The main finding of this study is that incorporation of regular, moderate-intensity aerobic exercise training during a dietary weight loss program does not confer additional benefits on resting sympathetic neural activity, compared with weight loss alone, in middle-aged subjects with MetS obesity. Body weight reduction of 8–9% was accompanied by a 22% reduction in whole-body norepinephrine spillover and comparable attenuation of MSNA in both lifestyle groups. Similarly, we identified no further enhancement of exercise training on MetS components (blood pressure, fasting plasma glucose, triglyceride, and HDL cholesterol levels or insulin sensitivity), despite a 19% increase in fitness and a significantly greater reduction in central adiposity in the WL+EX group. However, combined exercise and weight loss was associated with a reduction of plasma hs-CRP concentrations that was not observed in the WL group.
Our findings are in agreement with those of Trombetta et al. (23
), who conducted the only other comparable study in premenopausal obese women (albeit using nonadherent participants as control subjects) and observed similar reductions in resting MSNA after 4 months hypocaloric diet or hypocaloric diet and exercise training. Our metabolic results also concur with those of the CALERIE study, which identified no incremental benefit of weight loss through increased energy expenditure via exercise as opposed to weight loss by hypocaloric diet alone, on insulin action and coronary heart disease risk factors, when caloric deficit was matched in the two treatment groups (33
). On the other hand, the Oslo Diet and Heart Study showed that 1-year intervention with combined diet and exercise was more effective than diet alone in the treatment of the MetS (17
). It is likely that a combination of factors, including weight loss, negative energy balance, dietary composition, metabolic changes, and increased fitness in the WL+EX group, contributed to the observed sympathoinhibition after lifestyle intervention in the present study.
Considerable evidence exists that dietary-induced reductions in body weight are sympathoinhibitory: reductions in whole-body norepinephrine spillover (5
), MSNA (5
), and an increase in the parasympathetic indexes of heart rate variability (36
) have previously been reported. Similarly, exercise intervention alone, using the same bicycle riding protocol as in the present study, has been shown to lower whole-body norepinephrine spillover by 24% and renal norepinephrine spillover by 41% in healthy young men independent of changes in body weight (19
). It has been hypothesized that changes in central sympathetic outflow associated with body weight modification or increased fitness may have a reflex origin (35
). The cardiac baroreflex is a compound reflex, where ~70% of both vagal and sympathetic components of heart rate range are mediated by the arterial baroreceptors and ~30% by cardiopulmonary baroreceptors. Both weight loss (5
) and exercise training (38
) are known to potentiate cardiovagal baroreflex sensitivity and the baroreceptor-sympathetic reflex (18
); however, the present study is the first to examine their combined effects. Our results show no additive effect of exercise training and hypocaloric diet, beyond that attained by hypocaloric diet alone. The results do, however, emphasize that weight loss is a highly effective strategy to improve baroreflex function, as spontaneous cardiac baroreflex sensitivity increased by ~50% in both lifestyle groups. Potential contributing mechanisms include increased arterial distensibility or improved neural transduction of barosensory vessel stretch into vagal outflow (39
Sympathoinhibition after lifestyle intervention correlated positively with change in anthropometric variables in the present study. Change in waist-to-hip ratio and abdominal fat mass were most strongly associated with reduction in whole-body norepinephrine spillover, whereas changes in body weight, total body, and trunk fat masses and plasma leptin concentration were the strongest predictors of change in MSNA. The subcutaneous fat depot is the major source of leptin in humans, owing to the combination of a mass effect and a higher secretion rate in the subcutaneous than visceral adipose region (40
). Experimental evidence in obese rodents supports the notion of selective leptin resistance in obesity, with preservation of leptin-dependent sympathoexcitation, but resistance to its anorexigenic effects (41
). Although no definitive leptin administration studies have been performed in humans to characterize its effect on SNS activity, both the present study and an earlier weight loss trial performed by our group (5
