Diet-induced changes in sympathoadrenal activity: Implications for thermogenesis

Diet-induced changes in sympathoadrenal activity: Implications for thermogenesis

Life Sciences, Vol. 28, pp. 1801-1819 Printed in the U.S.A. Pergamon Press DIET-INDUCED CHANGES IN SYMPATHOADRENAL ACTIVITY: IMPLICATIONS FOR THERMO...

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Life Sciences, Vol. 28, pp. 1801-1819 Printed in the U.S.A.

Pergamon Press

DIET-INDUCED CHANGES IN SYMPATHOADRENAL ACTIVITY: IMPLICATIONS FOR THERMOGENESIS Lewis Landsberg and James B. Young The C h a r l e s A. Dana I n s t i t u t e and t h e Harvard Thorndike L a b o r a t o r y Department o f M e d ic in e , Beth I s r a e l H o s p i t a l and Harvard Medical S c h o o l , Boston, M a s s a c h u s e t t s

The sympathoadrenal system is an integrated functional unit comprised of the sympathetic nervous system and the adrenal medulla. Changes in the functional state of the sympathoadrenal system underlie the regulation of physiologic processes by catecholamines. Regulatory centers within the central nervous system control the release of norepinephrine at the sympathetic nerve endings and the secretion of epinephrine from the adrenal medulla. These regulatory centers respond to afferent neural impulses carried in somatic and visceral nerves, as well as to changes in the chemical constituents and physical properties of plasma. The central regulatory centers initiate integrated physiological responses that defend the constancy of the internal environment in the face of environmental challenge. One o f t h e most i m p o r t a n t f u n c t i o n s o f t h e sympathoadrenal system in t h e mammalian homeotherm i s t h e d e f e n s e o f normal body t e m p e r a t u r e d u r i n g c o l d e x p o s u r e ; w i t h o u t an i n t a c t sympathoadrenal system body t e m p e r a t u r e c a n n o t be m a i n t a i n e d ( 1 , 2 ) . In a d d i t i o n t o s y m p a t h e t i c a l l y mediated v a s o c o n s t r i c t i o n in t h e s u b c u t a n e o u s t i s s u e s , which d i m i n i s h e s h e a t l o s s , s y m p a t h e t i c s t i m u l a t i o n of metabolic processes i n c r e a s e s chemical heat production, a p~ocesses g e n e r a l l y r e f e r r e d to as n o n - s h i v e r i n g t h e r m o g e n e s i s (3). Although c o n s i d e r a b l e c o n t r o v e r s y s t i l l e x i s t s about th e s i t e s and b i o c h e m i c a l mechanisms i n v o l v e d i n n o n s h i v e r i n g t h e r m o g e n e s i s , t h e c r i t i c a l r o l e o f c a t e c h o l a m i n e s in s t i m u lating this process is well established (1-4). The s y m p a t h e t i c n e r v o u s system a p p e a r s t o p l a y t h e major r o l e in th e s t i m u l a t i o n o f n o n s h i v e r i n g t h e r m o g e n e s i s a l t h o u g h , when s y m p a t h e t i c n e r v o u s system f u n c t i o n i s i m p a i r e d , t he a d r e n a l m ed u ll a may c o n t r i b u t e s i g n i f i c a n t l y to t h i s p r o c e s s ( 2 , 5 ) . Despite the well-recognized role of catecholamines in the stimulation of non-shivering thermogenesis, the possibility that catecholamines might be involved in diet-induced thermogenesis has only recently received attention. The existence of diet-induced thermogenesis, simply defined as the increase in metabolic rate and heat production that occurs in association with caloric intake, despite a checkered past, appears well accepted today (4). Two recent lines of evidence strongly support an important role for the sympathetic nervous system in the regulation of this process. Part of the evidence, reviewed here, relates to the effect of diet on sympathetic activity. Supported by USPHS Grants AM 20378, HL 24084 and AM 26455

0024-3205/81/151801-19502.00/0 Copyright (c) 1981 Pergamon Press Ltd.

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Suppression of sympathetic activity with fasting and stimulation of the sympathetic nervous system during overfeeding might explain, at least in part, the changes in oxygen consumption known to occur in the disparate nutritional states (6-8). The other line of evidence, from the studies of Rothwell and Stock (9,10) indicates an important similarity between the processes of non-shivering thermogenesis in response to cold and diet~induced thermogenesis in response to overfeeding. Since the role of the sympathetic nervous system in non-shivering thermogenesis is well-established the demonstration of an important similarity between these two processes supports a crucial role for the sympathetic nervous system in diet-induced thermogenesis as well. Assessment of sympathetic nervous system activity has presented a difficult challenge to investigators interested in the role played by catecholamines in the regulation of metabolism. Since, under most circumstances, norepinephrine functions solely as a neurotransmitter and not as a circulating hormone, measurements of plasma norepinephrine (and therefore urinary norepinephrine levels as well) are relatively insensitive indices of sympathetic activity (ll). Plasma norepinephrine levels, furthermore, provide no information about possible heterogeneous sympathetic outflow and do not distinguish norepinephrine originating at the adrenergic synapses from norepinephrine secreted by the adrenal medulla (12,13). Nonetheless, despite these limitations, measurement of norepinephrine concentration in plasma, under appropriately controlled conditions, is the best currently available method for assessing sympathetic activity in man and has provided much useful information. In the experSmental animal it is possible to assess sympathetic activity by measuring norepinephrine turnover rate in individual sympathetically innervated organs. Measurement of norepinephrine turnover allows pricise distinction between the sympathetic nerves and adrenal medulla and has the potential to recognize differences in sympathetic outflow to different organs. In the studies described here the activity of the sympathetic nervous system was assessed by measurement of norepinephrine turnover rate in heart. THE NOREPINEPHRINE TURNOVER TECHNIQUE: EFFECT OF ACUTE COLD EXPOSURE ON CARDIAC NOREPINEPHRINE TURNOVER IN THE RAT. The experiment shown in Figure 1 demonstrates activation of the sympathetic nervous system during cold exposure and the use of the tritiated norepinephrine turnover technique as a measure of sympathetic activity. Acute exposure to cold is well known to sr~ulate the sympathetic nervous system (1,2,14-16). This sympathetic response is an essential component of the defense of body temperature in mammals. The application of the tritiated norepinephrine turnover technique in this setting is demonstrated in Fig. i. This technique utilizes the amine uptake process of the axonal membrane of sympathetic nerve endings. After intravenous administration tracer norepinephrine is rapidly cleared from the circulation by uptake into the sympathetic nerve endings; within the nerve endings the tracer rapidly equilibrates with the endogenous norepinephrine stores and is released, along with endogenous norepinephrine, in response to sympathetic nerve impulses. The rate of disappearance of tracer, as assessed by changes in specific activity of norepinephrine over time, is thus a measure of norepinephrine turnover in the particular organ under study (17-19). The decline in specific activity follows first-order kinetics; accordingly a slope representing the rate of disappearance (fractional turnover rate, k) can be calculated along with the half-time of disappearance (t i/2) of the transmitter. From the product of the slope and the steady-state norepinephrine level, which represents the pool size, the

Vol. 28, No.s 15 & 16, 1981

Dietary Changes in Sympathetic Activity

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CONTROL

104 -

k = 6.19 -I- 0.12 % / h r

A

=

::U

,½ = I , . 2 ± O . 2 h ,

h,

D I.d

z

o ¢3 n-

¢_) >I--

. COLD ~ k = u.6 -+ o.17 % / h r

to

t ~ = 6'0 + O'lhr

ow

~ . .

