 2011)

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ollective data from epidemiological, clinical, and animal studies indicate that perturbations in neuroadrenergic function play a key role in the genesis and progression of the metabolic syndrome (MetS) and its related cardiometabolic risk (1). This is perhaps not surprising given the homeostatic importance of the sympathetic ner-

vous system (SNS) in regulating energy balance under both basal and stimulated (exercise, food intake, stress) conditions via effects on resting metabolic rate, facultative thermogenesis, and glucose and fat metabolism (2). Current evidence regarding cause-effect relationships suggests that elevated plasma norepinephrine concentrations predict

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2010-2204 Received September 17, 2010. Accepted December 1, 2010. First Published Online December 22, 2010

Abbreviations: CRP, C reactive protein; MetS, metabolic syndrome; MSNA, muscle sympathetic nerve activity; NEFA, nonesterified fatty acids; PRA, plasma renin activity; SNS, sympathetic nervous system; WL, weight loss alone; WL ⫹ EX, weight loss plus exercise.

J Clin Endocrinol Metab, March 2011, 96(3):E503–E508

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Weight Loss and Weight Loss Maintenance

future rise in body mass index and insulin resistance (3), likely through desensitization of the ␤-adrenergic signaling pathway (1, 4). In established obesity, metabolic, hemodynamic, and medical (obstructive sleep apnea) factors contribute to sustained elevation in sympathetic tone, hence establishing a vicious cycle, which in the longerterm leads to target organ damage and a worse clinical prognosis (1, 5). All guidelines recommend weight loss and exercise as first-line treatments for the MetS (1). Typically, weight management strategies include an initial calorie restriction phase followed by longer-term weight loss maintenance. Published data indicate that active weight loss is more effective than maintaining a lower stable weight in regard to insulin sensitivity, lipoprotein profile, and plasma leptin and triacylglycerol concentrations (6, 7), whereas Creactive protein (CRP) and other inflammatory markers are less influenced by change in energy balance, but rather respond to body fat reduction (8). There is, however, a paucity of data with respect to autonomic function. Laaksonen et al. (9) demonstrated that the increase in cardiac parasympathetic tone and spontaneous baroreflex sensitivity and the reduction in ambulatory blood pressure during active weight loss were significantly attenuated after 4 months of weight loss maintenance. An earlier study in obese hypertensive subjects failed to find a consistent effect of energy restriction vs. weight reduction on venous norepinephrine concentration and 24-h urinary catecholamines (10). In the present study, we have applied the techniques of microneurography and isotope dilution to respectively measure postganglionic sympathetic nervous outflow to skeletal muscle vasculature and whole-body norepinephrine spillover in a group of untreated obese MetS subjects undergoing lifestyle interventions. The primary aim was to elucidate the discrete effects of active weight loss and weight loss maintenance on SNS activity.

Subjects and Methods Subjects Subjects aged 45– 65 yr who fulfilled Adult Treatment Panel III MetS criteria were studied. They were participating in a larger randomized controlled trial of the effects of lifestyle interventions on autonomic function (11). At the end of this trial, those in active treatment arms who lost more than 5% body weight were offered the option of continuing in a weight loss maintenance program. Exclusion criteria were history of type 2 diabetes, cardiovascular or thyroid diseases, and further weight loss or weight regain in excess of ⫾1.5 kg after initial weight loss. All subjects were untreated and gave written informed consent. The study was approved by the Alfred Hospital Ethics Committee.


Study design Qualifying participants were randomized to 12-wk dietary weight loss alone (WL) or together with aerobic exercise (WL⫹EX). A moderate hypocaloric diet (2500 kJ daily energy restriction) based on the Dietary Approaches to Stop Hypertension (DASH) eating pattern was used as the background diet (22% protein, 30% fat, and 48% carbohydrate). Exercise training comprised bicycle riding on alternate days for 40 min per session at 65% of maximum heart rate (11). During the 4-month weight maintenance phase, caloric intake was increased to stabilize energy balance. Subjects were encouraged to maintain the DASH diet and received general advice regarding exercise. They were monitored at 3-weekly visits. Investigations were performed at baseline and at the end of 12-wk active weight loss and 4-month weight loss maintenance.

Clinical investigations Subjects were studied after an overnight fast, having abstained from caffeine for 18 h and alcohol and exercise for 36 h. They collected a 24-h urine specimen immediately before attendance. Anthropometric measurements included a dualenergy x-ray absorptiometry scan (GE-LUNAR Prodigy Advance PA⫹130510; GE Medical Systems, Lunar, Madison, WI) (11, 12). Indirect calorimetry was performed over 30 min with breath-by-breath analysis of respiratory gases (Quark b2; Cosmed, Rome, Italy). Values were averaged, and energy expenditure and substrate oxidation were calculated (13). Fasting blood samples were obtained after a 30-min supine rest for the measurement of metabolic parameters and plasma renin activity (PRA).