) suggest that reduction in plasma leptin is a significant independent predictor of sympathoinhibition after lifestyle intervention. Improvement in insulin resistance as indicated by decreased fasting insulin concentration and increased whole-body insulin sensitivity index also correlated with change in MSNA and support the notion that hyperinsulinemia enhances central sympathetic outflow (42
). Changes in electrolyte status that coincide with energy restriction can modulate the response of the SNS. In particular, sodium depletion to ≤80 mmol/day has been shown to override the suppressive effect of energy restriction and instead trigger sympathetic activation and baroreflex impairment (43
). In the present study, we chose not to supplement with sodium, as we felt this was more representative of weight loss in the community at large. Average 24-h urinary sodium excretion decreased modestly to levels commensurate (at week 12) with intermediate sodium intake in the DASH-Sodium trial (44
). SNS activation would not be expected at this level of sodium intake; however, some contribution to sympathoinhibition versus baseline intake cannot be ruled out. Consumption of the DASH dietary pattern, which is rich in potassium and magnesium and reduced in total and saturated fat, may have also contributed to the observed reductions in blood pressure in the present study. Overall, however, absolute potassium intake did not change in our study, because of relatively high baseline consumption and use of the DASH diet at hypocaloric levels.
In our study, both WL and WL+EX produced comparable changes in metabolic risk factors, which were in the direction associated with reduced coronary heart disease risk. One exception was the change in plasma HDL cholesterol, which decreased significantly and by similar magnitude in both lifestyle groups. The impact of weight loss on lipids depends on a number of factors including energy balance, dietary composition, and concomitant exercise level (45
). Using the same moderate-intensity exercise protocol, Reid et al. (46
) demonstrated a significant increase in HDL cholesterol; however, this was diminished when exercise was prescribed together with weight loss. The relative reduction in total and saturated fat intake from baseline may have contributed to the decline in HDL cholesterol in our study (45
). Change in HDL cholesterol correlated inversely with change in sympathetic activity, which likely reflects favorable alterations in HDL metabolism with loss of visceral fat mass, since change in HDL also related inversely to change in abdominal fat. It is also possible that reduction in central sympathetic outflow per se may have increased levels of HDL by increasing blood flow to peripheral vascular beds, thereby enhancing lipoprotein lipase activity (47
). In our study, hs-CRP improved only in the WL+EX group, which was unexpected in light of previous work, including our own, which consistently shows that levels of this acute-phase reactant decrease after dietary weight loss (5
The strengths of the present study are its randomized controlled design, which accounted for the effects of familiarization on sympathetic measurements; the use of both norepinephrine kinetics methodology and direct measurement of postganglionic MSNA to quantify sympathetic neural drive; and the close individualized supervision of each participant. Our study also has some limitations. First, only a subset of subjects had paired MSNA data and hence the sample size precludes demonstration of differences smaller than 30% between groups. Second, exercise training has many different facets, including frequency, duration, intensity, and exercise type. Our exercise protocol was based on moderate-intensity aerobic training on alternate days over a 12-week period, and thus further studies are required to examine whether higher intensity or frequency training or the inclusion of resistance exercise has additional benefits on neuroadrenergic function. For instance moderate-intensity exercise training 7 days per week has been associated with greater reduction in norepinephrine spillover than the same protocol 3 days per week (49
). Resistance exercise training improves postexercise heart rate recovery and heart rate variability, reflecting improved cardiac vagal activity (50
), but there is a paucity of data to date using robust measurements of sympathetic activity in this setting.
In conclusion, this study provides evidence that both hypocaloric diet and hypocaloric diet with exercise training elicit significant improvements in resting sympathetic neural drive and MetS components. The results suggest that weight loss, and in particular abdominal fat loss, is the prime mover in sympathetic neural adaptation to a hypocaloric diet. These findings support the adoption of lifestyle changes for the prevention of cardiovascular sequelae of obesity.