NETR = 4 8 . 2 -+ 4.2rig N E / h e 0 r t / h r

U. UJ

(3. o3 2

6

12

24

HOURS

FIG. 1 Increase in cardiac norepinephrine turnover in the rat during cold exposure. At time zero 180 gm Sprague-Dawley rats were injected with tracer 3H-L-NE at time zero. After injection half the animals were placed in a cold room at 4° C while the other half (ambient temperature controls) were maintained at room temperature. Groups of 5 to 6 animals were killed at preselected times (2,6,12, and 24 hours) after injection and the hearts removed and analyzed for tritiated and endogenous norepinephrine. The specific activity of cardiac norepinephrine is .plotted semi-logarithmically as a function of time according to the method of least squares. The decrease in specific activity obeys first order kinetics and the slope, therefore, is equal to the fractional turnover rate (percent decline per hour). A norepinephrine turnover r a t e (NETp) can be calculated from the product of the steady state endogenou~ norepinephrine level and the slope. Acute cold exposure marked]y increases cardiac norepinephrine turnover. Reproduced from (8) with permission.

norepinephrine turnover rate for a particular organ may be calculated (17,18). Utilizing this technique the effect of different experimental manipulations on norepinephrine turnover may be compared statistically. Since turnover depends predominantly on sympathetic nerve impulses the turnover rate provides an index of sympathetic activity. In the experiment shown in Figure i, 180 gm unanesthetized female Sprague-Dawley rats (Charles River Breeding Laboratories, Wilmington, MA) were injected with a tracer dose of °H-L-NE (New England Nuclear Corp., Boston, Mass.) via the tail vein at time zero. The cold exposed group

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was placed at 4°C while the control group was kept at room temperature. At 2,6, 12, and 24 hours after the injection of tracer S to 6 animals from each group were killed and the hearts (and other organs) removed and analyzed for tritiated and endogenous norepinephrine (8,19). As shown graphically in Figure i, cold exposure markedly increases the turnover rate of norepinephrine in heart. The actual values for the turnover rate in control and cold exposed animals are shown on the figure. A similar effect of cold exposure can be shown in other organs (19) and has been demonstrated with other techniques of assessing norepinephrine turnover as well (8,15). Experiments with ganglionic blocking agents demonstrate that changes in norepinephrine turnover do, in fact, reflect changes in central sympathetic outflow (19). When sympathetic activity is increased ganglionic blocking agents have a greater effect on norepinephrine turnover since impulse traffic at the level of the ganglia is increased and there are more descending impulses to block; conversely when sympathetic activity is diminished, ganglionic blockade has a lesser effect. In cold exposure ganglionic blockade has a greater effect on norepinephrine turnover than in ambient temperature controls (19). The experiment shown in Figure i, thus, demonstrates increased cardiac sympathetic activity during acute cold exposure. EFFECT OF FASTING AND SUCROSE OVERFEEDING ON SYMPATHETIC NERVOUS SYSTEM ACTIVITY In Figure 2 the effect of two days of fasting on cardiac norepinephrine turnover in the rat is shown. The fasting group was without food for 2 days prior to and the day of the turnover study. During fasting the animals were allowed free access to a dilute electrolyte solution (78 mEq/l sodium, 15 mEq/l potassium) to prevent sodium depletion. Cardiac norepinephrine turnover was markedly reduced (p-~0.001) in the fasted rats as compared with ad lib fed controls (6). During fasting the fractional turnover of norepinephrine in heart was 2.7 + 0.2%/hr. as compared with 5.7 + 0.1%/hr in control; corresponding changes in half-time of disappearance and [alculated norepinephrine turnover rate were also demonstrated (Fig. 2). As compared with ad lib fed control animals ganglionic blockade had much less of an effect on norepinephrine turnover in fasting animals, consistent with a decrease in central sympathetic outflow (6,13,19). Decrease in norepinephrJne turnover with fasting is demonstrable with the synthesis inhibition technique of assessing norepinephrine turnover (6) as well. Additional studies have demonstrated that suppression of sympathetic activity during fasting occurs in organs other than heart (19), occurs when intake is restricted to 30% of ad lib feeding as well as during total fast, can be demonstrated during the first day of fasting, and is partially reversed during one day of refeeding (19). The finding of diminished sympathetic activity with fasting was contrary to initial expectations. Many physiologic and pathophysiologic states are known to activate the sympathetic nervous system; fasting is one of the few situations in which suppression of sympathetic activity has been demonstrated. In Figure 3 the effect of overfeeding sucrose on cardiac norepinephrine turnover in the rat is shown. In this experiment 180 gm female SpragueDawley rats were permitted free access to an 8% sucrose solution in addition to laboratory chow for 3 days prior to and during the turnover study. As compared with control rats fed ad lib, rats offered the dilute solution of sucrose voluntarily increased total caloric intake

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Dietary Changes in Sympathetic Activity

CONTROL

104

k= 5.66 ±O.14%/hr /'N~:

i m > I--

1805

:2'~ .: :':.:rng NE/heort/hr

103 k =2.66± 0.15%/hr t~2= 26.1± 1.Shr NETR=13.1± I.Zn9NE/hlmrt/hr

h m LIJ O. O3

i

2

~

6

[

12 HOURS

__

i

24

FIG. 2

Suppression of cardiac norepinephrine turnover during f a s t i n g in t h e r a t . Rats were f a s t e d f o r 2 d a y s p r i o r t o and d u r i n g t h e t u r n o v e r s t u d y . C o n t r o l s were f e d ad l i b . Cardiac norepinephrine t u r n o v e r was d i m i n i s h e d by f a s t i n g . Reproduced from (6) w i t h p e r m i s s i o n .