SNS activity Whole-body norepinephrine kinetics were studied by the isotope dilution technique, which quantifies the dynamic processes of norepinephrine spillover into and clearance from the central plasma compartment (14). Tracer doses of 1-[ring-2,5,6-3H]norepinephrine (Perkin-Elmer, Wellesley, MA; specific activity, 0.37–1.11 mBq/mmol) were administered iv by constant infusion rate of 3.92 kBq 䡠 m2 䡠 min⫺1, after a priming bolus. Steadystate blood samples were obtained from the brachial artery for measurement of endogenous and [3H]norepinephrine. Clearance (liters/minute) and spillover rates (nanograms/minute) were calculated (11, 14). Multiunit microneurographic recordings of resting efferent vasoconstrictor sympathetic nerve traffic [muscle sympathetic nerve activity (MSNA)] were made from a nerve fascicle in the right peroneal nerve at the fibular head, as previously described (11). Resting measurements were recorded over a 15-min period and averaged. Sympathetic bursts were counted manually and expressed as burst incidence (bursts/100 heartbeats).

Spontaneous cardiac baroreflex sensitivity Baroreflex sensitivity was assessed by the sequence method (15), which identifies a series of three or more consecutive heartbeats in which systolic blood pressure either increased or decreased. The slope of the regression line between cardiac interval and systolic blood pressure was calculated and averaged for validated sequences over a 15-min supine recording. Subjects then underwent a 75-g oral glucose (Glucaid; Lomb Scientific, Taren Point, NSW, Australia) tolerance test. Whole-



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TABLE 1. Demographic and clinical variables at baseline and at the end of 12-wk active weight loss and 4-month weight loss maintenance in the whole-group and lifestyle intervention subgroups P value

n Age (yr) Gender (M/F) Weight (kg) Baseline 12 wk 7 months Body mass index (kg/m2) Baseline 12 wk 7 months Waist (cm) Baseline 12 wk 7 months Fasting TG (mM/liter) Baseline 12 wk 7 months NEFA (mEq/liter) Baseline 12 wk 7 months HDL-C (mM/liter) Baseline 12 wk 7 months Fasting glucose (mM/liter) Baseline 12 wk 7 months Whole-body SI Baseline 12 wk 7 months Leptin (ng/ml) Baseline 12 wk 7 months hs-CRP (mg/liter) Baseline 12 wk 7 months PRA (ng/ml 䡠 h) Baseline 12 wk 7 months Uric acid (mM/liter) Baseline 12 wk 7 months Systolic BP (mm Hg) Baseline 12 wk 7 months Diastolic BP (mm Hg) Baseline 12 wk 7 months Heart rate (bpm) Baseline 12 wk 7 months

