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(Circulation. 1997;96:3423-3429.)
© 1997 American Heart Association, Inc.
Articles |
Regional Sympathetic Nervous Activity and Oxygen Consumption in Obese Normotensive Human Subjects
From Baker Medical Research Institute and the Alfred Baker Medical Unit, Alfred Hospital, Prahran, Victoria, Australia.
Correspondence to Prof Murray Esler, Baker Medical Research Institute, PO Box 348, Prahran 3181, Victoria, Australia.
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Abstract |
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Background Disturbed sympathetic nervous function may be of importance in obesity; sympathetic underactivity could contribute to deficient thermogenesis, positive energy balance, and weight gain, while in contrast, sympathetic nervous overactivity would predispose to the development of obesity-related hypertension. Global indices of sympathetic nervous system (SNS) function such as plasma or urinary norepinephrine (NE) have been unable to define SNS status in obesity. Since regional SNS activity can be altered in the absence of global changes, we investigated SNS activity in the heart, kidneys, and hepatomesenteric bed in healthy human subjects across a wide body mass index (BMI) range of between 19.6 and 35.5.
Methods and Results Whole-body and regional plasma NE kinetics using [3H]-labeled NE were assessed. Regional oxygen consumption was measured by combining arteriovenous differences in oxygen content and regional blood flow. Arterial plasma NE and whole-body plasma NE spillover were unrelated to BMI. With a BMI cutoff of 27, mean cardiac NE spillover was 46% lower in the obese subjects when compared with the lean subjects (P=.017). Renal NE spillover was significantly correlated with BMI (r=.668, P=.001), the mean value in the obese subjects being more than twice that in the lean subjects. Hepatomesenteric NE spillover was comparable in lean and obese subjects. Renal and hepatomesenteric oxygen consumption were both significantly higher in the obese subjects compared with lean subjects.
Conclusions Regional SNS activity is heterogeneous in the obese state. Important regional alterations, which may be clinically relevant, occur in the absence of changes in global indices of sympathetic nervous function. The enhanced renal NE spillover in obesity may have implications for the development of hypertension in this group, whereas the low cardiac sympathetic tone would be expected to be cardioprotective. Enhanced visceral oxygen consumption evident in the kidneys and hepatomesenteric circulation in proportion to body mass contributes to the greater resting oxygen consumption in obesity.
Key Words: obesity • norepinephrine • nervous system, autonomic • hypertension
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Introduction |
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The impetus for investigating sympathetic nervous activity in obesity lies in the putative role that the sympathetic nervous system has both in the genesis of obesity and in the cardiovascular complications that arise in the established obese state.
A reduction in sympathetic nervous activity has been implicated in the genesis of animal models of obesity.1 More recently, reduced sympathetic nervous activity has been highlighted as a potential mechanism predisposing to body weight gain in humans.2 This is in accordance with the apparent importance of the sympathetic nervous system in virtually all the individual components of daily energy expenditure, including resting metabolic rate,3 energy expenditure related to physical activity,4 the thermic effect of food,5 cold-induced thermogenesis,6 and thermogenesis related to various daily stimulants such as caffeine7 and nicotine.8
Obesity is a risk factor for a variety of cardiovascular conditions including hypertension, ischemic heart disease, and stroke.9 10 11 Landsberg12 has synthesized the diverse effects of the sympathetic nervous system on energy expenditure and the cardiovascular system into a unifying hypothesis with regard to the development of obesity-related hypertension. He suggests that while activation of the sympathetic nervous system in the obese helps to stabilize body weight and restore energy balance by driving thermogenesis, regional effects of sympathetic nervous activation in the heart, kidneys, and vasculature could result in hypertension.12 An elevation in sympathetic nervous activity in the established obese state could contribute to the development of hypertension through sympathetic nervous system–mediated vasoconstriction, stimulation of renal tubular reabsorption of sodium13 and of the renin-angiotensin system,14 and trophic effects on the vasculature.15 In addition, sympathetically induced increases in platelet number and aggregation16 could enhance cardiovascular morbidity.