a p p r o x i m a t e l y 30%. As shown in F i g u r e 3 s u c r o s e o v e r f e e d i n g was a s s o c i a t e d with a marked i n c r e a s e in c a r d i a c n o r e p i n e p h r i n e t u r n o v e r ( 7 ) . F r a c t i o n a l t u r n o v e r r a t e o f n o r e p i n e p h r i n e i n c r e a s e d from 4.8% ÷ 0 . 2 ~ / h r in a n i m a l s fed ad l i b t o 8 . 5 ÷ 0.1%/hr in t h e s u c r o s e f e d animaTs. C o r r e s p o n d i n g changes in t h e h a l T - t i m e o f d i s a p p e a r a n c e o f c a r d i a c n o r e p i n e p h r i n e and t h e c a l c u l a t e d n o r e p i n e p h r i n e t u r n o v e r r a t e were d e m o n s t r a t e d a s w e l l ( F i g u r e 3). An i n c r e a s e in c a r d i a c n o r e p i n e p h r i n e t u r n o v e r with s u c r o s e o v e r f e e d i n g was c o n f i r m e d u t i l i z i n g t h e s y n t h e s i s i n h i b i t i o n t e c h n i q u e (7). In s u c r o s e f e d a n i m a l s t h e e f f e c t o f g a n g l i o n i c b l o c k a d e was enhanced a s compared with ad l i b f e d c o n t r o l s i n d i c a t i n g t h a t t h e i n c r e a s e in n o r e p i n e p h r i n e t u r n o v e r i s c o n s i s t e n t w i t h an i n c r e a s e in c e n t r a l sympathetic outflow (7,13,19). Additional studies demonstrated that stimulation o f s y m p a t h e t i c a c t i v i t y in s u c r o s e o v e r f e d r a t s o c c u r s d u r i n g t h e f i r s t day o f s u c r o s e a d m i n i s t r a t i o n , i s p e r s i s t e n t t h r o u g h o u t a t l e a s t one week o f s u c r o s e o v e r f e e d i n g , and i s r e s t o r e d t o normal one day a f t e r t h e s u c r o s e i s removed. The i n c r e a s e in s y m p a t h e t i c a c t i v i t y with s u c r o s e o v e r f e e d i n g o c c u r s in a v a r i e t y o f o r g a n s in a d d i t i o n t o h e a r t (19). These studies demonstrate that fasting suppresses and overfeeding sucrose stimulates sympathetic a c t i v i t y in the rat. Thesediet-induced changes in sympathetic a c t i v i t y persist throughout the normal l i f e span of the rat (through 2 years of age) [20).

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10 4

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CONTROL k = 4.80+- O.16%/hr t ~ = 14.5 +--0.Sbr

L2 z-

NETR = 21.4 -+ 1.9ngNE/heort/hr

~J

z

o E3

r~ o I0 3 >-

SUCROSE FED J

> o

t½= 8.2-+ O.Ih r

o U.

NETR = 50.6 + 2.5 ng NE/heort/hr

uJ Q. CO

I

I

2

6

I

12 HOURS

I

24

FIG. 3 Figure 3. Increase in cardiac norepinephrine turnover during sucrose overfeeding in the rat. Sucrose fed animals were given free a c c e s s to a n 8% sucrose solution in addition to laboratory chow for 3 days prior to and during the turnover study. Caloric intake increased approximately 30% as compared with ad lib fed control animals. Sucrose feeding was associated with an increase in cardiac norepinephrine turnover. Reproduced from (7) with permission.

THE EFFECT OF HYPOGLYCEMIA ON SYMPATHOADRENAL ACTIVITY IN THE RAT: DISSOCIATION OF SYMPATHETIC NERVOUS SYSTEM AND ADRENAL MEDULLARY RESPONSES Classic and widely quoted studies from the laboratories of Cannon and Houssay clearly established over 50 years ago, that hypoglycemia is associated with marked stimulation of the adrenal medulla. The effect of hypoglycemia on the sympathetic nervous system, however, has only recently been elucidated (12,13,21). In Table 1 the effects of 3 diverse forms of hypoglycemia on the adrenal medulla and sympathetic nervous system are summarized. The three types of hypoglycemia studied include the fasting pregnant rat, the fasted phlorizin treated rat, and the normally fed rat treated with 2-deoxy-D-glucose (2-DG). The normal 150-200 gm Sprague-Dawley rat sustains a 4-day fast without developing hypoglycemia. Pregnant rats, and non-gravid rats treated with the glycosuric agent phlorizin, developed frank hypoglycemia during a fast (Table I). 2-deoxyD-glucose inhibits intracellular glucose metabolism within the central nervous system thus simulating hypoglycemia (Neuroglucopenia) in the face of an actual rise in plasma glucose concentration. In these three situations adrenal medullary stimulation is readily demonstrable by an increase in

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Table i.

Dietary Changes in Sympathetic Activity

Sympathoadrenal activity and hypoglycemia in the rat Plasma Glucose mg/dl

Sympathetic Nervous System Calculated Cardiac NE Turnover Rate (% d e c r e a s e )

Pregnancy Fed Fasted Phlorizin Fed Fasted Control Fed 2 DG-treated (fed ad lib)

*

means ± SEM.

1807

59 Z 4* 36 • 3

116 Z 3 49 z 3

Adrenal Medulla

Urinary E

(% increase)

-66%

+420%

-17%

+1000%

-25%

+440%

Data are summarized from (i~, 13, 21).

u r i n a r y e p i n e p h r i n e e x c r e t i o n (an i n c r e a s e c o m p l e t e l y blocked by a d r e n a lectomy or a d r e n a l d e m e d u l l a t i o n ) , and by d e p l e t i o n of a d r e n a l m e d u l l a r y epinephrine content. In the face of marked a d r e n a l m e d u l l a r y s t i m u l a t i o n , s y m p a t h e t i c a c t i v i t y , as measured by c a r d i a c n o r e p i n e p h r i n e t u r n o v e r , i s suppressed. The d i s o r d a n c e in s y m p a t h e t i c n e r v o u s system and a d r e n a l m e d u l l a r y r e s p o n s e s i n d i c a t e s t h a t i n t e r r u p t i o n of g l u c o s e s u b s t r a t e s u p p l y t o the c e n t r a l n e r v o u s system has o p p o s i t e e f f e c t s on t h e s y m p a t h e t i c n e r v o u s system and t h e a d r e n a l m e d u l l a . This d i s s o c i a t i o n p r o v i d e s c l e a r e v i d e n c e of d i s t i n c t c e n t r a l r e g u l a t i o n of the s y m p a t h e t i c n e r v e s and the a d r e n a l medulla and s u g g e s t s t h a t an i m p o r t a n t r o l e f o r the a d r e n a l medulla may be the p r o v i s i o n o f c a t e c h o l a m i n e s a t a time when t h e s y m p a t h e t i c n e r v o u s system i s f u n c t i o n a l l y s u p p r e s s e d . Since a d r e n a l m e d u l l a r y s t i m u l a t i o n r e s u l t s i n enhanced a d r e n a l m e d u l l a r y s e c r e t i o n of n o r e p i n e p h r i n e as well as e p i n e p h r i n e (12, 13, 21), t h i s d i s s o c i a t i o n emphasizes c l e a r l y t h e d i f f i c u l t y i n a c c u r a t e l y a s s e s s i n g s y m p a t h e t i c a c t i v i t y from plasma or u r i n a r y n o r e p i n e p h r i n e l e v e l s when a d r e n a l m e d u l l a r y a c t i v i t y i s s t i m u l a t e d . Furthermore s i n c e hypoglycemia i s o f t e n a s s o c i a t e d with a d e c r e a s e i n body t e m p e r a t u r e , d e s p i t e high c i r c u l a t i n g l e v e l s of c a t e c h o l a m i n e s of a d r e n a l m e d u l l a r y o r i g i n , t h e s e o b s e r v a t i o n s support o t h e r s t u d i e s (2,22,23) t h a t i n d i c a t e the primacy of the s y m p a t h e t i c n e r v o u s system (as compared with t h e a d r e n a l medulla) i n t h e s t i m u l a t i o n of thermog e n e s i s . The f a l l i n body t e m p e r a t u r e d u r i n g hypoglycemia i s c o n s i s t e n t with s y m p a t h e t i c n e r v o u s system s u p p r e s s i o n .