Whole-group

WL

WL ⴙ EX

18 53 ⫾ 1 14/4

8 54 ⫾ 2 6/2

10 52 ⫾ 1 8/2

93.2 ⫾ 2.7 84.3 ⫾ 2.2c 83.9 ⫾ 2.3c

91.4 ⫾ 3.5 84.6 ⫾ 2.7c 84.8 ⫾ 2.7c

94.6 ⫾ 4.0 84.2 ⫾ 3.5c 83.2 ⫾ 3.6c

30.9 ⫾ 0.9 28.0 ⫾ 0.8c 27.9 ⫾ 0.8c

30.6 ⫾ 1.4 28.3 ⫾ 1.1c 28.4 ⫾ 1.1c

31.2 ⫾ 1.1 27.8 ⫾ 1.1c 27.5 ⫾ 1.2c

104.9 ⫾ 1.9 95.4 ⫾ 1.9c 95.0 ⫾ 1.9c

104.3 ⫾ 2.6 97.4 ⫾ 2.3c 98.2 ⫾ 2.2c

105.5 ⫾ 2.8 93.8 ⫾ 2.9c 92.5 ⫾ 2.8c

2.3 ⫾ 0.3 1.4 ⫾ 0.2c 1.3 ⫾ 0.2c

2.4 ⫾ 0.7 1.6 ⫾ 0.4c 1.5 ⫾ 0.3c

2.2 ⫾ 0.3 1.3 ⫾ 0.2c 1.3 ⫾ 0.1c

0.56 ⫾ 0.04 0.55 ⫾ 0.05 0.51 ⫾ 0.06a

0.60 ⫾ 0.06 0.55 ⫾ 0.07 0.50 ⫾ 0.08

0.54 ⫾ 0.06 0.54 ⫾ 0.08 0.52 ⫾ 0.08

1.22 ⫾ 0.07 1.17 ⫾ 0.06 1.26 ⫾ 0.06

1.26 ⫾ 0.11 1.21 ⫾ 0.08 1.28 ⫾ 0.09

1.18 ⫾ 0.09 1.14 ⫾ 0.08 1.25 ⫾ 0.10d

5.5 ⫾ 0.1 5.0 ⫾ 0.1c 4.9 ⫾ 0.1c

5.4 ⫾ 0.2 5.0 ⫾ 0.2 4.9 ⫾ 0.1

5.7 ⫾ 0.2 5.0 ⫾ 0.2c 4.9 ⫾ 0.1c

2.77 ⫾ 0.29 4.40 ⫾ 0.60c 4.30 ⫾ 0.55c

2.34 ⫾ 0.25 3.66 ⫾ 0.71c 3.61 ⫾ 0.56c

3.11 ⫾ 0.46 5.00 ⫾ 0.91c 4.85 ⫾ 0.87c

12.7 ⫾ 2.6 6.4 ⫾ 1.4c 6.5 ⫾ 1.4c

15.9 ⫾ 4.8 7.5 ⫾ 2.3c 8.4 ⫾ 2.2c

10.2 ⫾ 2.7 5.5 ⫾ 1.9c 5.0 ⫾ 1.8c

2.64 ⫾ 0.51 1.92 ⫾ 0.49a 1.48 ⫾ 0.33c

2.39 ⫾ 0.93 2.13 ⫾ 1.07 1.67 ⫾ 0.59

2.82 ⫾ 0.61 1.78 ⫾ 0.44b 1.34 ⫾ 0.40c

1.06 ⫾ 0.12 0.79 ⫾ 0.08b 1.03 ⫾ 0.16d

1.24 ⫾ 0.22 0.87 ⫾ 0.08a 1.03 ⫾ 0.22

0.92 ⫾ 0.12 0.73 ⫾ 0.12 1.03 ⫾ 0.24

0.35 ⫾ 0.02 0.32 ⫾ 0.02 0.33 ⫾ 0.02

0.34 ⫾ 0.03 0.33 ⫾ 0.03 0.35 ⫾ 0.04

0.37 ⫾ 0.03 0.31 ⫾ 0.03b 0.32 ⫾ 0.02a

133 ⫾ 4 120 ⫾ 4c 123 ⫾ 4c

132 ⫾ 8 122 ⫾ 6b 124 ⫾ 6a

134 ⫾ 5 118 ⫾ 5c 123 ⫾ 5c

78 ⫾ 2 73 ⫾ 2c 75 ⫾ 2b

79 ⫾ 3 74 ⫾ 3 75 ⫾ 3

78 ⫾ 3 73 ⫾ 3b 74 ⫾ 2

63 ⫾ 2 59 ⫾ 3 59 ⫾ 2

67 ⫾ 4 63 ⫾ 5 63 ⫾ 4

60 ⫾ 3 56 ⫾ 3b 55 ⫾ 2b

Time

Group

⬍0.001

NS NS 0.93

⬍0.001

0.86

⬍0.001

0.48

⬍0.001

0.95

0.046

0.74

0.09

0.59

⬍0.001

0.65

⬍0.001

0.23

⬍0.001

0.22

0.009

0.96

0.015

0.50

0.088

0.77

⬍0.001

0.95

0.003

0.81

0.002

0.19

Values are expressed as mean ⫾ SEM. Statistical analysis was performed by 2-way repeat measures ANOVA. M, Males; F, females; NS, not statistically significant; BP, blood pressure (average of five supine readings measured by Dinamap monitor, Critikon Inc., Tampa, FL); HDL-C, high-density lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; SI, whole-body insulin sensitivity index, calculated by the method of Matsuda and DeFronzo (16); TG, triacylglycerol; WL, weight loss by hypocaloric diet; WL ⫹ EX, weight loss by hypocaloric diet and aerobic exercise. a

P ⬍ 0.05; b P ⬍ 0.01; c P ⬍ 0.001 vs. baseline; d P ⬍ 0.05 vs. wk 12.

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body insulin sensitivity was quantified using the Matsuda method (16).

