Diet-induced changes in sympathetic nervous system activity: Possible implications for obesity and hypertension

J Chron Dis Vol. 35, pp. 879 to 886, 1982 Printed in Great Britain

0021-9681/82/120879-08503.00/0 Pergamon Press Ltd

DIET-INDUCED CHANGES IN SYMPATHETIC NERVOUS SYSTEM ACTIVITY: POSSIBLE IMPLICATIONS FOR

OBESITY

AND

HYPERTENSION

JAMES B. YOUNG and L E w I s LANDSBERG Charles A. Dana Institute, Department of Medicine, Beth Israel Hospital and the Harvard Thorndike Laboratory, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, U.S.A.

Abstract--The sympathetic nervous system responds to changes in caloric intake; caloric restriction decreases and carbohydrate administration increases sympalhetic nervous system activity in animals and man. Insulin may be a major link between changes in dietary intake and changes in central sympathetic outflow. Caloric restriction reduces, and carbohydrate administration increases blood pressure in spontaneously hypertensive rats, changes consistent with a primary effect of caloric intake on sympathetic nervous system activity. Stimulation of the sympathetic nervous system by overfeeding may contribute to the development and maintenance of hypertension in biologically-predisposed animals and man. The association of obesity and hypertension may reflect chronic overfeeding, although diet-induced changes in sympathetic nervous system activity may affect blood pressure in non-obese individuals as well.

THE SYMPATHOADRENALsystem is an important determinant of metabolic and cardiovascular activity. In recent years the influence of nutrient intake on the functional state of this system has been recognized, thereby raising the possibility that physiological phenomena and disease processes associated with feeding and diet may, in part, be mediated through the agency of catecholamines. Obesity and hypertension are two prominent examples of health problems potentially related to diet-induced changes in sympathoadrenal activity. This brief presentation will attempt to review current understanding of the connection between dietary intake and sympathoadrenal function and to discuss the implications of this connection for obesity and hypertension. Both components of the sympathoadrenal system, the sympathetic nervous system and the adrenal medulla, are governed by centers in the brainstem through descending neural pathways. The neurons of these brainstem centers have an intrinsic activity of their own, but are also influenced by neural input from higher regions of the central nervous system and from visceral and somatic neural afferents such as the carotid baroreceptor. In addition constituents of the blood such as glucose, oxygen, H +, hormones, substrates, and the like, may alter the activity of these brainstem centers. Epinephrine is the principal secretory product of the adrenal medulla. After its release into the circulation epinephrine is distributed widely throughout the body and produces its effects in tissues distant from its source, thus meeting the classical definition of a hormone. In contrast, norepinephrine (NE), the adrenergic neurotransmitter, is not a hormone. Since the effects of NE are largely exerted within the immediate vicinity of release, the extent of its direct influence within the body in any given situation is determined by the distribution of sympathetic innervation in different tissues and by the pattern of sympathetic outflow. The role, if any, of circulating NE is currently unknown. Supported by USPHS Grants AM 20378, AM 26455 and HL 24084. Published, by special editorial arrangement, as part of the Proceedings of a Symposium on Obesity and Hypertension held by the International Society on Hypertension in Jackson, Mississippi May 1980. 879

880

JAMES B. YOUyG and LEwis LANDSBERG

These differences between sympathetic nerves and the adrenal medulla have become more important with the recognition that the two branches of the sympathoadrenal system are regulated separately. At the present time the evidence that nutrient intake alters sympathodrenal activity suggests that only the sympathetic nerves are so affected. In our studies of sympathetic nervous system function, measurements of NE turnover in various sympathetically innervated organs of rats and mice, and of plasma NE levels in human subjects have served as the indices of neuronal activity. The technique of [-3H]NE turnover depends upon the amine transport system of the axonal membrane. After i.v. administration, [3H]NE is rapidly cleared from the circulation by uptake into sympathetic nerve endings. After equilibration with endogenous NE stores, the tracer becomes a valid marker of NE release. Since the principal determinant of NE release is sympathetic nerve impulse traffic, the rate of disappearance of the tracer provides an estimate of neuronal activity in the tissue in which it is being measured. The disappearance of tracer conforms to a monoexponential kinetic model which permits the computation of a fractional NE turnover rate by standard least squares methods and subsequently the statistical comparison of turnover rates in a given organ in groups of animals under different conditions. Because of the correspondence between sympathetic nerve impulse traffic and NE release, more rapid turnover reflects increased sympathetic activity and slower turnover, decreased sympathetic activity. The effect of nutritional state on sympathetic activity utilizing NE turnover methodology was first examined in fasting rats (Fig. 1) [1]. Prior to these experiments the general presumption had been that many of the metabolic adjustments associated with the fasting state, such as fuel mobilization and the suppression of insulin secretion, were consequent to an increase in sympathetic nerve activity. The results of the fasting experiments, however, were not compatible with that earlier hypothesis. Animals fasted for 48 hr before the start of the turnover measurement and during the 24 hr of the expert-

