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Food intake, sympathetic activity, and adrenal steroids
Bruin Rcsearcl? Buiielin. Vol. 32, pp. 537-541,
1993 Copyright
Printed in the USA. All rights reserved.
036 l-9230/93 $6.00 + .OO (LI 1993 Pergamon Press Ltd.
Food Intake, Sympathetic Activity, and Adrenal Steroids GEORGE
A. BRAY
PenrzingfonBiomedical Research Center, Departmenf i~~~edicine, Louisiana State University, School qf Medicine, 6400 Perkins Rmd, Baton Rouge, LA ~08~~-4~~4 BRAY, G. A. Food intake, .~~vlnputh~ti~~ activity and adrenul simids. BRAIN RES BULL 32(5) 537-541. 1993.--Food intake is reciprocally related to the activity of sympathetic nerves to brown adipose tissue. This reciprocal or feedback relation is shown for hypothalamic lesions, drugs, and many peptides. These peptides also modulate intake ofspecific nutrients. Galanin and opioids increase fat intake, whereas enterostatin decreases fat intake, NPY increases carbohydrate intake and growth hormone releasing hormone decreases protein intake. The activity of the sympathetic nervous system is low in obesity and adrenalectomy reverses this decrease in sympathetic activity and reverses or stops the progression of obesity. One mechanism for this effect of adrenal steroids is through a transacting substance which is involved in steroid actions and the production of obesity. Food intake
Sympathetic activity
Adrenal glucocorticoids
SYMPATHETIC
Hypothaiamus
Genetics
Obesity
activity (28). 2-Deoxy-D-glucose, an analog of glucose that blocks intracellular metabolism of this metabolite, stimulates food intake and reduces sympathetic activity (3) (Table 2). The site of action on the sympathetic nervous system for some of these substances has been identified (Fig. 1). The dosedependent reduction in firing rate following the injection of norepinephrine into the paraventricular nucleus was blocked by phentolamine, an alpha adrenergic blocking drug (40), but not by propranolol, a beta adrenergic blocking drug, suggesting the involvement of cu-adrenergic receptors. In contrast to the decreased firing rate produced by injecting NE into the PVN, injection of NE into the ventromedial hypothalamus produced a dose-dependent increase in firing rate but the quantities required were iO-100 times greater than those injected into the PVN (40). This effect of norepineph~ne was also blocked by phentolamine but not propranolol. Serotonin increased sympathetic firing rate when injected into either the ventromediai or paraventricular nucleus and the doses were similar (40). Glucose increased sympathetic firing rate when injected into the ventromedial nucleus but decreased firing when injected into the LHA (38). When injected into the paraventricular nucleus, glucose produced an increase in sympathetic activity to IBAT, which was considerably smaller than when injected into the VMH (4 I ). Insulin reduced sympathetic firing when injected into the ventromedial nucleus, (39) but produced a small increase when injected into the lateral hypothalamus (38), and a small decrease when injected into the paraventricular nucleus (41). It is conceivable that the effects of insulin and glucose in the paraventricular nucleus were the result of their diffusion to the ventromedial hypothalamus where the effects of these two substances were much more robust. Corticotropin releasing hormone (CRH) increases sympathetic activity when injected into the third ventricle of the brain (4,20) or into the medial preoptic area, but not when injected into the lateral hypothalamus, the ventromedial hypothalamus, or the paraventricular nucleus (19). Neuropeptide-Y reduced