Laboratory analyses PRA, insulin, and leptin were measured by RIA, nonesterified fatty acids (NEFA) by enzymatic colorimetry, high sensitivity CRP by immunoturbidimetric assay and plasma glucose and lipids by automated enzymatic methods (11). Epinephrine and endogenous and [3H]norepinephrine were determined by HPLC with electrochemical detection (11). Samples from the three time-points were assayed together.

Statistical analysis Data are expressed as means ⫾ SEM. Two-way repeat measures ANOVA was used to test for time, group (WL vs. WL ⫹ EX), and interaction effects (SigmaStat version 3.5; Systat Software Inc., Point Richmond, CA). The Holm-Sidak test was used for post hoc analyses, with adjustment for multiple comparisons. Pearson’s and Spearman’s correlations were performed to examine associations between variables. Differences were considered statistically significant at P ⬍ 0.05 (two-tailed).

Results Anthropometric, dietary, fitness, and metabolic parameters Table 1 summarizes demographic, clinical, and metabolic characteristics of the 18 subjects (eight WL and 10 WL ⫹ EX) who successfully maintained their initial weight loss of ⫺9.3 ⫾ 0.8% (P ⬍ 0.001). Fitness (maximal oxygen consumption) (11) increased by 14 ⫾ 6% in the WL ⫹ EX group only, and this increment was sustained at 7 months. In contrast, fitness level remained unchanged in the WL group throughout the study. Dietary changes in-


cluded a reduction in saturated fat and an increase in relative protein intake (P for both, ⬍0.01). Urinary sodium excretion decreased by 53 ⫾ 13 and 33 ⫾ 8 mmol/d at 12 wk and 7 months, respectively (P for both, ⬍0.01 vs. baseline). During active weight loss, carbohydrate oxidation decreased (by 56 ⫾ 24 g/d; P ⬍ 0.05) and fat oxidation tended to increase (by 11 ⫾ 5 g/d; P ⫽ 0.07). Resting metabolic rate decreased nonsignificantly. PRA decreased by 16.6 ⫾ 9.8% (P ⫽ 0.009) at wk 12, but rebounded to near baseline values by 7 months in both lifestyle groups (Table 1). SNS activity and baroreflex sensitivity Whole-body norepinephrine spillover rate decreased by 23.0 ⫾ 7.4% at wk 12 (Fig. 1A), and this was maintained at 7 months (⫺28.6 ⫾ 7.8%; P for both, ⬍0.01 vs. baseline). Norepinephrine clearance and plasma epinephrine concentration did not change at any time-point. The strongest correlate of ⌬ norepinephrine spillover at wk 12 was improvement in baroreflex sensitivity (r ⫽ ⫺0.54; P ⫽ 0.038), although the association was weaker at 7 months (r ⫽ ⫺0.42; P ⫽ 0.12). Paired MSNA measurements were available in 11 subjects (four WL, seven WL ⫹ EX; Fig. 1B). Burst incidence decreased at wk 12 by 25 ⫾ 3 bursts/100 heartbeats (P ⬍ 0.001). However, in contradistinction to whole-body norepinephrine spillover, MSNA rebounded significantly at 7 months. In the same 11 subjects, plasma norepinephrine spillover averaged 477 ⫾ 69, 336 ⫾ 59 (P ⫽ 0.009), and 302 ⫾ 50 ng/min (P ⫽ 0.004) at the three time-points. The increase in MSNA during weight maintenance correlated positively with change in abdominal fat mass (⌬ values ranged from ⫹0.372 to ⫺0.194 kg) measured by dual-energy x-ray absorptiometry scan at the L1-L4 cut (r ⫽ 0.61; P ⫽ 0.05). Baroreflex sensitivity increased by 5.2 ⫾ 2.2 msec/mm Hg at wk 12 (P ⫽ 0.005), but this increment was attenuated at 7 months to 2.7 ⫾ 1.3 msec/mm Hg (P ⫽ 0.11 vs. baseline).

Discussion

FIG. 1. SNS activity quantified as whole-body norepinephrine spillover rate (A; n ⫽ 18) and MSNA (B; n ⫽ 11) at baseline and at the end of 12-wk active WL and 4-month weight loss maintenance (WM). **, P ⬍ 0.01, and ***, P ⬍ 0.001 vs. baseline; ##, P ⬍ 0.01 vs. WL phases for the whole-group. Whole-body norepinephrine spillover: time effect, P ⬍ 0.001; group effect, P ⫽ 0.48; interaction, P ⫽ 0.48. MSNA: time effect, P ⬍ 0.001; group effect, P ⬍ 0.001; interaction P ⫽ 0.68. The WL ⫹ EX group had higher MSNA burst incidence at baseline and wk 12 (P for both, ⬍0.01 vs. WL group).