There is a considerable amount of literature reviewed recently17 that addresses the issue of the status of sympathetic nervous system in the obese. The vast majority of these studies have used either plasma or urinary norepinephrine estimates as indices of sympathetic nervous activity, with variable results. More recently, several investigators have used microneurography to delineate muscle sympathetic nervous activity in the obese state.2 18 19 In the context of the Landsberg hypothesis, it becomes particularly pertinent to investigate the status of the sympathetic nervous system in visceral organs such as the heart and kidneys.
In this study we used isotope dilution methodology20 21 to prospectively determine whole-body norepinephrine spillover and regional norepinephrine spillover across the heart, hepatomesenteric bed, and kidneys in a group of healthy, normotensive subjects covering a wide body mass index (BMI) range. We also determined regional oxygen consumption in these vascular beds and studied the relationship between regional sympathetic nervous activity and regional oxygen consumption.
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Methods |
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Subjects
Thirty-seven healthy male adults between the ages of 18 and 50 years, encompassing a wide BMI (weight in kg/height in m2) range of between 19.6 and 35.5, with body weight range of 63 to 130 kg, were studied. Subjects were recruited either by advertisement in newspapers or in the case of a majority of the overweight subjects, utilizing the database of a weight reduction center (Gutbusters; Melbourne, Australia). All subjects had a thorough clinical screen that included a clinical examination and routine biochemistry to exclude hepatic and renal dysfunction. Respondents with a history of cardiovascular disease, diabetes, chronic medication, blood pressure >140/90 mm Hg, and alcohol intakes of more than two standard drinks per day were excluded from the study. All overweight subjects recruited from the weight reduction center had undergone the program at least 1 year before the study but had regained their original body weights and like the rest of the subjects had been weight-stable for at least 3 months before the study.
Complete details of the experimental protocol were outlined to all participants, and written consent to the investigation, which was approved by the Ethical Review Committee of the Alfred Hospital, was obtained.
General Procedure
All subjects were studied in the supine position and received a
tracer infusion of [3H]-labeled
norepinephrine (specific activity, 11 to 25 Ci/mmol; New
England Nuclear) intravenously at 0.6 to 0.8 µCi/min. The
details of the methodology related to the estimation of plasma
norepinephrine kinetics have been outlined in earlier
reports.20 21 The merits and limitations of the
radiotracer technique of determining plasma norepinephrine
spillover have been comprehensively reviewed.21
Whole-body spillover of norepinephrine from plasma was calculated for all subjects (n=37) from arterial samples obtained from a 21G cannula placed percutaneously under local anesthesia in the brachial or radial artery. Regional plasma norepinephrine kinetics were calculated for the heart (n=25), hepatomesenteric bed (n=24), and kidneys (n=22). To determine regional plasma norepinephrine kinetics, venous samples were obtained from subjects from a central venous catheter inserted percutaneously as previously described,22 with positioning of the catheter tip under fluoroscopic control in the coronary sinus, right renal vein, and hepatic vein. Renal plasma flow was determined from the steady-state clearance and renal extraction of p-aminohippurate. Coronary sinus plasma flow was obtained by thermodilution with adjustment for the hematocrit; hepatomesenteric plasma flow was obtained from the steady-state clearance and hepatic extraction of indocyanine green.
