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Laboratories of Cardiovascular Nutrition (N.E.S., P.J.N.) and Human Neurotransmitters (E.A.L., G.W.L., K.M., M.D.E.), Baker Heart Research Institute, Melbourne, Victoria 8008, Australia
Address all correspondence and requests for reprints to: Dr. Nora E. Straznicky, Cardiovascular Nutrition Laboratory, Wynn Domain, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail: nora.straznicky{at}baker.edu.au.
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Abstract |
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Objectives: The objectives of this study were to test the hypothesis that dietary weight loss attenuates both insulin resistance and SNS activity and to examine the relationships between SNS activity and metabolic syndrome (MetS) components.
Design: This was a single-sample, repeated measures design study.
Setting: This study was performed at a tertiary referral center.
Participants: Twenty-three MetS subjects (age, 58 ± 2 yr; body mass index, 33.3 ± 0.8 kg/m2; mean ± SEM) were studied.
Intervention: A hypocaloric modified Dietary Approaches to Stop Hypertension diet (26% fat, 22% protein, and 51% carbohydrate; 100 mmol/d sodium) was consumed for 3 months.
Main Outcome Measures: The main outcome measures were postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), whole-body plasma norepinephrine spillover rate, spontaneous cardiac baroreflex function, and insulin sensitivity.
Results: The hypocaloric diet significantly reduced body weight by 7% and improved all MetS components. Norepinephrine spillover decreased from 877 ± 180 to 503 ± 39 ng/min (P = 0.005), and muscle sympathetic nerve activity decreased from 40.6 ± 2.1 to 34.6 ± 2.4 bursts/min (P = 0.01), whereas cardiac baroreflex sensitivity increased by 23.0 ± 8.0% (P = 0.02). The change in the norepinephrine spillover rate correlated positively and independently with the change in plasma leptin concentration (r = 0.49; P = 0.03).
Conclusion: Weight loss by a hypocaloric diet with moderate sodium restriction diminishes SNS activity in MetS subjects. This may be due to the consequences of decreased leptin concentration, enhanced insulin sensitivity, or improvements in cardiac baroreflex function.
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Introduction |
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There are currently two merging streams of thought regarding the pathogenesis of the MetS: first, that it is a consequence of abdominal obesity (4) and second, that insulin resistance (primarily in skeletal muscle and liver) may be the underlying cause (5). The sympathetic nervous system (SNS) is an important regulatory mechanism of both metabolic and cardiovascular functions, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. To date, it remains unresolved whether aberrations of the SNS contribute to obesity or, rather, are a consequence of it. The possibility that a primary increase in sympathetic tone might contribute to the development of MetS obesity is supported by longitudinal data in Japanese men. Masuo et al. (6) reported that elevated plasma norepinephrine levels at baseline predicted future higher blood pressure readings, gain of weight, and higher insulin values over a 5-yr follow-up. Current knowledge of SNS activity in MetS subjects is limited to cross-sectional data, which show that abdominal visceral fat is an important adipose tissue depot linking obesity with elevated SNS activity. In the study by Alvarez et al. (7), resting muscle sympathetic nerve activity (MSNA) was 55% higher in men with elevated abdominal visceral fat compared with age-, total fat mass-, and abdominal sc fat-matched controls with lower abdominal fat. Significant associations between waist circumference and urinary catecholamine excretion (8), MSNA (9), and norepinephrine plasma appearance rate (10) have also been reported. Furthermore, our group has previously reported a positive correlation between forearm vascular responses to norepinephrine and waist circumference in middle-aged obese subjects (11). Elevated abdominal visceral fat has also been associated with reduced cardiovagal baroreflex gain (12).
Several components of the MetS may enhance sympathetic drive. Hyperinsulinemia, the hallmark of reduced insulin sensitivity, can directly stimulate SNS activity in man (13). Products of adipose tissue, such as leptin and nonesterified fatty acids (NEFAs), may also contribute to neurogenic activation and insulin resistance in persons with abdominal obesity (14, 15). An elevation of NEFAs in humans acutely impairs baroreflex sensitivity (16).
Weight reduction, the first line treatment for the MetS, is beneficial in lowering blood pressure, enhancing insulin action on peripheral tissues (17), and preventing the development of type 2 diabetes (18). Decreased MSNA and plasma norepinephrine concentrations have been reported in young obese normotensive subjects after dietary weight loss (19). However, there are no prospective data for middle-aged obese subjects who fulfill current definitions of the MetS. Therefore, the primary aims of the present study were 1) to test the hypothesis that dietary weight loss would attenuate whole body and MSNA, and 2) to examine the relationships between SNS activity and metabolic, anthropometric, inflammatory, and cardiovascular variables in these high-risk obese subjects.