CONTROL k= 5.66 -+ O.14%/hr

104

tJ~2 • 12.3+ O.3hr /NETR

c

< U

103

= 23.1 + I.Sr~ NE/h@ort/hr

/~

I04

CONTROL k : 4.80~: O.I6%/hr tJ~ - 14.5. O.Shr

FASTED k = 2.66± 0.i5 %/hr tJ/2= 26.1-+ I.Shr

NETR: 21.4 +- 1.9nqNE/hlmrt/hr

NETR= 13.1:1: 1.2nQ N E / h ~ r t / h r

o~

HOURS

FIG. 1. Effect of fasting on norepinephrine turnover in rat heart. Control animals received water and lab chow ad libit.m while fasted animals received only a dilute electrolyte solution to drink for 48 hr prior to and during the experiment. Tracer norepinephrine was injected at time 0 and 3H and endogenous norepinephrine were measured in rat hearts 2, 6, 12 and 24 hr after injection, k, the slope of the exponentialcurve fitted to the data, was calculated by the method of least squares. The norepinephrine turnover rate (NETR) is the product of the rate of disap,pearance (k) and the endogenous norepinrphrine level. Fasting reduced cardiac norepinephrine turnover by 43~,. Reproduced from Ref. [2] with permission.

V-

I0 3 SUCROSE FED J t½= 8,2 t: 0+1hr

,'7

,,4,

NETR= 50.6-+ 2.3 ngNE/heort/~

HOURS

FIG. 2. Effect of sucrose feeding on norepinephrine turnover in rat heart. Sucrose-fed animals received an 8 ~ sucrose solution and lab chow for three days prior to and during the turnover study. Experimental design was otherwise similar to that in Fig. 1. Sucrose supplementation increased cardiac norepinephrine turnover by 43~o., Reproduced from Ref. [2] with permission.