Sympathoinhibition is a goal in the therapeutic approach to the MetS, and energy-restricted diet and physical training are first-line strategies to achieve this (1). The key findings of our study are that active weight loss, which elicited a 9% reduction in body weight, was accompanied by marked sympathoinhibition, av-


eraging ⫺23% for whole-body norepinephrine spillover and ⫺40% for MSNA. However, after 4 months of successful weight loss maintenance, there was a divergence of effects, with benefits on norepinephrine spillover and most metabolic parameters being retained, whereas MSNA, baroreflex sensitivity, and PRA rebounded significantly. The increase in MSNA during weight loss maintenance correlated strongly and positively with change in abdominal fat mass. This finding suggests that small fluctuations in the visceral fat depot under conditions of stable energy balance are closely associated with MSNA. Whole-body norepinephrine spillover represents the summation of regional sympathetic outflows to various organs and tissue beds. Skeletal muscle and the kidneys each contribute approximately 20% to whole-body sympathetic activity (17), and outflows to these regions are known to be increased in obesity (18). The rebound of MSNA during stable energy balance together with unchanged whole-body norepinephrine spillover implies either that further reduction in sympathetic outflow occurred in another organ or tissue bed, or that there is a mismatch between sympathetic nerve firing and norepinephrine overflow into the plasma (due to alterations in neurotransmitter disposition) during weight loss maintenance (17). Renal sympathetic nerves play an important role in cardiovascular homeostasis via effects on both renal hemodynamics and renin release. In the present study, changes in MSNA during lifestyle interventions were closely mirrored by the changes in PRA, which suggests that initial benefits on the renin-angiotensin system and/or efferent sympathetic outflow to the kidneys during active weight loss may have been attenuated during weight loss maintenance. Notably, whereas sodium intake decreased during lifestyle interventions, the urinary excretion rates were similar at 12 wk and at 7 months and remained above the level known to trigger sympathetic activation (19). It is well established that regional activation of the SNS in response to certain stimuli can occur. For example, Young and Landsberg (20, 21) showed that in rodents, fasting elicits suppression of norepinephrine turnover in the heart, pancreas, and liver, but it elicits stimulation of the adrenal medulla. Moreover, fasting has been shown to increase norepinephrine spillover from abdominal sc adipose tissue by more than 100% in healthy subjects (22). Although an overall decrease in SNS activity during active weight loss makes biological sense as an adaptive response to conserve energy expenditure, the tissue-specific increases reported in fat depots may be part of the same adaptive response that facilitates mobilization of energy stores during negative energy balance and thus may subserve a critical role in metabolic regulation (22). Our NEFA data, which showed decreases only at the end of


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weight maintenance but not during active weight loss, support this concept. Reduced cardiovagal baroreflex gain is a recognized feature of MetS that is a positive prognostic indicator for cardiovascular risk (23). Our assessment of cardiac vagal modulation of heart rate indicated significant improvement during active weight loss but attenuation during weight loss maintenance, which concurs with the only other published study in MetS subjects (9). Baroreflex sensitivity is a function of arterial distensibility (modulated by nitric oxide and local vasoconstrictor milieu), central integration of afferent vagal nerve traffic, and cardiac muscarinic receptor number and/or sensitivity, which may be differentially influenced by negative vs. stable energy balance. It is unlikely that deconditioning contributed to the attenuation in baroreflex sensitivity at 7 months because fitness level was sustained throughout the study in the WL ⫹ EX group. Limitations of our study include the small sample size, of which only a proportion had paired MSNA measurements (albeit the pattern of change in norepinephrine spillover was the same in this subset as in the whole group), and the lack of controls. However, our previous work demonstrates stability of sympathetic measurements in untreated subjects over similar intervention periods (11). Further research is warranted to explore the nature of organ-specific differentiation in sympathetic neural adaptation and the specific drivers during the course of active weight loss and successful weight loss maintenance.

Acknowledgments Address all correspondence and requests for reprints to: Dr. Nora E. Straznicky, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail: [email protected]. This work was supported by Diabetes Australia Research Trust Grants (2005–2008) and a National Health & Medical Research Council (NHMRC) of Australia Project Grant (472604). E.A.L., M.P.S., and G.W.L. are supported by NHMRC Fellowships. Clinical Trial Registration: www.ClinicalTrials.gov trial NCT0016394. Disclosure Summary: The authors have nothing to declare.

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