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Subjects and Methods |
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Nonsmoking subjects, 15 males and eight postmenopausal females, aged 45–69 yr, with a body mass index ranging from 28.6–42.0 kg/m2 were recruited through newspaper advertisement. Diagnosis of the MetS was based on having three or more of the National Cholesterol Education Program Adult Treatment Panel III criteria (20): waist circumference greater than 102 cm in men and greater than 88 cm in women; plasma triglycerides 1.69 mmol/liter or more; high-density lipoprotein (HDL) cholesterol below 1.04 mmol/liter in men and below 1.29 mmol/liter in women; blood pressure of 130/85 mm Hg or higher; and fasting plasma glucose of 6.1 mmol/liter or more. All subjects had been weight stable for the preceding 6 months. Exclusion criteria comprised a history of diabetes; secondary hypertension; obstructive sleep apnea; cardiovascular, cerebrovascular, renal, liver, or thyroid disease; and use of drugs known to affect measured parameters (e.g. hormone replacement therapy). Participants currently treated for hypertension (n = 1) or hypercholesterolemia (n = 1) were included only after antihypertensive or cholesterol-lowering medications had been discontinued for at least 4 wk. Two subjects continued to take low dose aspirin during the study. Habitual dietary intake was assessed by food frequency questionnaire. The study was approved by the Alfred Hospital human research ethics committee. All participants provided written informed consent.
Study design and dietary regimen
The study used a single-sample, repeated measures design. The Dietary Approaches to Stop Hypertension (DASH) diet (21), which resembles the optimal diet for the MetS, was used as the background diet. This diet is low in saturated fat, cholesterol and total fat, with an emphasis on fruits, vegetables, nuts, legumes, whole-grain products, low-fat dairy foods, and lean red meat, fish, and poultry. Olive oil and polyunsaturated margarine were the major fat sources. Because increased dietary protein has positive effects on body composition, glucose homeostasis, and satiety during weight loss (22), we modified the original DASH diet by increasing its protein content from 18% to 22% at the expense of carbohydrate. Sodium intake was kept constant at 100 mmol/d. Eligible subjects entered a 2-wk weight stabilization phase during which they consumed the DASH diet in accordance with their usual caloric intake. A 12-wk weight loss period followed, during which they were prescribed hypoenergetic versions of the DASH diet, designed to elicit 0.5–1 kg weight loss/wk. Subjects were provided with 14-d menu plans and recipes, and prepared meals in their homes. To aid compliance, they were also provided with low-energy frozen meals, which met the study’s nutritional targets (Dolmio Bowls, Masterfoods, Wodonga, Australia). Subjects received fortnightly dietary counseling. Compliance was assessed by 4-d prospective diet records, which were analyzed using Australian Food Composition Tables (FoodWorks, Xyris Software, Highgate Hill, Australia). Sodium and potassium intake were quantified by 24-h urine collections. Subjects were instructed to keep their exercise level constant during the study, and this was monitored by prospective exercise records.
Anthropometric, metabolic, and blood pressure measurements
Body weight was measured in indoor clothes without shoes using a digital scale. Waist circumference was measured at its smallest girth, and hip circumference at the level of the greater trochanters. A 75-g oral glucose tolerance test was performed after a 12-h overnight fast. Blood samples were drawn from an indwelling venous cannula at 0, 30, 60, 90, and 120 min for plasma glucose and insulin determinations. Whole-body insulin sensitivity was calculated by an oral glucose tolerance test data using the method described by Matsuda and DeFronzo (23). Insulin resistance was calculated using the homeostatic model assessment (HOMA) method. For categorical analyses, insulin resistance was defined as a HOMA index of 2.5 or more, which represented the 50th percentile value in our subject group. Supine blood pressure was measured in the right arm by a Dinamap monitor (model 1846 SX; Critikon, Inc., Tampa, FL). Subjects rested for 5 min before five recordings, 1 min apart, which were averaged.
Measurement of SNS activity
Investigations were performed in a quiet, temperature-controlled room at the same time of day. After a standard light meal, subjects rested in the supine position for 30 min. All had abstained from caffeine for 12 h, alcohol for 24 h, and exercise for 36 h. They voided before commencement of the study.