Arterial and regional venous samples obtained were analyzed for oxygen saturation with the use of a hemoximeter (OSM2 Haemoximeter, Radiometer). Arteriovenous differences in oxygen content were combined with regional blood flow to obtain regional oxygen consumption as described earlier.23 24 25
Thirty of the 37 subjects were studied in the fasting state, in the
morning, with abstinence from food, beverages, and smoking for 12 hours
before the experiment. Seven subjects, all lean (BMI range, 20.3 to
24.1), who formed the basis of another report,24 received
a standard breakfast of a single slice of toast with thinly spread
margarine, cereal, and milk (345 kcal). These seven subjects form a
part of the data set pertaining to the hepatomesenteric bed. We have
earlier demonstrated that consumption of a much larger meal (
700
kcal) increases oxygen consumption only minimally across the
hepatomesenteric bed.23 Postprandial sympathetic nervous
activation after the ingestion of a 700-kcal mixed meal is seen
predominantly in skeletal muscle and the renal vascular bed and
excludes the hepatomesenteric bed.26
Calculation of Whole-Body and Regional Plasma Norepinephrine
Kinetics
Whole-body plasma clearances and rates of spillover of
norepinephrine (NE) were calculated as follows:
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Biochemical Analysis
Blood samples for the estimation of catecholamines
were transferred immediately to ice-chilled tubes containing EGTA and
reduced glutathione, centrifuged at 4°C, and the plasma
stored at -70°C before assay. The plasma concentration was
determined by high-performance liquid
chromatography with electrochemical detection. Timed
collection of the eluate leaving the detection cell, by use of a
fraction collector, permitted separation of 3H-labeled
norepinephrine for counting by liquid scintillation
spectroscopy. Intra-assay variations were 4.5% for plasma
norepinephrine at a concentration of 140pg/mL and
7.2% for 3H-labeled norepinephrine.
Statistical Analysis
All results are presented as mean±SEM. Linear
associations between BMI and indices of sympathetic nervous activity,
as well as regional oxygen consumption, were determined using
Pearson's product moment correlation. The effect of obesity on
regional oxygen consumption and sympathetic nervous activity was also
determined by separating lean from obese individuals, by use of a BMI
cutoff of 27 and applying the independent t test for
determining significance between groups. To obtain an adequate
separation of the groups, lean subjects were restricted to BMI <26 and
obese subjects to BMI >28. The null hypothesis was rejected at
P<.05.
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Results |
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Resting heart rate and systolic blood pressure were similar in the lean and obese subjects (59±2 versus 62±2 bpm, P=.337, and 132±3 versus 131±4 mm Hg, P=.827). Diastolic blood pressure, while normal in both groups, was significantly higher in the obese compared with the lean subjects (74±2 versus 70±2 mm Hg, P=.003).
Whole-body and regional plasma norepinephrine
spillovers were not linearly related to age within the age range
that we studied (whole body, r=-.21, P=.203;
cardiac spillover, r=.08, P=.697;
hepatomesenteric spillover, r=.08, P=.711;
renal spillover, r=.30, P=.169). Tables 1
and 2
summarize the relationship between obesity and sympathetic nervous
activity as estimated from [3H]-labeled
norepinephrine kinetics. In Table 1, BMI is treated as a
continuous variable, and linear associations between BMI and
whole-body as well as regional plasma norepinephrine
spillover are presented. In Table 2, subjects were assigned
to either a lean group or an obese group, with a BMI cutoff of 27.
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The data indicate that there is no significant linear relationship of
arterial plasma norepinephrine concentrations
or whole-body plasma norepinephrine spillover with BMI.
The whole-body clearance of norepinephrine from plasma
decreases with increasing BMI (r=-.28, P=.1);
the mean clearance in the obese subjects was 17% lower than in the
lean subjects (Table 2
).
The scatterplot of BMI and cardiac norepinephrine
spillover suggested an exponential inverse relation, and there was
a trend toward a negative correlation between the log of cardiac plasma
norepinephrine spillover and BMI (r=.33,
P=.111). The mean cardiac norepinephrine
spillover was 46% lower in the obese subjects compared with the
lean subjects (Fig 1 and Table 2). In
contrast, renal norepinephrine spillover was positively
correlated with BMI (Fig 2), the mean
value in the obese subjects being twice that of the lean subjects (Fig 1 and Table 2). When the data were pooled, renal
norepinephrine spillover was unrelated to blood
pressure (systolic r=.09, P=.696, and
diastolic r=.34, P=.126).