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In t h e e x p e r i m e n t s w i t h 2 - d e o x y - D - g l u c o s e , chow i n t a k e a c t u a l l y i n c r e a s e d a t a t i m e when t h e a d r e n a l m e d u l l a was s t i m u l a t e d and t h e sympathetic nervous system suppressed. This indicates that diminished glucose utilization w i t h i n the c e n t r a l nervous system i s r e l a t e d to the s u p p r e s s i o n o f s y m p a t h e t i c a c t i v i t y t h a t o c c u r s d u r i n g 2-DG a d m i n i s t r a t i o n , and, r a i s e s t h e p o s s i b i l i t y that diminished glucose utilization in the c e n t r a l n e r v o u s s y s t e m may be i n v o l v e d i n t h e f a s t i n g r e s p o n s e as w e l l . These e x p e r i m e n t s s u g g e s t , t h e r e f o r e , t h a t g l u c o s e m e t a b o l i s m w i t h i n t h e c e n t r a l n e r v o u s s y s t e m i s an i m p o r t a n t l i n k b e t w e e n d i e t a r y i n t a k e and sympathetic activity. DIET-INDUCED CHANGES IN SYMPATHETIC NERVOUS SYSTEM ACTIVITY: ROLE OF INSULIN

POSSIBLE

Changes in central sympathetic outflow in response to changes in dietary intake must be initiated by a signal that communicates nutritional status to the central nervous system. The studies described above are consistent with a role for glucose metabolism within central neurons. The observation that, in normal human subjects, an oral glucose tolerance test (I00 gms) stimulates the sympathetic nervous system as measured by an increase in plasma norepinephrine level (24,25) with a concomitant increase in pulse rate, pulse pressure, and resting oxygen consumption (24,25) also supports a potential role for glucose in initiating changes in central sympathetic outflow in accordance with changes in dietary intake. On theoretical grounds, however, it hardly seems likely that the plasma glucose level per se is an adequate or sufficient signal. Plasma glucose levels are maintained within rather narrow limits despite large changes in caloric or carbohydrate intake. The plasma insulin level, however, is highly responsive to changes in carbohydrate intake and the circulating level of insulin itself may serve as an index of insulinmediated glucose metabolism within the central nervous system. Insulin m i g h t make a v e r y e f f e c t i v e s i g n a l i n t h e c o o r d i n a t i o n o f s y m p a t h e t i c a c t i v i t y and c a r b o h y d r a t e i n t a k e s i n c e i n s u l i n l e v e l s v a r y w i d e l y and reflect, in a g e n e r a l sense, the c a r b o h y d r a t e load a s s i m i l a t e d . Insulin, furthermore, is the major signal to tissues outside the central nervous s y s t e m t h a t c a r b o h y d r a t e s (and o t h e r n u t r i e n t s ) have b e e n a s s i m i l a t e d and i t would be b o t h p a r s i m o n i o u s and I o g i c a l f o r i n s u l i n t o s e r v e a similar function for the central nervous system as well. To e v a l u a t e t h e s i g n i f i c a n c e o f p l a s m a l e v e l as compared w i t h e n h a n c e d i n s u l i n secretion in the stimulation of the sympathetic nervous system studies were p e r f o r m e d w i t h i n s u l i n and g l u c o s e clamp t e c h n i q u e s . These t e c h n i q u e s , which depend upon p r i m i n g and v a r i a b l e i n f u s i o n s o f g l u c o s e , o r g l u c o s e and i n s u l i n , p e r m i t t h e d e v e l o p m e n t o f e i t h e r s t e a d y s t a t e hyperglycemia (hyperglycemic clamp), or hyperinsulinemia in association w i t h n o r m a l p l a s m a g l u c o s e l e v e l ( e u g l y c e m i c clamp) ( 2 6 ) . Utiiizing t h e s e t e c h n i q u e s t h e e f f e c t o f h y p e r g l y c e m i a on s y m p a t h e t i c a c t i v i t y can be compared w i t h t h e e f f e c t o f e u g l y c e m i c h y p e r i n s u l i n i s m . In F i g u r e 4 t h e e f f e c t s o f h y p e r g l y c e m i a and 2 l e v e l s o f e u g l y c e m i c h y p e r i n s u l i n e m i a on p l a s m a n o r e p i n e p h r i n e l e v e l s a r e shown. The r e s u l t s a r e compared w i t h a c o n t r o l clamp i n which s a l i n e a l o n e was i n f u s e d . No c h a n g e i n p l a s m a n o r e p i n e p h r i n e l e v e l was n o t e d i n t h e c o n t r o l o r hyperglycemic clamps; in both euglycemic hyperinsulinemic studies there was a s i g n i f i c a n t r i s e i n p l a s m a n o r e p i n e p h r i n e l e v e l d u r i n g t h e i n s u l i n infusion. T h i s e f f e c t o f i n s u l i n was d o s e r e l a t e d w i t h a s i g n i f i c a n t l y

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600 500

Dietary Changes in Sympathetic Activity

o Control • G ÷ 125 Hyperglycemic 2mU Euglycemic • 5mU Euglycemic

1809

/ A

./

.t /

400

200

I00

0

6,~O

i

O

i

i

30 60 Minuta$

i

90

,

120

IO

FIG. 4 Increase in plasma norepinephrine level during euglycemic hyperinsulinism in human subjects. Twelve normal male volunteers, aged 18-36, were studied in four different experimental protocols. In the control group saline only was infused; in the hyperglycemic clamp (G + 125) the glucose concentration was raised 125 mg/dl above basal and maintained at that level for 120 min (7 subject); in the euglycemic clamp studies insulin was infused at 2 mU/kg/min in the low dose infusion (7 subjects), and at 5 mU/kg/min in an additional study (high dose insulin infusion; 7 subjects). In both the euglycemic hyperinsulinemic clamps glucose was infused at sufficient rat to maintain plasma glucose at the basal level. Arterial samples of venous blood were removed for measurement of insulin and norepinephrine concentration and pulse and blood pressure were measured throughout the study. During the insulin infusion the insulin was infused for 120 min& glucose was maintained at euglycemic levels for an additional 50 min. after the insulin infusion was terminated. Mean plasma glucose concentration between 20 and 120 min. was 81 mg/dl + 1.0 SEM in control study; in the hyperglycemic clamp 208 + 1.6; in the ~ mU euglycemic clamp 78.6 + 0,5; and in the 5 mU eugl~cemic clamp 80.2 + 1.0. Mean plasma insulin concentration between 20 and 120 min. in the--control test was 7.3 uU/ml + I.i SHM; in the hyperglycemic clamp 44 ÷ 0.7; in the euglycemic 2 mU clamp 154 ~ 52; and in the 5 mU euglycemic [lamp 601 + 74. Plasma norepinephine levels were significantly greater during--the 2 mU clamp than during control and significantly greater in the 5 mU clamp than in the 2 mU study (both p 0.001 by ANOVA). As noted in the text the cross product (pulse rate x systolic blood pressure) and pulse pressure were increased in both euglycemic clamps and mean arterial blood pressure was increased in the 5 mU euglycemic clamp as compared with control group. Data from (26).