activity is affected by food intake. Young and Landsberg (60) first showed that fasting lowered sympathetic activity and, subsequently, that ingesting sucrose solutions increased sympathetic activity (59). Following this lead, Yoshida et al. (56) found that food intake in the dark increased sympathetic activity more than when food was eaten in the light. When Sakaguchi et al. (42) explored this phenomenon further they observed a highly significant inverse relationship between sympathetic activity and spontaneous food intake. The inverse relationship between sympathetic nervous system firing rate to brown adipose tissue and food intake was of particular interest because it suggested a potential feedback loop between sympathetic activity and food intake (10). Several studies on the reciprocal relationship of food intake and sympathetic activity are summa~zed in Table I. VMH lesions increase food intake and decrease sympathetic activity (43,54). Conversely, LH-lesions reduce food intake and produce an increase in sympathetic activity (2,57). One exception to this relationship appears to be a lesion of the paraventricular nucleus, which increases food intake but does not decrease SNS activity. However, for the level of hyperphagia in PVN-lesioned rats the level of SNS activity might be lower than anticipated. Neurotransmitters, such as norepinephrine and serotonin, show a reciprocal relationship between food intake and sympathetic activity (40). This reciprocal association is also noted for several peptides (9,141, including neuropeptide Y (NPY) (20,2 I), P-endorphin ( 18). cholecystokinin (CCK) (58), corticotropin releasing hormone (CRH) (4%19,20), anorectin (I), and MSH (52), which are found in the hypothalamus or pituitary (Table 1). A reciprocal relationship between food intake and sympathetic activity has also been found with several drugs. Fenfluramine ($30) amphetamine and mazindol(28) decrease food intake and increase sympathetic activity. Nicotine slightly decreases food intake but significantly increases sympathetic activity (29). Diethylpropion is an exception, which reduces food intake but does not show a measurable increase in sympathetic
537
538
TABLE RELATIONSXIP
OF FOOD
INTAKE
1
1 SYMPATHETIC NERVOUS ACTIVITY 1
AND SYMPATHETIC Effects
Procedure
Lesion or Injection Site
Lesion Lesion ~~repinephrine Serotonin Neuropeptide Y &Endorphin CRH Cholecystokinin Glucagon Anorectin
VMH 1-H VMH VMH PVN 3rd ventricle 3rd ventricle 3rd ventricle LH 3rd ventricle
Experimental
Food Intake
ACTIVITY
of Treatment
on
Sympathetic Nervous System Activity
c s : r
;
?
:
!
f
4 i
?
t = increased: 4 = decreased: --+ = no change PVN = Paraventricular nucleus. VMH = Ventromedial hypothalamus. LH = Lateral hypothalamus. C‘RH 7 Corticotropin releasing hormone.
. . . . . . . . . . Par8SyIIIpathetiC BAT
sympathetic activity when injected into the third ventricle (20) or into the PVN (21). Interestingly. NPY, like CRH, increased sympathetic firing when injected into the MPOA. CRH increases SNS activity after injection into the VMH or LH, but not other areas. PEPTIDES
AFFECT
THE INTAKE
OF SPECIFIC
NUTRIENTS
has been known for more than a decade that peptides located in the gut and brain can either selectively increase or decrease food intake (32). For example, the opioid peptides. neuropcptide Y, pancreatic peptide YY, galanin, and growth hormone releasing hormone can increase food intake (27). On the other hand, cholecystokinin, bombesin, anorectin, enterostatin, corticotrophin releasing hormone, glucagon, neurotensin, calcitonin, and TRH decrease food intake (32). As noted above. there is a reciprocal relationship between the effect of food intake and the activity of the sympathetic nervous system for a number of these peptides (12). Many of these peptides It
TABLE EFFECT
2
OF DRUGS ON FOOD INTAKE SYMPATHETIC ACTIVITY
AND
Effect of Treatment
Injection Food intake
Site
Treatment
on
Pancreas
rm
Symp8theti~
Ly
FIG. I A model of the hypothalamic control of sympathetic function. This model shows the sites at which several peptides have been shown to affect sympathetic activity. Solid lines refer to sympathetic connections; dashed lines to parasympathetic connections.