Hepatomesenteric norepinephrine spillover was unrelated
to BMI (Fig 2).
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Table 3 summarizes the regional oxygen
consumptions in the heart, hepatomesenteric bed, and kidneys and
compares lean with obese subjects. The obese had 20% lower
coronary blood flows and 22% lower cardiac oxygen consumptions
than the lean subjects, although these differences did not reach
statistical significance (Table 3). Hepatomesenteric oxygen consumption
was positively related with BMI and was 68% higher in the obese
than in the lean subjects (P=.001). This was associated with
a 39% increase in hepatomesenteric blood flow in the obese
(P=.018), with extraction of oxygen being similar in both
groups (Table 3). In contrast, the 97% higher renal oxygen consumption
in the obese subjects was related to a significantly higher oxygen
extraction in the face of comparable renal blood flows in the two
groups (Table 3). Cardiac oxygen consumption was significantly related
to cardiac norepinephrine spillover in the lean group
(r=.67, P=.007) but not in the obese
(r=-.31, P=.495). Renal oxygen consumption was
not related to renal norepinephrine spillover either in
the lean (r=.07, P=.88) or the obese group
(r=.351, P=.263).
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Fasting serum insulin was obtained for 29 subjects (17 lean, 12 obese) and was higher in the obese than in the lean subjects (10.3±2.0 versus 6.0±0.6 mU/L, P=.06). Neither whole-body plasma norepinephrine spillover (n=29, r=-.22, P=.268) nor renal norepinephrine spillover (n=18, r=.16, P=.528) was related to fasting serum insulin levels.
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Discussion |
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Our data demonstrate the heterogeneity of regional sympathetic nervous outflow in obese subjects, with significantly elevated sympathetic nervous activity in the kidneys, reduced sympathetic activity in the heart, and normal sympathetic tone in the splanchnic bed compared with lean control subjects. A reduction in cardiac norepinephrine turnover has previously been described in obesity-prone rats.27 Whole-body sympathetic nervous activity in the obese subjects was almost identical to that in the lean subjects. Previous research simultaneously measuring the plasma concentration of norepinephrine as an index of overall sympathetic nervous system activity and skeletal muscle sympathetic nerve firing by clinical microneurography similarly have provided evidence of regional sympathetic nervous activation in the obese in the innervation of the skeletal muscle vasculature, whereas a normal plasma norepinephrine concentration argued against generalized sympathetic nervous system stimulation.19 These observations and the present study suggest that in the obese there exists a dissociation between muscle sympathetic nerve activity, which is increased,18 19 28 and cardiac sympathetic activity, which is reduced. This contrasts with findings in healthy, lean people in whom a close relationship exists between muscle and cardiac sympathetic activity.29
Several earlier studies have explored the relationship between obesity and whole-body plasma norepinephrine kinetics as a measure of overall sympathetic nervous system activity. Poehlman et al30 demonstrated that whole-body plasma norepinephrine spillover was significantly correlated with waist circumference; fat mass did not enter into the model because of its covariance with waist circumference. Christin et al31 also demonstrated that whole-body norepinephrine spillover was strongly related to body size and that independent of body surface area, subjects with more central adiposity had lower clearance rates. This may be of relevance to our findings of a lower clearance of norepinephrine from plasma in obese subjects. The exact mechanisms that may be involved remain to be elucidated. The present study, however, underscores the limitations of applying global indices of sympathetic nervous activity and demonstrates that important regional alterations in sympathetic nervous activity may occur in the absence of changes in global sympathetic activity.
The higher renal and lower cardiac norepinephrine spillover in the obese most likely represents differentiation of central nervous system (CNS) sympathetic outflow, with increased traffic in the renal sympathetic nerves and reduced cardiac sympathetic nerve firing. Norepinephrine spillover from individual organs is influenced by the regional blood flow, with potentially greater transmitter washout at high flows and the capacity for neuronal reuptake of the neurotransmitter after its release,21 but these mechanisms were not operative here. Neuronal norepinephrine uptake, gauged from the extraction of tritiated norepinephrine from plasma,21 was similar for obese and lean people in the three organs studied, as were regional blood flows.