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greater plasma norepinephrine response during the high dose insulin infusion. In addition, indices of cardiovascular stimulation consistant with sympathetic activation were noted during the insulin infusion; thus, pulse pressure and double product (systolic blood pressure X pulse rate) were increased in both euglycemic hyperinsulinemic clamps. In the high dose (5 mU) clamp mean arterial blood pressure was increased (26). These data must be interpreted with caution since the insulin levels achieved during both euglycemic hyperinsulinemic clamps (see Figure 4 Legend) exceed those usually achieved during feeding. The unphysiologic route of administration of glucose and insulin in these infusion studies may be partially responsible for the need to achieve high levels in order to see an effect. Nonetheless, the data in Figure 4 do indicate that hyperinsulinemia, without a change in blood glucose, has the capacity to stimulate the sympathetic nervous system while steady state hyperglycemia per se appears to have less of an effect. CENTRAL INTEGRATION OF TIIE FASTING AND FEEDING SIGNAL: TURNOVER IN THE GOLD-THIOGLUCOSE TREATED ~OUSE.

CARDIAC NOREPINEPHRINE

In order to characterize the central neuronal structures involved in the relationship between fasting, overfeeding and sympathetic activity studies were performed in the gold thioglucose-treated mouse. Treatment with gold thioglucose destroys portions of the hypothalamus particularly the ventromedial region (27). This portion of the brain is sensitive to insulin and glucose and appears to be intimately involved in the regulation of food intake 628). Gold thioglucose treatment results in the development of an obesity syndrome characterized by hyperphagia, hyperinsulinism, and an increase in body fat stores. The development of obesity, therefore, in treated animals serves as a marker for the development of the central nervous system lesion. ]'he ettects of fasting and sucrose overfeeding on cardiac norepinephrine turnover in obese gold thioglucose treated mice and control animals are shown in Table 2. As compared with control animals, goldthioglucose treated mice do not show diet=induced changes in sympathetic nervous system activity (Table 2). Both fasting and sucrose fed goldthioglucose treated mice have cardiac norepinephrine turnover rates similar to those of sucrose-fed control animals. Pretreatment with gold= thioglucose thus prevents the suppression of sympathetic activity that normally occurs during fasting (29). In the study presented in Table 2 the mice were fasted for one day prior to the turnover study; additional studies demonstrated that a two day fast in gold thioglucose treated mice was not associated with suppression of cardiac norepinephrine turnover (29). The results summarized in Table 2 are not explicable in terms of a nonspecific effect of gold since mice treated with gold thiomalate (which does not produce the obesity syndrome) show a normal suppression of cardiac norepinephrine turnover with fasting. Additional experiments with ganglionic blocking agents were consistent with failure of suppression of sympathetic activity during fasting in the gold thioglucose treated mice; ganglionic blockade had a much greater effect on cardiac norepinephrine turnover in fasted gold-thioglucose treated mice as compared with fasted control animals. Gold thioglucose treatment, furthermore, did not result in a non-specific paralysis of sympathetic activity since the response to cold exposure in gold thioglucose treated mice was well preserved as was the adrenal medullary response to 2-deoxy-D-glucose administration (29). It thus appears that the gold thioglucose pretreatment disrupts the normal suppressive effect that fasting exerts on sympathetic activity.

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Table II.

Dietary Changes in Sympathetic Activity

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Effect of gold-thioglueose pretreatment on diet-induced changes in sympathetic nervous system activity

k (heart) %/hour

Calculated NE turnover rate ng NE/heart/hour

Control Fast

1.7 ± 1.0"

1.6 ± 1.0

Sucrose-fed

6.1 ± 1.0

4.6 ± 1.0

(p < 0.001) Gold-thioglucose Fast

5.9 ± 1.5

5.5 ± 1.6

Sucrose-fed

7.2 ± 0.7

5.4 +_ 0.8

(NS)

* means Z SEM.

Data are from 29.

The failure of suppression of the sympathetic nervous system in the gold thioglucose-treated mouse implies that, under normal circumstances, hypothalamic neurons sensitive to gold thioglucose exert a suppressive effect on sympathetic outflow during a fast. This suggests that suppression .of sympathetic activity with fasting is an active process and not simply the passive withdrawal of sympathetic stimulation induced by feeding. A model of hypothalamic regulation of sympathetic outflow in response to changes in diet based on these findings is shown in Figure 5. According to this model, descending inhibition of sympathetic activity during fasting is dependent upon stimulation of an inhibitory pathway or pathways between the hypothalamus and the brainstem (Figure 5). Conversely, stimulation of sympathetic activity by feeding is associated with suppression of the inhibitory pathway thus resulting in disinhibition of tonically active lower neurons (29). In conjunction with the studies described above these experiments suggest that insulin mediated glucose metabolism within goldthioglucose sensitive neurons in the hypothalamus may be involved in initiating changes in sympathetic activity in response to changes in diet. CALORIC INTAKE AND SYMPATHETIC NERVOUS SYSTEM ACTIVITY: IMPLICATIONS FOR THERMOGENESIS

POTENTIAL

The e x p e r i m e n t s d e s c r i b e d h e r e , i n t h e r a t and mouse, d e m o n s t r a t e that fasting suppresses the sympathetic nervous system while overfeeding sucrose exerts a stimulatory effect. Recent evidence indicates that diet-induced changes in sympathetic nervous system activity occur in

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Hypothalamus Brainstem centers (+)

Fasting Sucrose feeding

Sympathetic outflow FIG. S Hypothalamic regulation of sympathetic outflow in response to changes in diet; model based on descending inhibition. The experiments in the gold-thioglucose-treated mouse are consistent with stimulation (+) of an inhibitory pathway (or pathways) between the hypothalamus and the brainstem during fasting. These pathways may involve the ventromedial portion of the hypothalamus (V~4). Overfeeding, according to this model, is associated with suppression of the inhibitory pathways with resultant disinhibition of brainstem sympathetic centers and increase in central sympathetic outflow. Reproduced from (29) with permission.

human subjects as well (24,25,30-32). One stimulus for diet-induced changes in sympathetic nervous system activity, particularly in response to carbohydrate feeding, appears to be glucose metabolism (perhaps insulin mediated) within the hypothalamus (perhaps in the ventromedial portion). Since preliminary studies in our laboratory indicate that fat may stimulate sympathetic nervous system activity in the rat as well as sucrose it appears likely that other mechanisms and other signals may be involved when nutrients other than carbohydrates are administered. The role of the sympathetic nervous system in the generation of metabolic heat in response to cold exposure (non-shivering thermogenesis) is well established (I-3). The site of this metabolic heat production, as well as the biochemical processes involved, has been the subject of debate (3). In the rodent evidence implicating an important role for brown adipose tissue is increasing (33). Brown adipose tissue is a highly specialized organ located in the interscapular and paraspinal regions; it is endowed with unusual morphological, biochemical, and physiological properties. It is densely innervated with sympathetic nerve endings (3). The major function of this organ, in distinction to white adipose tissue (which is a storage depot for fat) is the generation of heat. Brown adipose tissue is particularly prominent in neonates, small mammals accli,mted to cold, and hibernators. Although the physiologic significance of this tissue in adult mammals, particularly in larger non-hibernating species has been much debated, recent studies indicate that it may be of a more general significance than previously