affect the intake of specific nutrients ( 12) (Table 3). Of part&tar interest in a circulating satiety factor is a pentapeptide derived from enzymatic cleavage of pancreatic procolipase into colipase the pentapeptide Val-Pro-Asp-Pro-Arg (VPDPR) (22). This pentapeptide, VPDPR is released by trypsin hydrolysis during activation of the colipase which is involved in digestion of triglycerides. Enterostatin was found to reduce food intake and to specifically reduce the intake of fat (23,45). Galanin, on the other hand, stimulates fat intake. Neuropeptide Y stimulates carbohydrate intake, and cycle-his-pro reduces carbohydrate intake. Recently, glucagon has been shown to reduce protein intake (12). Thus, there are now peptides that can selectively reduce or stimulate the intake of each of the macronut~ents. Because
Sympathettc Nervous System Activity
TABLE 7-deoxy_D-glucose Fenlluramine Nicotine Mazindol d-Amphetamine Diethylpropion t = increased;
ICV IP SC IP IP IP
4 = decreased:
ICV = intracerebroventricle. IP = intraperitoneal. SC = subcutaneous.
i
-,
I *
T
i 4
F +
= no change
PEPTIDES
AFFECTING
3
SPECIFIC
NUTRIENTS
Nutrient
1ncreasc
Decrease
Carbohydrate Protein Sodium
Galanin Opioids p-Casomorphin Neuropeptide Y Growth hormone RH Angiotensin
Enterostatin Vasopressin Corticotropin RH Cholecystokinin Glucagon
Fat
FOOD
INTAKE
AND
SYMPATHETIC
539
ACTIVITY
of its long half life, VPDPR (enterostatin) is a prime candidate for a circulating satiety factor for fat intake.
FATIY
RECIPROCAL RELATIONSHIP OF SYNAPTOSOMAL UPTAKE OF NOREPINEPHRINE
Uptake of norepinephrine by hypothalamic synaptosomes is reciprocally related to sympathetic activity (46). An inverse relationship between synaptosomal uptake of norepinephrine and sympathetic activity was found in rats and mice under a variety of experimental conditions. When sympathetic activity was low there was a high reuptake of norepinephrine and, thus, probably low extracellular norepinephrine concentration as compared to states of high sympathetic activity where reuptake of norepinephrine was low and. thus, the extracellular concentration of norepinephrine was probably high. These data would suggest that hypothalamic norepinephrine concentration directly modulates the sympathetic nervous system. An anatomic model of the hypothalamus and its adrenergic controls (see Fig. I) show that the ventromedial, lateral, and paraventricular areas interact with each other primarily through the dorsomedial hypothalamus. The ventromedial hypothalamus has an important input into the sympathetic nervous system through the periaqueductal gray matter in the medulla, and, hence. into the dorsal motor nucleus (DMH) of the vagus. The lateral hypothalamus also has an input into the vagal complex in the hindbrain and, in turn, modulates the sympathetic nervous system. Sympathetic activity is reduced in most known forms of obesity. Following the classical work of Rothwell and Stock (36) who showed that sympathetically innervated brown adipose tissue responded to overeating by an increase in thermogenic activity, Himms-Hagen and Desautels (24) measured the thermogenic activity of brown adipose tissue in genetically obese mice. They observed a reduction in sympathetic activity in these animals as had been observed in animals with hypothalamic obesity (14). Subsequent work by York and his colleagues (25.3 1). as well as Vander Tuig (53) and Knehans and Romsos (26). demonstrated a reduced level of sympathetic activity to brown adipose tissue in all of the recessively inherited forms of genetic obesity. Thus, reduced sympathetic activity exists in both hypothalamic and genetic forms of obesity. ADRENAL
DEPENDENCE
OF OBESITY
Adrenal glucocorticoids are essential for the development of hypothalamic obesity whether from VMH or PVN lesions (9). Bruce et al. ( 16) Debons et al. ( 17) and, subsequently, Tokunaga et al. (5 I) all showed that adrenalectomy reverses hypothalamic obesity and that in such animals treatment with corticosterone restores the hyperphagia and obesity. Thus, adrenal glucocorticoids play a critical role in the development of hypothalamic obesity. Circulating adrenal glucocorticoids are also essential for the development of all forms of genetic obesity, [fatty rat (62,63). obese mouse (33,37,61), diabetes mouse (48) and yellow mouse (48)] and for dietary obesity (34) and castration-induced obesity (8). Adrenalectomy profoundly influences the expression of obesity in genetically obese animals as it does in those with hypothalamic obesity (8.9). Solomon et al. (50) and Naeser (33) have shown that adrenalectomy improved glucose tolerance. However, it was the work of Yukimura and his colleagues (61-63) Bray ( 15) and Saito and Bray (37) that clearly demonstrated the role of adrenalectomy in the phenotypic expression for almost all of the defects in genetically obese animals. Following adrenalectomy, insulin and glucose levels fall (6,6 l), food intake returns
FA GENE Protein
& -
2% 1
(Steroid Responsive)
I
I Protein (Enzyme)
4 Permissive
1 Steroid Responsive4
FIG. 2. Transacting model for the genetic defect in the fatty rat. The FA gene is depicted as producing a protein that modulate the action of steroid responsive genes.