Diet-induced Changes in Sympathetic Nervous System Activity

881

ment displayed a marked reduction of over 40~o in NE turnover in heart. Similar changes have also been found in pancreas and liver [-3], suggesting that the suppression of sympathetic activity by fasting is a generalized phenomenon and not one unique to the heart. Subsequent experiments explored the possibility that overfeeding might increase sympathetic activity (NE turnover) (Fig. 2) [4]. The model of voluntary overfeeding chosen was the provision of sucrose in the drinking water (8 100/~,) to rats fed a standard lab chow diet. Such a regimen leads to an increase in total caloric intake of approximately 30~o. After three days of sucrose feeding the overfed rats exhibited increased NE turnover in heart, pancreas and liver. Thus, the effect of dietary intake on neuronal activity occurs over a continuum from suppressed sympathetic activity with fasting to increased sympathetic activity with overfeeding. In the three years since these NE turnover studies in fasted and sucrose-fed rats appeared, evidence has accumulated that diet induces similar changes in sympathetic activity in human subjects. Untreated patients with primary anorexia nervosa demonstrated lower supine blood pressures and plasma NE levels and diminished blood pressure, heart rate and plasma NE responses to upright posture and to isometric handgrip than a comparably-aged control group [5]. Nutritional therapy of these anorectic patients restored both changes in blood pressure and plasma NE towards normal. Nonhypertensive obese subjects on a constant sodium intake exhibited lower supine heart rates, blood pressures and plasma NE levels after being switched from a high calorie diet to one containing 77% fewer carlories, a difference in caloric content of the two diets achieved by decreasing carbohydrate intake only [6]. In a more recent study of caloric restriction and sympathetic activity nonhypertensive obese subjects had lower supine and upright blood pressures and plasma NE levels when placed on a 400 kcal protein diet than when on control diet or on a 400 kcal mixed diet consisting of 50°o protein and 500L carbohydrate [-7-]. Thus caloric restriction is associated with decreased blood pressure and plasma NE concentrations in human subjects. From these preliminary studies carbohydrate lack appears to be the important dietary variable. On the other hand, feeding increases sympathetic activity in man. Hyperalimentation of patients suffering from protein calorie malnutrition leads to a marked increase in cardiac index and to a rise in plasma NE levels [8]. In studies from our own group the oral administration of 100 g of glucose in a standard glucose tolerance test produced a rise in plasma NE (Fig. 3) and evidence of cardiovascular stimulation manifested by an increase in pulse pressure and in heart rate systolic blood pressure product without any change in heart rate or mean arterial pressure [9]. Interestingly the plasma NE response to the glucose load was significantly greater in healthy elderly individuals above the age of 68 than in young subjects below the age of 33, although the cardiovascular changes were similar in young and old. In these stimulatory responses the role of carbohydrate administration figured prominently, as it did in the suppressive effects of caloric restriction, raising the possibility that plasma glucose and/or insulin concentrations might be an important signal to the central nervous system coupling sympathetic activity to dietary intake. To clarify the roles of plasma insulin and glucose in the sympathetic stimulation associated with carbohydrate administration studies were undertaken of the plasma NE and cardiovascular responses to glucose and insulin infusions [10]. The investigational methods employed in these experiments were variations on the glucose clamp technique developed by Dr Reubin Andres in Baltimore and were carried out in collaboration with Dr John W. Rowe at our institution. In the hyperglycemic protocol a 20~:'~,j, glucose solution was infused by Harvard pump to raise blood glucose concentration 125 mg'~ above the basal level. The rate of infusion was adjusted every 5 min to maintain stable hyperglycemia for the duration of the 2 hr study. In the insulin infusion protocols insulin was administered intravenously for 2 hr at doses of 2 and 5 mU/kg per min. In these studies glucose levels were maintained constant by an adjustable glucose infusion. Thus the influences of elevated glucose and/or insulin levels upon sympathetic and cardiovas-

882

JAMES B. YOUNG and LEWIS LANDSBERG

600 200

T Glucose

° Y°urR

•i

180 160 140

'~ ol a.

120 I00 ol ¢).

UJ Z o E i=1 o el

<~

60

z o E el

40

o

80

50o

o ConlrOl • G÷ 125 Hyperglycemic & 2mU Eugl~.,emic • 5mU Eu~lycemic

/ • •/

400

200

20

IOO

0

< 0.05

Control

-30

60

0

30

60

90

120 150

Min

40 20 0 1

[

I

0

30

60

Time,

1

b

120

180

rain

FIG. 3. Effect of oral glucose and control drinks on plasma norepinephrine (NE) levels in young and old healthy individuals. Seven young (18-33yr) and eight old (67 83 yr) subjects drank 200 ml containing glucose (100 g) or an artificial sweetener on separate occasions. Plasma NE rose 3 2 ~ with glucose in the young (not statistically significant) and 79~,, in the old (p < 0.0001). Statistical significance in the figure refers to comparisons between young and old. Reproduced from Ref. [9] with permission.

FZG. 4. Effect of glucose and insulin infusions on plasma norepinephrine levels in young men. In the G + 125 infusions blood glucose concentration was raised 125mg/dl at time zero and maintained at that level for 120min. In the 2 m U and 5 m U insulin infusions insulin was infused at the rate of 2 m U / k g per rain and 5 m U / k g per min, respectively, for 120 min while blood glucose concentration was maintained at basal levels for 150min. Data represent the mean plasma NE levels for seven G + 125, 2 m U and 5 m U infusions and for five control infusions. Plasma NE increased 500/0 over the course of the 2 m U infusion (p < 0.001) and 117'~0 during the 5 m U infusion (p < 0.001), but did not change during either the control or G + 125 infusion. Adapted from Ref. [10] with permission.