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Dietary Changes in Sympathetic Activity

r e c o g n i z e d [9). In r o d e n t s brown a d i p o s e t i s s u e a p p e a r s t o p l a y a major r o l e in c o l d a c c l i m a t i o n , a p r o c e s s t h a t r e q u i r e s t h e p r e s e n c e o f t h y r o i d hormone (34). In c h r o n i c a l l y c o l d exposed r o d e n t s brown f a t h y p e r t r o p h i e s , t h e t h e r m o g e n i c e f f e c t s o f c a t e c h o l a m i n e s a r e markedly enhanced, and h e a t output is s t r i k i n g l y increased. Heat p r o d u c t i o n by brown a d i p o s e t i s s u e in r e s p o n s e t o c o l d i s s t i m u l a t e d by th e s y m p a t h e t i c n er v o u s system (23). Recent e v i d e n c e from t h e l a b o r a t o r y o f Rothwell and Stock i n d i c a t e s t h a t brown a d i p o s e t i s s u e may have an i m p o r t a n t r o l e in d i e t - i n d u c e d t h e r m o g e n e s i s in t h e r a t . This l a t t e r p r o c e s s , which r e f e r s t o an i n c r e a s e in m e t a b o l i c h e a t p r o d u c t i o n d u r i n g o v e r f e e d i n g , i s a s s o c i a t e d with h y p e r t r o p h y o f brown a d i p o s e t i s s u e and i n c r e a s e d r e s p o n s i v e n e s s o f brown a d i p o s e t i s s u e t o t h e t h e r m o g e n i c e f f e c t s o f n o r e p i n e p h r i n e (9, 10), changes e n t i r e l y a n a l o g o u s t o t h o s e o c c u r r i n g in c o l d a c c l i m a t i o n . The d i e t - i n d u c e d changes in s y m p a t h e t i c n e r v o u s system a c t i v i t y r e v i e w e d h e r e s u p p o r t t h e m o rph o lo g i c and b i o c h e m i c a l e v i d e n c e i n d i c a t i n g a s i m i l a r i t y between n o n - s h i v e r i n g t h e r m o g e n e s i s and d i e t - i n d u c e d t h e r m o g e n e s i s {Figure 6 ) . O v e r f e e d i n g , as w e l l as c o l d e x p o s u r e i n c r e a s e s s y m p a t h e t i c a c t i v i t y and i t a p p e a r s l i k e l y t h a t s t i m u l a t i o n o f m e t a b o l i c h e a t

Cold exposure. ......

t Dietary intake

$NS activity

Thermogenesis (NST or DTT)

Caloric expenditure FIG. 6 S t i m u l a t i o n o f s y m p a t h e t i c n e r v o u s system a c t i v i t y and t h e r m o g e n e s i s by c o l d e x p o s u r e and o v e r f e e d i n g . Both e x p o s u r e t o c o l d and c a l o r i c e x c e s s i n c r e a s e s y m p a t h e t i c n e r v o u s system (SNS) a c t i v i t y which r e s u l t s i n an i n c r e a s e in t h e r m o g e n e s i s and enhanced c a l o r i c expenditure. When c o l d i s t h e p r o x i m a t e s t i m u l u s t h e i n c r e a s e in h e a t p r o d u c t i o n i s r e f e r r e d t o as n o n s h i v e r i n g t h e r m o g e n e s i s (NST); when i n c r e a s e d d i e t a r y i n t a k e i s t h e s t i m u l u s t h e r e s u l t a n t i n c r e a s e in oxygen consumption i s r e f e r r e d t o as d i e t - i n d u c e d t h e r m o g e n e s i s (DIT). Evidence r e v i e w e d in t h e t e x t s u g g e s t s t h a t t h e s e two p r o c e s s e s a r e closely related. Reproduced from [4) with p e r m i s s i o n .

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production by catecholamines underlies both these processes. It is particularly interesting in this regard that preliminary experiments performed by Elizabeth Saville in our laboratory indicate that chronic overfeeding as well as chronic cold exposure increase norepinephrine turnover in brown adipose tissue of the rat. These considerations suggest an important physiological role for diet-induced changes in sympathetic nervous system activity. During fasting or caloric restriction suppression of the sympathetic nervous system would result in diminished oxygen consumption and conservation of calories; the survival value of a diminished metabolic rate under these circumstances is obvious. Conservation of calories at a time when caloric intake is limited is a metabolic adaptation certain to be favored by evolutionary pressures. Similarly, an increase in sympathetic activity with overfeeding would result in the dissipation of excess calories as heat. The ability to dissipate calories consumed in excess might be of particular value to organisms on a subsistence diet of marginal nutritional quality. Under these circumstances the need for nitrogen might be satisfied by increasing dietary intake of foodstuffs low in protein; the resultant increase in sympathetic activity might prevent excess accumulation of fat while insuring adequate nutrition and the maintenance of body weight. The h>~othesis that dietinduced changes in sympathetic activity contribute to the changes in oxygen consumption and metabolic rate known to occur during fasting and over-feeding appears reasonable and warrants further study. Diet-induced changes in sympathetic activity have important potential implications for the development of obesity and for the association of obesity with hypertension and cardiovascular disease. If the sympathetic nervous system plays an important role in diet-induced thermogenesis, then a disorder in either the activation of the sympathetic nervous system, or a reduction in the sensitivity to the thermogenic effects of norepinephrine might predispose to the development of obesity. The physiologic result of either abnormality would be diminished thermogenic responses to feeding; such individuals would have a thrifty metabolic trait with efficient utilization of foodstuffs and fuel storage that would serve well during periods of caloric restriction or famine; in the presence of an abundant food supply, however, these same individuals would be predisposed toward excessive fuel storage in the form of fat. Both sympathetic responses to feeding and the responsiveness of obese individuals to the thermogenic effects of catecholamines require further study. The physiologic significance of diet-induced changes in sympathetic activity, however, may not be limited to changes in thermogenesis and oxygen consumption. Stimulation of the sympathetic nervous system during overfeeding may be associated with secondary undesirable effects on the cardiovascular system. An increase in sympathetic activity with overfeeding may account, at least in part, for the association of obesity and hypertension. Similarly, the beneficial effect of weight loss on blood pressure (35) may be secondary to suppression of sympathetic activity in association with caloric restriction. Studies of the effect of fasting and overfeeding on blood pressure in the spontaneously hypertensive rat support just such a mechanism (36,37). A similar relationship between dietary intake and the sympathetic nervous system may also be important in ischemic heart disease. The development of angina or myocardial infarction in overfed individuals may depend, at least in part, upon increased myocardial oxygen demand consequent to enhanced sympathetic activity in individuals predisposed by preexistent

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1815

coronary a r t e r y disease. According to t h i s h y p o t h e s i s s y m p a t h e t i c s t i m u l a t i o n of the c a r d i o v a s c u l a r system c o n s e q u e n t t o d i e t - i n d u c e d changes i n s y m p a t h e t i c a c t i v i t y may be an u n d e s i r a b l e s i d e e f f e c t of a b a s i c a d a p t i v e mechanism whereby the s y m p a t h e t i c n e r v o u s system c o u p l e s changes i n d i e t a r y i n t a k e with changes i n t h e r m o g e n e s i s . REFERENCES i.