critical
to normal (37). muscle mass increases (37,44), insulin resistance is reduced (35). growth occurs (62,37), sympathetic activity returns to normal (53,55), and the accretion of body fat occurs only at normal rates (37). Because the adrenal gland and its secretion of glucocorticosteroids plays a key role in modulating the activity of the sympathetic and parasympathetic nervous system, it has been proposed that these two systems act together to regulate nutrient partitioning, and fat storage. One explanation for the effects of adrenalectomy is through modulation of gene expression. Adrenal steroids modulate the expression of genes involved in Iipogenesis after replacement of corticosterone in adrenalectomized genetically obese rats differently from lean rats (7, I I). In fatty rats that are adrenalectomized, the levels of mRNA for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) declines to low levels. This contrasts with the effects in lean animals where little or no change is observed in adrenalectomized animals. With steroid replacement there was an increase in mRNA for GAPDH in the liver from genetically obese rats but little effect in the lean animal. Similar findings were observed in adipose tissue when the mRNA for malic enzyme was studied. Because the mRNA for these two enzymes are transcribed from different genes our observations suggest that the genetically obese animal may have a defect in the synthesis of a peptide in response to corticosteroids which would regulate indirectly the function of other enzymes such as GAPDH and malic enzyme. Such a transacting factor could explain the diverse defects in these genetically obese animals and how steroid hormones modulate these functions, and is diagrammed in Fig. 2. Adrenalectomy reverses not only genetic but hypothalamic and other types of obesity as well. In the absence of a hypothalamic lesion or the genetic defect of the obese animal adrenal steroids do not produce significant obesity. Yamamoto and his group have proposed that steroids modulate some transcription events by interacting with transcription factors. C-fos and c-jun would be two possible examples. If either the steroid or the transacting factor are missing, the genes will be appropriately transcribed. For genetically obese animals this would result from a genetic defect in the production of the factor. For hypothalamic obesity the loss of neuronal stimulation might reduce the production oft-fos or c-jun and, thus, alter gene transcription controlled by steroids. This transcriptional model for steroidal control of obesity can be applied to all of the know defects. ACKNOWLEDGEMENT
Supported in part by Grant No. DK32089.
I. Arase. K.; Sakaguchi. T.: Takahashi. M.: Bray. Ci. A.: Lmg. N. Effects
2.
3.
4.
5.
6.