cular function can be separated. Control experiments were also carried out to assess the impact of the testing procedure itself on plasma NE and cardiovascular measurements. Control infusions produced no significant changes in plasma NE (Fig. 4). Stable hyperglycemia was also without effect upon plasma NE levels although the changes in plasma NE over time were slightly but not significantly higher than those obtained during control studies. During the two insulin infusions, plasma NE concentrations rose significantly and progressively, increases that were greater than changes observed with control tests. Moreover the plasma NE response to the higher rate of insulin infusion (5 mU/kg per min) was significantly greater than that during the lower dose insulin infusion. Additional studies demonstrated no impact of the insulin infusions on NE clearance from the circulation. Thus insulin administration in the absence of hypoglycemia is associated with increased sympathetic activity. Hemodynamic measurements were unaffected by the control tests and only pulse pressure increased during stable hyperglycemia. With the insulin infusions the double product rose to a similar extent in both studies. In the low dose infusion heart rate increased without any change in mean arterial pressure, while in the higher dose infusion mean arterial pressure rose 5-6mmHg in these normotensive volunteers without any change in heart rate. Thus insulin stimulates the cardiovascular system in normal young men in a pattern consistent with primary sympathetic activation. The studies confirm and extend earlier work in the 1960's from the laboratory of Dr Francois Abboud in which bolus injections' of insulin were shown to produce transient hypertension in dogs before hypoglycemia developed [11]. Ganglionic and adrenergic blockade attenuated the cardiovascular stimulation suggesting a role for the sympathetic nervous system in mediating this response. Moreover intracarotid injection of insulin was more effective at producing hypertension than systemic administration of insulin.

Diet-induced Changes in Sympathetic Nervous System Activity

883

Coordination of dietary intake and sympathetic activity whatever the afferent signal(s) is likely to take place within the hypothalamus. This region of the brain contains insulinsensitive areas, has known connections with brainstem sympathetic centers, is involved in other aspects of feeding physiology, such as hunger and satiety and coordinates autonomic activity with other environmental conditions, such as temperature. To begin to investigate the role of the hypothalamus in the dietary regulation of sympathetic activity we have measured NE turnover under different dietary conditions in intact mice and in obese mice previously treated with gold thioglucose [12]. Gold thioglucose is an agent that produces obesity in mice in association with destruction of the ventromedial hypothalamus. The sensitivity of this region to gold thioglucose is presumed to be related to the glucose moiety which, in the presence of insulin, carries the gold into certain cells important for appetite regulation and other processes. Although the mechanisms by which obesity is produced by gold thioglucose are uncertain, ventromedial hypothalamic damage does follow gold thioglucose treatment. Intact mice show the expected dietary variation in NE turnover (Fig. 5); fasting animals have a rate of NE turnover significantly slower than sucrose-fed ones. Gold thioglucose mice, in contrast, show no dietary variation. Both fasted and sucrose-fed mice demonstrate the same rate of NE turnover seen in the intact, sucrose-fed mice. Thus, gold thioglucose treatment abolishes the fasting suppression of sympathetic activity seen in normal mice. A model of dietary regulation of sympathetic nervous system activity has been developed which incorporates these findings in the gold thioglucose-treated mice. In this scheme (Fig. 6) the brainstem centers controlling sympathetic outflow receive inhibitory input from the hypothalamus. When the appropriate region of the hypothalamus is destroyed by gold thioglucose this descending inhibitory influence is removed. Fasting then increases the activity of this inhibitory pathway while sucrose feeding reduces it. Based upon the stimulatory effect of insulin and upon studies demonstrating a decrease in sympathetic activity in feeding animals treated with 2-deoxyglucose, a non-metabolizable glucose analogue [13], the effects of fasting and sucrose-feeding may result from changes in the rate of insulin-mediated glucose metabolism within certain neurons of the hypothalamus. Such a connection between dietary intake (principally carbohydrate intake) and sympathetic nervous system activity has important implications for both obesity and hypertension. The problem of obesity is clearly one of excess caloric intake relative to caloric expenditure. In recent years the focus of research attention in this area has been drawn to the

io3

Control

c~ •

AuTG

Fasted

/ - tl/_ 40.2 hr Fasted

:>

~o ioz

O0 Ld Z

t.~ ll4hr

Hours

t ~ 9 6 hr

Hours

FIG. 5. Effects of fasting and sucrose feeding on norepinephrine turnover in hearts of control and gold thioglucose (AuTG)-treated mice. Fasting began one day and sucrose feeding three days prior to the start of the turnover experiment. AuTG treatment had occurred 6-8 weeks previously. In control animals fasting was associated with reduced (65~Jo) norepinephrine turnover compared to sucrose feeding, while in AuTG-treated animals fasting and sucrose feeding yielded identical norepinephrine turnover rates. Reproduced from Ref. 1-12] with permission.