Whole-body sympathetic activity was assessed by measurement of the apparent rate of appearance of endogenous norepinephrine in plasma (norepinephrine spillover rate), using the isotope dilution technique (24). The plasma concentrations of neurochemicals were determined by HPLC with electrochemical detection. Intraassay coefficients of variation in our laboratory are 3% for norepinephrine and 7% for [3H]norepinephrine; interassay coefficients of variation are 11 and 6%, respectively.
Multiunit postganglionic sympathetic activity was recorded using microneurography in a muscle fascicle of the peroneal nerve at the fibular head. The same investigator (E.A.L.) performed all studies. The common peroneal nerve was first located by palpation and electrical stimulation via a surface probe. A tungsten microelectrode (FHC, Bowdoinham, ME) was then inserted percutaneously and adjusted until satisfactory spontaneous MSNA was observed. Resting measurements were recorded over a 15-min period. Sympathetic bursts were counted manually and expressed as burst frequency (bursts per minute) and burst incidence (bursts per 100 heart beats). The amplitude of the largest burst during the analyzed period of the recording was defined as 100, and all other bursts were expressed as a percentage of the largest one. Total MSNA was calculated by multiplying the mean burst amplitude per minute by the burst rate, expressed as units per minute and units per 100 heart beats. Blood pressure, electrocardiogram, respiration, and MSNA signals were monitored continuously and digitized (PowerLab recording system, model ML785/8SP, American Diagnostica, Stamford, CT). Intraindividual MSNA recordings have been shown to be stable over 3 months (25).
Assessment of spontaneous cardiac baroreflex function
Baroreflex sensitivity was assessed by the sequence method using BaroCor software (AtCor Medical, West Ryde, Australia) as previously described (26). The slope between cardiac interval and systolic blood pressure was calculated for each validated sequence, and an average slope was calculated for each recording.
Laboratory determinations
Plasma total cholesterol, HDL cholesterol and triglycerides were determined by automated enzymatic methods. Low-density lipoprotein cholesterol was calculated using the Friedewald equation. Urinary sodium and potassium were quantitated by ion-selective electrode technology, and plasma high sensitivity C-reactive protein was determined by immunoturbidimetric assay. All other biochemical measurements were performed on frozen potassium EDTA plasma samples. Plasma glucose and NEFA were measured by enzymatic and colorimetric methods (Gluco-quant, Roche, Basel, Switzerland; and NEFA C, Wako Chemicals, TX, respectively); leptin and insulin were determined by RIA (Linco Research, Inc., St. Charles, MO).
Statistical analyses
Data are expressed as the mean ± SEM. Statistical analysis was performed using SigmaStat version 2.03 (SPSS, Inc., Chicago, IL) for Windows. Comparison of variables before and after weight loss intervention was made by Student’s paired t test and Wilcoxon signed-rank test. Data were transformed when appropriate to normalize them. Subgroup analyses were performed by two-way repeat measures ANOVA with pairwise comparisons (Tukey’s test) when appropriate. The degree of association between variables at baseline and between changes in variables was evaluated by Spearman’s rank correlation. Forward stepwise regressions were carried out with those univariate correlations where r 
0.35. Statistical significance was accepted at a two-sided value of P < 0.05.
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Results |
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presents anthropometric, metabolic, and dietary characteristics of the study population. At entry, 15 of the participants were hypertensive, two had impaired fasting glucose, and 11 were insulin resistant (HOMA index, 2.5). Twenty-two subjects completed both study phases. For technical reasons, paired norepinephrine kinetics and MSNA data were available for 19 and 17 subjects, respectively.
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), the strongest predictors of whole-body norepinephrine spillover rate were insulin sensitivity (r = –0.67; P = 0.002) and fasting plasma leptin concentration (r = 0.48; P = 0.03; Fig. 1). Blood pressure, HOMA index, and HDL cholesterol (inverse relationship) had the strongest correlation to MSNA. In stepwise regression, insulin sensitivity maintained an independent inverse association with norepinephrine spillover and accounted for 35% of the variance (Table 3). Body weight was an independent predictor of MSNA (burst frequency and burst incidence), accounting for about a third of the variance, whereas waist circumference and HDL cholesterol were independent predictors of total MSNA. Hypertensive subjects had significantly greater MSNA than normotensives (47 ± 3 vs. 36 ± 3 bursts/min; P = 0.01). A similar trend was seen for norepinephrine spillover (1082 ± 283 vs. 683 ± 116 ng/min, respectively); however, the difference was not statistically significant. Baseline baroreflex sensitivity correlated inversely with systolic blood pressure (r = –0.44; P = 0.05).