This heterogeneity of sympathetic nervous activation in the obese is in keeping with what we have found in a variety of physiological and pathological conditions,23 26 32 33 in which stimulation of the sympathetic outflow to one organ may be accompanied by normal or reduced sympathetic tone in others. The only context in which we have previously detected stable renal sympathetic nervous activation accompanied by unchanged or reduced cardiac sympathetic activity in humans is with sodium depletion produced by extreme dietary sodium restriction.34 Although not totally excluded, given a recent report that leptin promotes the renal excretion of sodium,35 it is most unlikely that the obese are chronically sodium depleted.36 On the contrary, it is more probable but not tested by us that cardiac sympathetic nervous activity is reflexly depressed in response to circulatory overloading36 brought on by enhanced renal sympathetic nervous activity and sodium retention.13 The variance in cardiac norepinephrine spillover values was greater in lean than in obese men. The reason for this greater variability in lean men is not clear but is unlikely to result from differences in their physical fitness, as aerobic exercise training appears not to influence resting cardiac sympathetic activity.21 The difference possibly more truly represents greater homogeneity in the obese, perhaps reflecting a rather uniform degree of reflex dampening of cardiac sympathetic activity in them. We are unable from the present data to comment on whether cardiac sympathetic nervous activity may be different in more morbid obesity. Sympathetic nervous suppression in the heart would be expected to be cardioprotective.37 The increased incidence of sudden death in the morbidly obese9 perhaps suggests that low cardiac sympathetic tone is not present in all grades of obesity.
The acute postprandial sympathetic response to a high carbohydrate meal in lean people23 24 25 bears close similarity to the regional sympathetic nervous patterning we find in the fasting obese, with renal sympathetic nervous activity being high in both, hepatomesenteric sympathetic activity unaltered, and cardiac sympathetic activity unchanged (postprandially) or reduced (obesity). This similarity suggests that increased release of insulin, present in both contexts, may perhaps trigger the sympathetic response.
While fasting serum insulin concentrations were higher in the obese, we found serum insulin and renal norepinephrine spillover values to be not quantitatively related overall, perhaps arguing against hyperinsulinemia per se causing the elevated renal sympathetic nervous activity.38 39 Our results certainly do not entirely exclude the possibility that hyperinsulinemia is the prime mover for sympathetic nervous activation in the obese. With infusion of insulin in humans to acutely produce hyperinsulinemia, and clamping of blood glucose concentrations, vasodilatation in skeletal muscle is seen, accompanied by activation of the sympathetic nervous outflow recorded with microneurography. This acute effect of insulin is not attributable to increased glucose utilization40 and is mediated through the CNS either as a reflex response to vasodilatation or as a direct effect of insulin on forebrain areas regulating sympathetic outflow.40 41 In contrast to this effect of insulin on skeletal muscle sympathetic fibers, and probably pertinent to our finding of activation of the renal sympathetic outflow in the obese, euglycemic insulin infusion in humans (lean hypertensive patients were studied) does not appear to activate the renal sympathetic nerves.42 The continuing difficulty with studies such as these, in which the relation of acute changes in serum insulin to sympathetic nervous system activity is investigated, is to establish relevance to the chronic hyperinsulinemia of obesity. This being said, it does appear that sympathetic nervous activation in obesity is likely to have its origins in altered CNS regulation of sympathetic nervous outflow but involving mechanisms other than hyperinsulinemia. In this context it should be noted that the chronic hyperinsulinemia accompanying an insulinoma was recently reported to be associated with normal muscle sympathetic nerve activity.43 Current thinking would suggest the CNS mechanisms for sympathetic activation in obesity reside in the hypothalamus, with neuropeptide Y being an important central neurotransmitter44 and the protein leptin, produced in adipose tissue, a peripheral signal.45
The significantly higher renal sympathetic nervous activity in the
obese may have implications for the development of hypertension in this
group. A large number of studies, recently reviewed,13
have demonstrated that complete renal denervation delays or prevents
the development of hypertension in various animal models. It has been
suggested that obesity-induced hypertension may be caused by some
factor that tends to increase renal tubular sodium
reabsorption.38 This hypothesis is supported by evidence
from obesity-induced hypertension in dogs, in which there was a marked
retention of sodium despite increases in glomerular
filtration rate (GFR) and renal plasma flow.39 Studies in