884

JAMES B. YOUNG a n d LEWIS LANDSBERG

Hypothaiamus (?VMH)

B ra instem

Fasting

centers

Sucrose feeding Sympathetic outflow

FIG. 6. Model of dietary regulation of central sympathetic outflow. +, stimulary influences: inhibitory influences.

,

possibility that obese individuals may dissipate a smaller fraction of ingested calories as heat than their lean counterparts. Since catecholamines, in general, and the sympathetic nervous system, in particular, are of major importance in governing the rate of heat production in mammals, dietary variations in sympathetic activity may account for a considerable portion of the increase in heat production associated with increased dietary intake. Thus derangements in dietary regulation of sympathetic activity could conceivably contribute to diminished dietary thermogenesis in obese animals and man. Potential defects in the proposed regulatory scheme might include deficient afferent signals, disordered central integration of the signal with appropriate sympathetic response, impaired peripheral thermogenic responses to catecholamines or combinations of all three. Although the pathophysiological importance of abnormal catecholamine-mediated thermogenesis has not been demonstrated in any form of human or animal obesity, further investigations in this area are likely to assist in the recognition and classification of different obesity syndromes. Changes in diet also affect blood pressure in a pattern consistent with the forementioned diet-induced alterations in sympathetic activity. In the human studies described earlier caloric restriction was associated with reduced blood pressure while acute carbohydrate administration led to evidence of cardiovascular stimulation. Studies in our laboratory with the spontaneously hypertensive rat demonstrate that this animal is particularly sensitive to changes in caloric intake, decreasing blood pressure when intake is

200

A T

E

.EE 150 0~ D_ "10 O

o m

10a

AdLib

.~

,~

)J( I---~AdLib"~'--ll ~ AdLib'--)(

,;

~o

~

~'o

3;

go

Days

FIG. 7. Effectof caloric restriction on blood pressure in SHR and WKY rats. Ten-week-old SHR and WKY rats were fed rat chow and water except during periods l and II. In period I, diet animals (0) were fed 4g rat chow per 100 g body weight while controls (©) received 8 g, approximately the same chow intake consumed in ad libitum periods. Both diet and control animals were given a hypotonic electrolyte solution instead of water during periods I and II. *, p < 0.025 and **, p < 0.001 for comparisons between diet and control animals. Reproduced from Ref. [-14] with permission.

Diet-induced Changes in Sympathetic Nervous System Activity

885

175 I

°-E~ I 15o[ 125~ Weeks

FIG. 8. Effect of oral sucrose and fat on blood pressure in SHR. Ten-week-old SHR were fed rat chow (7 g per 100 g body weight) and water. Control animals (O) received only chow and water. Sucrose-fed animals (0) received sucrose (2.3 g per 100g) in the chow and fat-fed animals (A) received fat isocaloric to sucrose (1.04 g per 100 g). Diet supplements were given from week 1 to week 3. Chow intake was the same for all groups for the first four weeks of the study after which chow was given ad libitum. Blood pressure in sucrose-fed SHR was greater than in either of the other groups (p < 0.01, analysis of variance). Reproduced from Ref. [15] with permission.