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). Urinary sodium excretion and total time spent exercising were similar during baseline and weight loss phases. The arterial plasma norepinephrine concentration and whole-body norepinephrine spillover rate decreased by 27% (P < 0.001) and 43% (P = 0.005), respectively, after dietary intervention, whereas the norepinephrine plasma clearance rate was unchanged (Fig. 2). MSNA burst frequency and total MSNA were also significantly reduced after the hypocaloric diet (Fig. 3). These changes were accompanied by an improvement in spontaneous cardiac baroreceptor function with an increase in the cardiac interval/systolic blood pressure slopes from 7.4 ± 0.6 to 9.0 ± 1.0 msec/mm Hg (P = 0.02).
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Subgroup analyses (Fig. 4) showed that only those subjects who were insulin resistant at baseline (HOMA, 2.5) experienced a significant reduction in norepinephrine spillover despite similar weight loss in insulin-resistant and insulin-sensitive subjects (6.4 ± 1.1 and 6.6 ± 1.0 kg, respectively; P = 0.88). This finding was also confirmed by a positive correlation between baseline HOMA score and change in noradrenaline spillover (r = 0.59; P = 0.007). MSNA decreased in both insulin-sensitive (by 8 ± 3 bursts/min; n = 9) and insulin-resistant subjects (by 4 ± 3 bursts/min; n = 8), and the difference between the two groups was not statistically significant. Hypertensive status did not influence norepinephrine spillover responses to dieting, but did influence MSNA responses, with hypertensive subjects showing a greater reduction than normotensives (Fig. 4). However, corresponding weight losses tended to be greater in the hypertensives (8.1 ± 1.0 and 5.8 ± 1.1 kg, respectively; P = 0.13). There were no gender-related differences in weight loss (males, 6.9 ± 0.9 kg; females, 5.3 ± 1.2 kg; P = 0.30) or norepinephrine kinetics. However, only the males showed a significant reduction in total MSNA with weight loss (males, 2619 ± 322 vs. 1671 ± 136 U/min; P < 0.001; n = 12; females, 1818 ± 120 vs. 1947 ± 189 U/min; P = 0.64; n = 5).
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Discussion |
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In our MetS subjects who fulfilled the National Cholesterol Education Program Adult Treatment Panel III criteria, the plasma norepinephrine spillover rate was approximately 2-fold greater than those previously reported by our group in young obese normotensives (27) and those reported by others in middle-aged lean normotensive individuals (28). In agreement with recently published data (29), the presence of hypertension further increased sympathetic activity in our MetS subjects. Univariate and stepwise regression analyses suggest that insulin sensitivity and leptin may be important mediators of sympathetic activation in this clinical setting. Body weight and central adiposity, measured as the waist circumference, and plasma NEFA were also associated with sympathetic activity, but the strength of these associations was weaker. These findings are consistent with data in humans indicating that elevations in plasma insulin, even within the physiological range and under euglycemic conditions, activate the SNS (13). These actions of insulin are mediated through the central nervous system either as a reflex response to vasodilation or as a direct effect of insulin on forebrain areas regulating sympathetic outflow (30). Visceral obesity is characterized by hemodynamic abnormalities, namely, large artery stiffness and impaired endothelial function (31), which may reduce the potential depressor effects of insulin while maintaining its pressor actions.
Obesity is known to be associated with circulating hyperleptinemia, reflecting a high fat mass and partial resistance to leptin. Intravenous administration of leptin in rodents increases sympathetic outflow to the kidneys, adipose tissue, adrenal gland, and skeletal muscle vasculature (32). The positive correlation between the plasma leptin concentration and whole-body sympathetic activity seen in our MetS subjects has not been reported previously. We have shown the existence of a strong correlation between plasma leptin concentration and renal norepinephrine spillover in men with widely differing adiposities (14). These results together with our finding that the decrease in norepinephrine spillover with weight loss correlated with the decrease in plasma leptin levels provide some support for the view that leptin stimulates the SNS. It is of note that the spectrum of associations at baseline differed for whole-body norepinephrine spillover and MSNA. Norepinephrine spillover was most strongly associated with insulin sensitivity (inverse relationship) and plasma leptin, whereas MSNA was most strongly associated with body weight and HDL cholesterol (inverse relationship). These discrepancies may be explained by the fact that MSNA accounts for only 20% of total sympathetic activity (33) and the relatively small sample size in the present study.