7.
on feeding behavior of rats of a cryptic peptide from the c-terminal end of prepro-gro~h hormone-pleasing factor. Endoc~nol~)g~ I 21: 1960-1965: 1987. Arase. K.: Sakaguchi, T.: Bray. G. A. Lateral hypothalamic lesions and activity of the sympathetic nervous system. Life Sci. 4 I :h57662: 1987. Arase. K.: York, 0.: Bray, G. Corticosterone inhibition of the intracerebrovent~cular effects of 2-deoxy-D-ghtcose on brown adipose tissue thermogenesis. Physiol. Behav. 41:489-495: 1987. Arase, K.; Shargill, N.; Bray, G. A. Effects of intraventricular infusion of co~icotropin-reieas~ng factor on VMH-lesioned obese rats. Am. J. Physiol. 256:R75 I-E756; 1989. Arase. K.; Sakaguchi, T.: Bray, B. A. Effect offenfluramine on sympathetic firing rate. Pharmacol. Biochem. Behav. 29(3):675-680: 1988. Bailey, C. J.; Day. C.; Lipson, L.; Bray, G. A. Role ofadrenal glands in the development ofabnormal ghtcose and insulin homeostasis in genetically obese (ob/ob) mice. Horm. Metah. Res. 18:357-360: 19x7. Bray, G. A. Genetic and hypothalamic mechanisms for obesity. Finding the needle in the haystack. Am. J. Clin. Nun. 50:X91-902:
1989. 8. Bray. G. A.; York, D. A.; Fisler. J.S. Experimental obesity: A homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam. Horm. 45:l-124: 1989. 9. Bray. G. A.; Fisler, J. S.; York, D. A. Neuroendocrine control of the development of obesity: Unde~tanding gained from studies of experimental animal models. Front. Neuroendoc~nol. I I : i28- IX I ; 1990. IO. Bray, G. A. Obesity-A disease of nutrient or energy balance’? Nutr. Rev. 45:33-43: 3987. 1I. Bray. G. A.: York, D. A.; Lavau, M. Co~icosteroids induce a timerelated increase in mRNA in fatty but not in lean rats. lnt. J. Obes. 13:547; 1989. 12. Bray, G. A. Peptides affect the intake of specific nutrients and the sympathetic nervous system. Am. J. Clin. Nutr. 55:265S-271% 1992. 13. Bray. G. A.; Shim& H.; Retzias, A.; York, D. Studies of the metabolic basis for obesity: Sympathetic activity. ad~nal~tomy and reduced acetylation of MSH. In: Lardy. H.; Stratman, F.. eds. Hormones thermogenesis and obesity. New York: Elsevier; 1989:245256. 14. Bray. G. A. Obesity. a disorder of nutrient pa~itioning: The Mona Lisa hypothesis. J. Nutr. 121:1146-l 162: 1991. IS. Bray, G. A, Regulation of energypalance: Studies on genetic. hypothalamic and dietary obesity. Proc. Nun. Sot. 41:95-10X: 1982. 16. Bruce, B.: King, B.; Phelps, G. R.: Veitia. M. Effects of adrenalectomy and corticosterone administ~tion on hypothaiam~c obesity in rats, Am. J. Physiol. 243:E152-E157: 1982. 17. Debons, A.: Siclari, E.: Das. K.; Fuhr, B. Gold thioglucose-induced hypothalamic damage, hyperphagia. and obesity: Dependence 011 the adrenal gland. Endocrinology 110:2024-2029: 1982. IX. Egawa, M.; Yoshimatsu. H.: Bray, G. A. Effect of B-endorphin on sympathetic nerve activity to inte~apular brown adipose tissue. Am. J. Psyiol. 264(33):RlO9-RI 15: 1993. 19. Egawa, M.; Yoshimatsu, H.; Bray, G. A. Preoptic area injection Of corticotropin-releasing hormone stimulates electrophysiological sympathetic activity to interscapular brown adipose tissue. Am. J. Physiol. 259:R799-R806; 1990. 20, Egawa, M.; Yoshimatsu, H.; Bray, G. A. Effect of CRH and NPY on electrophysioiogical activity of sympathetic nerves to interscapular brown adipose tissue. Neuroscience 34:77 I-775; 1990. 21 Egawa, M.; Yoshimatsu, H.; Bray, G. A. Neuropeptide Y (NPY) suppresses sympathetic activity to ~nte~pular brown adipose tissue in’&. Am: J.Physiol. (in press). 22 Erlanson-Albertsson, C.; Larsson, A. A possible physiological function of pro-colipase activation peptide in appetite regulation, Biochemistry 70:1245-1250; 1988. 23 Erlanson-Albertsson, C.; Lamson, A. The activation peptide of pancreatic pro-colipase decreases food intake in rats. Regul. Pept. 22: 324-331: 1988.