reduced [14] and increasing blood pressure when fed sucrose [153. In these experiments SHR and normotensive Wistar-Kyoto rats (WKY) were divided into two groups, one a control group and the other a diet-manipulated group (Fig. 7). While both groups of SHR and of WKY had similar blood pressures measured by the tail-cuff technique when fed ad libitum, SHR showed a 10~o reduction in blood pressure after 4 days of 50~o feeding and a 19~o fall after 4 days of fasting while sodium intake is maintained by provision of salt in the drinking water. WKY, on the other hand, showed no effect of 50~/o feeding and only a 7~, drop in blood pressure after the 4-day fast. Overfeeding carbohydrate produces the opposite effect in SHR (Fig. 8). In these experiments all SHR were fed a fixed amount of chow daily. After one week on such a regimen one-third of the animals received a sucrose supplement with the chow sufficient to raise total caloric intake by 30~o. A second third received a fat supplement with the chow that was isocaloric to the added sucrose while a third group was given no supplement. By this design sodium intake was equivalent in all three groups. After one week on these different diets blood pressure in sucrose-fed SHR had increased 12~o while in control and fat-fed SHR blood pressures had not changed. This difference was still maintained after an additional week on the three diets. Following withdrawal of the diet supplements blood pressures in all three groups were the same. No effect of one week of sucrose supplementation on blood pressure was observed in WKY. Thus changes in carbohydrate intake without altering sodium intake are associated with alteration in blood pressure in SHR and possibly, but to a lesser extent, in WKY. In summary, the sympathetic nervous system responds to changes in caloric intake; caloric restriction decreases and carbohydrate administration increases sympathetic nervous system activity in animals and man. Insulin may be a major link between changes in dietary intake and changes in central sympathetic outflow. Caloric restriction reduces, and carbohydrate administration increases blood pressure in spontaneously hypertensive rats, changes consistent with a primary effect of caloric intake on sympathetic nervous system activity. Stimulation of the sympathetic nervous system by overfeeding may contribute to the development and maintenance of hypertension in biologically-predisposed animals and man. The association of obesity and hypertension may reflect chronic overfeeding, although diet-induced changes in sympathetic nervous system activity may affect blood pressure in non-obese individuals as well.

REFERENCES 1 Young JB, Lansberg L: Suppression of sympathetic nervous system during fasting. Science 196:1473 -1475, 1977 2. Landsberg L, Young JB: Fasting, feeding and the regulation of the sympathetic nervous system. N Engl J Med 298: 1295-1301, 1978 3. Young JB, Landsberg L: Effect of diet and cold exposure on norepinephrine turnover in pancreas and liver. Am J Physiol 236: E524-E533, 1979 ~.1). 35,'12

c

886 4. 5. 6. 7. 8. 9. 10. 11. 12. 15. 14. 15.

JAMES B. YOUNG and LEWIS LANDSBERG Young JB, Landsberg L: Stimulation of the sympathetic nervous system during sucrose feeding. Nature 269: 615-617, 1977 Gross HA, Lake CR, Ebert MH, Ziegler MG, Kopin IJ: Catecholamine metabolism in primary anorexia nervosa. J Clin Endocr Metab 49: 805-809, 1979 Jung RT, Shetty PS, Barrand M, Callingham BA, James WPT: Role of cateeholamines in hypotensive response to dieting. Br Med J 1:12 13, 1979 DeHaven J, Sherwin R, Hendler R, Felig P: Nitrogen and sodium balance and sympathetic-nervoussystem activity in obese subjects treated with a low-calorie protein or mixed diet. N Engl J Med 302: 477 482, 1980 Heymsfield S, Chandler J, Nutter D: Hyperalimentation causes a hyperdynamic hypermetabolic state. Clin Res 26: 284A, 1978 (abstr) Young JB, Rowe JW, Pallotta JA, Sparrow D, Landsberg L: Enhanced plasma norepinephrine response to upright posture and oral glucose administration in elderly human subjects. Metabolism 29: 532-539, 1980 Rowe JW, Young JB, Minaker KL, Stevens AL, Pallotta JA, Landsberg L: Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes 30:219 225, 1981 Pereda SA, Eckstein JW, Abboud FM: Cardiovascular responses to insulin in the absence of hypoglycemia. Am J Physiol 202:249 252, 1962 Young JB, Landsberg L: Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse. J Clin Invest 65: 1086-1094, 1980 Rappaport EB, Young JB, Landsberg L: Dissociation of sympathetic nervous system (SNS) and adrenal medullary responses to 2-deoxy-D-glucose (2-DG). Clin Res 28: 403A, 1980 (Abstr) Young JB, Mullen D, Landsberg L: Caloric restriction lowers blood pressure in the spontaneously hypertensive rat. Metabolism 27:1711-1714, 1978 Young JB, Landsberg L: Effect of oral sucrose on blood pressure in the spontaneously hypertensive rat. Metabolism 30: 421-424, 1981