humans have confirmed that GFR and effective renal plasma flow are
increased in overweight subjects compared with lean subjects, whether
normotensive or hypertensive.46 In this study, renal blood
flow was similar in lean and obese subjects. It is therefore pertinent
to note that while renal nerve stimulation at high frequencies is
associated with a decrease in urinary sodium excretion with a
concomitant reduction in blood flow and GFR, at lower nerve firing
frequencies the decrease in urinary sodium excretion occurs in the
absence of any changes in GFR and blood flow.13 Renal
sympathetic nervous activity can regulate the excretion of sodium and
water in several ways, including an alteration of renal
hemodynamics and a stimulation of the release of renin
with increased formation of angiotensin II.47
In addition, renal sympathetic nerves also have direct effects on the
renal tubules. The changes in renal tubular sodium and water
reabsorption occur throughout the nephron approximately in proportion
to the density of tubular innervation and are mediated by
1-adrenergic receptors located on the peritubular
membranes.13
Thus it is conceivable that the enhanced renal sympathetic activity in obese subjects promotes an increase in sodium retention that leads to the development of hypertension in the long term. This is supported by the renal oxygen consumption data in this study, which demonstrated significantly higher renal oxygen consumptions in obese subjects compared with lean subjects. It is believed that as much as 75% to 85% of renal oxygen consumption is used to support the active reabsorption of ions and other solutes, there being a linear relationship between renal oxygen consumption and the extent of sodium reabsorption.48 A closer scrutiny of the renal norepinephrine spillover data reveals that while there were significant intergroup differences, not all obese subjects had high renal norepinephrine spillovers. The challenge, therefore, will be to identify the specific determinants of the elevated renal sympathetic nervous activity in the obese.
An incentive for studying sympathetic nervous function in obesity has been provided by the view that diminished basal sympathetic nervous system activity and reduced sympathetic responses may cause positive energy balance and possibly contribute to the development of obesity. A reduction in sympathetic nervous activity has been implicated in the genesis of animal models of obesity1 and body weight gain in humans.2 This is in accordance with evidence mainly involving pharmacological inhibition of CNS sympathetic outflow or adrenergic receptor blockade, pointing to a role of the sympathetic nervous system in most of the individual components of daily energy expenditure, including resting metabolic rate,3 energy expenditure related to physical activity,4 the thermic effect of food,5 and cold-induced thermogenesis.6
The link between sympathetic activity and thermogenesis in humans, when studied with direct assessment of sympathetic function and oxygen utilization in individual organs, in some instances has been weaker than these studies using pharmacological adrenergic blockade would suggest and in some contexts is nonexistent. In lean, fasting men, oxygen consumption and regional sympathetic activity are related for the heart but not for skeletal muscle, kidneys, and the hepatomesenteric circulation.23 24 25 Similarly, although stimulation of the sympathetic nerves of the kidneys and skeletal muscle occurs after a high carbohydrate meal, no direct quantitative relation was found to exist between these postprandial changes in regional sympathetic activity and oxygen consumption.23 24 25 The observations are in general agreement with the recent finding that whole-body energy expenditure increases normally after a meal in tetraplegic patients, indicating that the sympathetic nervous system may not be the prime mover for postprandial thermogenesis.49
Our study demonstrates that hepatomesenteric and renal oxygen
consumption in fact are both increased significantly in obesity. This
is in keeping with the earlier findings of workers who also
demonstrated that splanchnic oxygen consumption at rest was
significantly higher in obese subjects compared with lean control
subjects50 and discordant with the typical observation of
reduced thermogenesis in rodent models of obesity.1 The
data suggest that part of the absolute increase in resting oxygen
consumption seen in obese subjects is accounted for by an increase in
the oxygen consumption of visceral organs. The liver, heart, and
kidneys account for a little more than 3% of the total body weight of
a reference 70-kg man. However, because these organs have a high
metabolic rate per unit tissue mass, they account for
45% of the resting metabolic rate.51 We
expected an increase in cardiac oxygen consumption in the obese
consistent with higher reported blood volumes36
and possibly driven by an increase in cardiac sympathetic nervous
activity. In fact, we observed no differences in cardiac oxygen
consumption between lean and obese subjects, and cardiac
norepinephrine spillover was significantly lower in the
obese.