34. Himms-Hagcn.
J.: Desautels. M. .A mitochondrial defect in brown adipose tissue of the obese (ob/ob) mouse: Reduced binding of purinc nucleotides and a failure to respond to cold by an increase in bmding. Biochem. Biophys. Res. Comm. 83:62X-634: 197X. ‘5. Holt, S.; York, D. 4. The effect of adrenalectomv in GDP binding on brown adipose tissue mitochondria of obesc~rats. Biochem. .r 20X8 19-8’2: 1982. 26. Knehans, A. W.: Romsos. D. R. Reduced norcpinephrine turnover in brown adipose tissue of ob/ob mice. Am. J. Physiol. 247:E253E261: 1982. 27. Leibowitt, S. Brain monoamines and peptides: Role in the control of eating behavior. Fed. Proc. 45: 1396 1403: 1986. 2x. Lupien, J.: Bray. G. Effect of mazindol, d-amphetamine and diethylpropion on purine nucleotide binding to brown adipose tissue. Pharmacol. Biochem. Behav. 25:733-77X‘ ioX6 _, 29. Lumen. J. R.; Bray, G. A. Nicotine increases thermogenesis in brown adipose tissue in rats. Pharmacol. Biochem. Behav. 29:33-37; 198X. 30. Lupien, J.: Tokunaga. K.: Kemnitz, J.; Groos. E.: Bray. G. l.ateral h~pot~lamic Icsions and fentluramine increase thermogencsis in brown adipose tissue. Physiol. Behav. 38: 15-20: 1486. 31. Marchington, D.: Rothwell. N.; Stock, M.: York, D. Thermogenesis and sympathetic activity in BAT of overfed rats after adrenalectomy Am. J. Phvsiol. 25O:E362-E.366; 1986 ..,... 32. Morley, J..Ncuropeptidc regulation ofappetitc and weight. Endocr. Rev. X256-287: 19X7. 33. Naeser, P. Elfects of adrenalectomy in the obese-hyperglycemic syndrome in mice (gene symbol ob). Diabetologia 9:?76-379; 1973. 34. Okada, S.: York, D. 4.: Bray. G. A. ~~ifep~stone (RU-4X6), a blocker of type II ~luc~~co~icold and progestin receptors. rcvcrses a dietary form ofobesity. Am. J. Physiol. 262(Regul. Int. Camp. Physiol. 3 I ): RI 106-I I IO; 1992. 35. Oshima. K.: Shargili, N.: Ghan. ‘I’.:Brav, G. Adrenalectomv reverses insulin resistance in muscle from obe~~ob/ob) mice. Am. .i.Physiol. 24h:E193-El97: 1984. 36. Rothwell. N. J.: Stock. M. J. A paradox in the control of energy intake in the rat. Nature 273: 146 147, 197X 37. Saito. M.; Bray>G. Adrenalectomy and food restriction in the genetically ohese (oh/oh) mouse. Am. J. Physiol. 246:R20-R2S: 1984. 3X. Sakaguchi. T.: Takahashi. M.: Bray, G. A. The lateral hy~thalamus and sympathetic firing rate. Am. J. Physiol. 355:R507-R5 12: 1988. BY. Sakaguchi, T.: Brav. G. Intrahypothalamic injection of insulin decreases firing rate sympatheticnerves. Proc. Natl. Acad. Sci. USA 84:2012-2014: 1987. 30. Sakaguchi, I-.: Brat.