Jansky, L.: Non-shivering thermogenesis and its thermoregulatory significanc E . Biol. Rev. 48:85-132, 1973.

2.

Himms-Hagen, J . : Role o f the a d r e n a l m e d u l l a i n a d a p t a t i o n to c o l d . Chap. 38 I n : Handbook of P h y s i o l o g y , S e c t i o n 7 E n d o c r i n o l o g y , Yol Yl. Adrenal Gland eds. Blaschko, H., S a y e r s , G. and Smith, A.D., American P h y s i o l o g i c a l S o c i e t y , Washington, D.C. pp. 637-665, 1975.

3.

Himms-Hagen, J. Cellular thermogenesis. 1976.

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Landsberg, L. and Young, J.B. D i e t - i n d u c e d changes i n sympathoadrenal activity: I m p l i c a t i o n s f o r t h e r m o g e n e s i s . O b e s i t y & Metabolism (In p r e s s ) .

5.

Young, J.B. and Landsberg, L. E f f e c t of c o n c o m i t a n t f a s t i n g and c o l d exposure on sympathoadrenal a c t i v i t y i n r a t s . Am. J. P h y s i o l . (In p r ess) .

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Young, J.B. and Landsberg, L. S u p p r e s s i o n of the s y m p a t h e t i c n e r v o u s system d u r i n g f a s t i n g . Science 196:1473-1475.

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Landsberg, L. and Young, J.B. (1978): F a s t i n g , f e e d i n g , and t h e r e g u l a t i o n of s y m p a t h e t i c a c t i v i t y . N. Engl. J. Hod. 298:1295-1301.

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Rothwell, N.J. and Stock, M.J. A r o l e f o r brown a d i p o s e t i s s u e i n d i e t - i n d u c e d t h e r m o g e n e s i s . Nature 281:31-35, 1979.

10.

Rothwell, N . J . , and Stock, H.J. S i m i l a r i t i e s between cold and d i e t induced t h e r m o g e n e s i s i n t h e r a t . Can. J. P h y s i o l . Pharmacol. 58:985-991.

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12.

Young, J.B. and Landsberg, L.: Sympathoadrenal a c t i v i t y i n f a s t i n g pregnant rats: d i s s o c i a t i o n of a d r e n a l m e d u l l a r y and s y m p a t h e t i c n e r v o u s system r e s p o n s e s . J. C l i n . I n v e s t . 6 4 : 1 0 9 - 1 1 6 , 1979.

13.

Landsberg, L., G r e f f , L., Gunn, S. and Young, J.B. A d r e n e r g i c mechanisms i n the m e t a b o l i c a d a p t a t i o n t o f a s t i n g and f e e d i n g : E f f e c t s of p h l o r i z i n on d i e t - i n d u c e d changes i n sympathoadrenal a c t i v i t y i n the r a t . Metabolism, (In p r e s s ) .

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LeDuc, J . : Catecholamine p r o d u c t i o n and r e l e a s e i n exposure and a c c l i m a t i o n to c o l d . Acta P h y s i o l . Scand. 53 ( S u p p l . ) 1-101, 1961.

Annu. Rev. Physiol 38:315-351,

S t i m u l a t i o n of the s y m p a t h e t i c nervous Nature, 269:615-617, 1977.

Hormone and n e u r o t r a n s m i t t e r i n man.

Am. J .

Physiol.

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IS.

Gordon, R., Spector, S. Sjoerdsma, A. and Udenfriend, S.: Increased synthesis of norepinephrine and epinephrine in the intact rat during exercise and exposure to cold. J. Pharmacol. Exp. Ther. 183:440-447, 1966.

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Olivario, A, and Stjarne, L.: Acceleration of noradrenaline turnover in the mouse heart by cold exposure. Life Sci. 4:2339-2343, 1965.

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Landsberg, L. and Axelrod, J. Influence of pituitary, thyroid and adrenal hormones on norepinephrine turnover and metabolism in the rat heart. Circulation Res., 22:8S9-571.

18.

Neff, N.H., Tozer, T.N., Hammer, W., Costa, E., and Brodie, B.B. A~plication of steady-state kinetics to the uptake and decline of H ~ -NE in the rat heart. J. Pharmacol. Exp. Ther. 160:48-52.

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Young, J.B. and Landsberg, L. Effect of diet and cold exposure on norepinephrine turnover in pancreas and liver. Am. J. Physiol. 256:ES24-E553, 1979.

20.

Rappaport, E.B., Young, J.8. and Landsberg, L.: Impact of age on basal and diet-induced changes in sympathetic nervous system activity of Fischer rats. J. Gerontology, in press.

21.

Rappaport, E.B., Young, J.B. and Landsberg, L.: Dissociation of sympathetic nervous system (SNS) and adrenal medullary responses to 2-deoxy-D-glucose (2-DG). Clin. Res. 28:403A, 1980.

22.

Seydoux, J. and Girardier, L.: Control of brown fat thermogenesis by the sympathetic nervous system. £xperientia 33:1128-1130, 1977.

23.

Depocas, F., Behrens, W.A. and Poster, D.O.: Noradrenaline-induced calorigenesis in warm-and in cold-acclimated rats: The interrelation of dose of noradrenaline, its concentration in arterial plasma, and calorigenic response. Can. J. Ph/siol. Pharmacol. 56:168-174, 1978.

24.

Young, J.B., Rowe, J.W., Pallotta, J.A., Sparrow, D. and Landsberg, L. Enhanced plasma norepinephrine response to upright posture and oral glucose administration in elderly human subjects. ~Jetabolism 29:532-539.

25.

Welle, S., Lilavivanthana, U. and Campbell, R.G: Preliminary Report: Increased plasma norepinephrine concentrations and metabolic rates following glucose ingestion in man. Metabolism (in press).

26.

Rowe, J.W., Young, J.B. Minaker, K.L., Stevens, A.L. Pallotta, J. and Landsberg, L. (In press): Insulin increases sympathetic activity independent of changes in blood glucose. Diabetes.

27.

Brecher, G., Laquer, G.L. Cronkite, E.P. Edelman, P.M. and Schwartz, I.L. The brain lesion of gold thioglucose o~oesity. J. Exp. Med. 121:395-401, 1965.

28.

Debons, A.F., Krimsky, I., From, A., and Cloutier, R.J. Rapid effects of insulin on the hypothalamic staiety center. Am. J. Physiol. 217:1114-1118, 1969.

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29.

Young, J.B. and Landsberg, L.: Impaired suppression of sympathetic activity during fasting in the gold thioglucose-treated mouse. J. Clin. Invest. 65:1086-1094, 1980.