As hypothesized, a hypocaloric diet decreased whole-body and MSNA. It is likely that both diet-induced weight loss and negative energy balance (active weight loss) contributed to the observed dampening of sympathetic activity. The centrally acting negative feedback signals, insulin and leptin, are sensitive to both body adiposity and the prevailing energy balance. Indeed, previous studies suggest that negative energy balance is associated with greater reductions in plasma insulin and leptin levels and a greater improvement in insulin sensitivity than successful weight loss maintenance (17, 34). These observations have also been extended to cardiac parasympathetic tone, which is increased during active weight loss, but attenuated during an isoenergetic state (35). Insulin responses to meals are the primary mediators of changes in leptin production observed during energy restriction and of the diurnal variation in circulating leptin levels (36). A limitation of the present study is that it does not distinguish between the effects of weight loss per se and negative energy balance because the two were superimposed. The lack of correlation between anthropometric changes and sympathetic activity supports the idea that negative energy balance may exert a dominant influence on sympathetic tone. Another possibility is that the DASH diet may have contributed to the changes in sympathetic activity. This diet has been shown to lower blood pressure in the setting of stable weight (21) and has several potentially beneficial elements, such as increased potassium and decreased saturated fat content. Another limitation of our study is that we used waist circumference as a surrogate marker of abdominal visceral fat. However, waist circumference is recognized to be an excellent predictor of abdominal visceral fat measured from a computed tomography image (r = 0.86 in men; r = 0.84 in women) (37).
Published work by others shows that cardiovagal baroreflex gain, which plays a key role in the beat to beat regulation of arterial blood pressure, is reduced in MetS subjects (12). Dietary weight loss in the present study was accompanied by a 23% increase in cardiac baroreflex sensitivity. Both mechanical and neurogenic mechanisms may have contributed to this improvement. Carotid artery distensibility is an important physiological determinant of cardiovagal baroreflex gain. An improvement in arterial mechanical properties would enhance the barosensory stimulus. Although we did not assess arterial function in the present study, we have previously reported improved systemic arterial compliance after dietary weight loss of a similar magnitude (38). The rise in plasma HDL cholesterol concentration with weight loss may have favorably influenced arterial function by increasing endothelial NO synthase activity (39). It is also possible that dietary weight loss may have altered central integration of afferent vagal nerve traffic or cardiac muscurinic receptor function (12).
An interesting finding in the present study is that despite similar reductions in body weight, only insulin-resistant subjects showed a significant reduction in whole-body norepinephrine spillover. This divergence in benefit between insulin-resistant and insulin-sensitive subjects was not evident for MSNA. Hypertensive subjects and males had the greatest reductions in MSNA with weight loss, albeit hypertensives tended to lose more weight than normotensives. Although these subgroup analyses are of interest, type 2 errors cannot be excluded given the small subject numbers. Overall, weight loss had a greater effect on whole body norepinephrine spillover than MSNA. It is possible that other organs, such as the kidneys, could have contributed significantly to the observed reduction in total sympathetic activity. Additional studies are warranted to examine the effects of weight loss on organ-specific norepinephrine spillover.
The absence of a control group in the present study means that we may not have fully accounted for the effects of time and familiarization on study parameters. However, as in all studies where weight loss is the intervention, we observed a range of weight loss (0.2–11.1 kg), which was studied in relation to attendant changes in metabolic parameters and SNS activity. In such a study design, the subjects who do not lose weight act as internal controls; thus, the use of an external control group (who will often lose weight and therefore be treated) is less critical.
In summary, the novel finding of the present study is that moderate weight loss not only improves MetS components, but also suppresses whole-body sympathetic activity and MSNA. Chronic sympathetic hyperactivity increases cardiovascular workload and hemodynamic stresses and predisposes to endothelial dysfunction, coronary spasm, left ventricular hypertrophy, and serious dysrhythmias. These results underscore the importance of weight loss in the nonpharmacological treatment of the MetS.
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Acknowledgments |
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Footnotes |
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First Published Online August 9, 2005
Abbreviations: DASH, Dietary Approaches to Stop Hypertension; HDL, high-density lipoprotein; HOMA, homeostatic model assessment; MetS, metabolic syndrome; MSNA, muscle sympathetic nerve activity; NEFA, nonesterified fatty acid; SNS, sympathetic nervous system.
Received May 2, 2005.
Accepted August 1, 2005.
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