Landsberg12 has synthesized the diverse effects of the sympathetic nervous system on energy expenditure and the cardiovascular system into a unifying hypothesis with regard to the development of obesity-related hypertension. He has suggested that while activation of the sympathetic nervous system in obese subjects in response to increased dietary calorie intake helps to stabilize body weight and restore energy balance by driving thermogenesis, regional effects of sympathetic nervous activation in the heart, kidneys, and vasculature could result in hypertension.12 Overeating in lean men does increase sympathetic nervous activity, as evident in increases in whole-body norepinephrine spillover.52
The pattern of regional sympathetic activation in obese humans with normal blood pressure is similar to but not identical with that described by Landsberg12 and Young and MacDonald17 with overfeeding in rodents. Consistent with the hypothesis is our finding of renal sympathetic nervous activation in the obese and earlier microneurographic studies demonstrating enhanced sympathetic nervous activity to skeletal muscle.2 18 19 Unlike with overfeeding in rodents, however, which stimulates the cardiac sympathetic nerves,12 cardiac norepinephrine spillover was lower in obese humans. We are unable at this stage to explain this latter finding other than noting that there may be reflex suppression of cardiac sympathetic activity consequent on circulatory overloading, as suggested above. Whether obese humans with elevated blood pressure conform more closely to the Landsberg hypothesis in having increased cardiac sympathetic tone has not been tested to date.
Study Limitations
In this study we characterized obesity on the basis of an easily
measurable clinical parameter, BMI. However, it is possible
that the relationships that we determined might be influenced by the
type of obesity, given that obesity is a heterogeneous
disorder.53 Further studies will be needed to delineate
the relationships between regional sympathetic nervous activity and
subgroups of obesity including familial obesity, central obesity, and
so forth. The results of this study must be interpreted within the
context of our subject group; we are therefore unable to extend these
findings to more morbidly obese subjects. We did not measure whole-body
oxygen consumption in this study and are therefore unable to quantify
the extent to which increased visceral oxygen consumption contributes
to the absolute increase in resting oxygen consumption in the obese.
Finally, there are limitations in the interpretation of
hepatomesenteric norepinephrine spillover, given the
complexity of the splanchnic circulation. A substantial portion of
norepinephrine released from the gut to the plasma is
removed in transit through the liver.54 Separation of
liver and mesenteric effects would have allowed for a more detailed
delineation of sympathetic nervous activity. While this has been
achieved in instrumented animals,54 it clearly remains a
limitation in human studies.
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Acknowledgments |
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This work was supported by an Institute Grant from the National Health and Medical Research Council of Australia to the Baker Medical Research Institute. The authors would like to thank Glen Sheffield, Garry Eiger, and the staff of Gutbusters for their help in recruiting obese subjects and Sr Leonie Johnston, Kaye Varcoe, and Elizabeth Dewar for their assistance and technical expertise in the catheter laboratory.
Received June 2, 1997; revision received July 11, 1997; accepted July 15, 1997.
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