30.

Gross, H,A., Lake, C.R., Ebert, H.H., Ziegler, M.G., and Kopin, l.J. Catecholamine metabolism in primary anorexia nervosa. J. Clin. Endocrinol. Metab. 49:805-809, 1979.

31.

Jung, R.T., Shetty, P.S., Barrand, M., Callingham, B.A., and James, W.P.T. Role of catecholamines in h)~otensive response to dieting. Br. Med. J., 1:12-13, 1979.

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DeHaven, J., Sherwin, R.,' Hendler, R., and Felig, P. Nitrogen and sodium balance and sympathetic-nervous-system activity in obese subjects treated with a low-calorie protein or mixed diet. N. Engl. J. Med. 302:477-482.

oo.

Foster, D.O. and Frydman, M.L. Nonshivering thermogenesis in the rat. It. Measurements of blood flow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can. J. Physiol. Pharmacol. 56:110-122.

54.

Sellers, E.A., Flattery, K.V. and Steiner, G.: Cold acclimation of hypothyroid rats. Am. J. Physiol. 226:290-294, 1974.

35.

Reisen, E., Abel, R., Modan, M., Silverberg, D.S., Eliahou, H.E. and Modan, B. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. New Engl. J. Med. 298:1-6, 1978.

36.

Young, J.B., Mullen, D., and Landsberg, L. Caloric restriction lowers blood pressure in the spontaneously hypertensive rat. Metabolism 27:1711-1714, 1978..

37.

Young, J.B., and Landsberg, L. Sucrose feeding increases blood pressure in the spontaneously hypertensive rat. Metabolism (In press).

EDITED GENERAL DISCUSSION

Fisher inquired about the relationship between euglycemic hyperinsulinism and sympathetic nervous system stimulation on the one hand, and hypoglycemia and stimulation of the adrenal medulla on the other; he wondered whether the data implied that insulin stimulated the sympathetic nervous system while glucose regulated the adrenal medulla. Landsberg replied that the important variable appeared to be a glucose metabolism within certain critical neurons in the hypothalamus. During the fed state insulin-mediated glucose metabolism within these critical hypothalamic neurons results in stimulation of the sympathetic nervous system~ during fasting glucose metabolism within these cells is diminished (as both glucose and insulin levels fall) and sympathetic nervous system activity is suppressed. If hypoglycemia supervenes a different set of central neurons stimulates the adrenal medulla while the sympathetic nervous system remains suppressed. Brown wondered what happened to sympathetic nervous system activity in absolute or relative insulin deficiency

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states, such as experimental diabetes or somatostatin infusions with supplemental glucose, and whether or not changes in sympathetic nervous system activity have been demonstrated in experimental models of obesity other than the gold thioglucose treated mouse. Landsberg replied that experiments with somatostatin had not yet been performed and that experiments with streptozotocin-induced diabetes were thus far inconclusive although there was a preliminary indication that diabetic animals had smaller changes in sympathetic activity with changes in dietary intake than control animals. The ob/ob mouse displays normal changes in sympathetic nervous system activity with fasting and overfeeding unlike the gold thioglucose treated mouse in which fasting is not associated with sympathetic nervous system suppression. Fain wondered how lipid mobilization occurs in the fasting state if both sympathetic nervous system and peripheral conversion of T 4 to T 3 is suppressed during fasting. Landsberg indicated that he agreed with Cahill that the low circulating level of insulin in the fasting state is probably of paramount importance; he also indicated that modest stimulation of the adrenal medulla might occur as the plasma glucose level falls during fasting even when the glucose is above the usual threshold for a full counterregulatory response. A modest rise in epinephrine secretion, in conjunction with a diminished insulin level might contribute to substrate mobilization during fasting under these circumstances. Goodner raised the question of important species differences in the sympathetic nervous system response to fasting. He emphasized that evidence for sympathetic suppression during fasting in human and nonhuman primates is much less conclusive than in the rodent, particularlv early in the course of a fast. Landsberg responded that at least three studies in man provided data consistent with a decrease in sympathetic nervous system activity during the course of fasting or semi-starvation, although in none of these was the situation examined critically during the first three or four days of diminished caloric intake. Landsberg emphasized the difficulty in demonstrating sympathetic nervous system suppression in man with currently available techniques. Johnson emphasized nonhomogenous sympathetic outflow and cautioned against overinterpretation of data based on turnover studies in heart or even plasma catecholamine levels; he wondered whether sympathetic outflow to selected regions such as adipose tissue might in fact be increased during fasting. Landsberg replied that although that was possible, all the tissues studied, including brown adipo@e tissue, showed suppression of sympathetic activity in the rat during fasting. Oppenheimer and Danforth both raised the question of the potential significance of insulin resistance at central nervous system sites concerned with the regulation of sympathetic nervous system activity. Oppenheimer wondered whether the decrease in oxygen consumption that occurs in aging rats might be a manifestation of this insulin resistance and reflect a failure of sympathetic activation during feeding. In a similar vein Danforth wondered whether central insulin resistance and diminished dietary-induced thermogenesis might contribute to the obesity of the Pima Indian. Landsberg replied that these speculations were interesting and worthy of study. Experiments with aged rats indicate that diet-induced changes in sympathetic nervous system activity occur in rats up to 24 months of age. Insulin infusion in aged human subjects, however, on the basis of preliminary experiments, appears to be much less effective at stimulating sympathetic nervous system activity than in younger subjects, a finding consistent with central insulin resistance. Landsberg raised the possibility that loss of brown adipose tissue, a critically important organ in the production of metabolic heat and regulation of oxygen consumption, may be important in regard to both aging human subjects and animals, and Pima Indians. Landsberg pointed out that the sympathetic nervous system is the switch that turns on heat production by brown adipose tissue. Danforth remarked that overfeeding

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results in an increase in interscapular brown adipose tissue within three days in the rat and that by 50 days of overfeeding the increase in mass is over three-fold. He pointed out that this is due almost entirely to cellular hyperplasia and suggested that the increase in peripheral conversion of T 4 to T 3 with overfeeding may play a role in the adaptive increase in this tissue. Fain pointed out that although rodent models are interesting it is important to keep in mind that extrapolation of the results to man may be unwarranted; the significance of brown adipose tissue, in particular, in human subjects is open to question. Danforth remarked that brown fat in human subjects may be considerably more important than previously recognized. Brown fat is relatively easy to identify in the newborn; with advancing age brown fat becomes more diffuse and from a histological point of view, unless special studies are performed, may appear superficially like white adipose tissue and may, therefore, be underestimated unless a specific search is made to identify this tissue. Danforth called attention to studies recently performed in the United Kingdom in the laboratories of Stock and Rothwell, and James, in which activation of brown adipose tissue was demonstrated in vivo by infra red thermography and thermistor probes in normal human subjects receiving sympathomimetic amines or norepinephrine infusions. Danforth emphasized that it is important to keep an open mind about the physiological and clinical significance of brown adipose tissue. Factors involved in the disappearance of this tissue either with aging or with obesity and the possibility of increasing brown adipose tissue mass may have important cinical implications.