z
,\,l-l
of
1988. 32. Sakaguchi. T.; Takahashi. M.: Bray? G. Diurnal changes in sympathetic activity: Relation to intake and to insulin injected into the vcntromedial or suprachiasmatic nucleus. J. Clin. Invest. 32:282286: 1988. 43. Sakaguchi, 1.: Arase, K.: Bray, G. A. Svmuathetic activity and food intake of rats with ~‘entromedial hypothalamic lesions. Int. J. Obes. I2:43-49: 1988. 44. Shargill. N.; Oshima. K.: Bray. G.: Chan. T. Muscle protein tumovet in the perfused hindquarters of lean and genetically obese-diabetic (db/db) mice, Diabetes 33:i 160-I 164; 1984. C. En45. Shargill, N. S.; Tsujii, S.; Bray, G. A.: Erlanson-Allison, terostatin suppresses food intake following injection into the third ventricle of rats. Brain Res. 544: 137-140; 199 I. 46. Shim& If.; Shargiti, N.: Arase, K.; York, D. A.; Bray, G. A. Relationsh~p between synaptosomai uptake of norepineph~ne and the activity of brown adipose tissue. Brain Res. 5 I Cl:?16-222; 1990. 41. Shimizu, I-I.; Shargill. N.; Bray. G.: Yen. T.: Gesellchen. P. Effects of MSH on food intake, body weight and coat color of the yellow obese mouse. Life Sci. 4.5:543-552: 1989. 48. Shimizu, H.: Shargill, N. S.: York. D. A.: Bray. G. A. Etfects 01 adrenaIectomy on the development of obesity in the yellow mice. Clin. Res. 36(l):l27,4: 1988.
FOOD
INTAKE
AND
SYMPATHETIC
ACTIVITY
49. Shimomura, Y.; Bray, G. A.; Lee, M. Adrenalectomy and steroid treatment in obese (ob/ob) and diabetic (db/db) mice. Horm. Metab. Res. 19:295-299; 1987. 50. Solomon, J.; Bradwin, G.; Cocchia, M.; Coffey, D.: Condon, T.: Garrity. W.; Grieco, W. Effects of adrenalectomy on body weight and hyperglycemia in 5 month old ob/ob mice. Horm. Metab. Res. 9:152-156; 1977. K.; Fukushima, M.; Lupien, J.; Bray, G.: Kemnitz, J.; 51. Tokunaga, Schemmel, R. Effects of food restriction and adrenalectomy in rats with VMH or PVN lesions. Physiol. Behav. 45: 113 I-1 137: 1989. 52. Tsujii. S.: Bray, G. A. Acetylation alters the feeding response to MSH and beta-endorphin. Brain Res. Bull. 23: 165-169; 1989. 53. Vander Tuig, J. G.: Ohshima, K.: Yoshida. T.: Romsos, D.: Bray, G. A. Adrenalectomy increases norepinephrine turnover in brown adipose tissue of obese (ob/ob) mice. Life Sci. 34: 1423- 1432; 1984. 54. Vander Tuig, T.; Knehans, A.; Romsos, D. Reduced sympathetic nervous activity in rats with ventromedial hypothalamic lesions. Life Sci. 30:9 13-920: 1982. 55. York. D. A.; Holt, S.; Marchington, D. Regulation ofsympathetic activity by corticosterone in obese fafa rats. Int. J. Obes. 9(Suppl. 2):89-96: 1985.
541
56. Yoshida. T.: Bray, G. Effects of food and light on norepinephrine turnover. Am. J. Physiol. 254:R821-R827; 1988. lesions 57. Yoshida, T.; Kemnitz, J.; Bray, G. Lateral hypothalamic and norepinephrine turnover in rats. J. Clin. Invest. 72:919927: 1983. H.: Egawa. M.; Bray. G. A. Effects of cholecystokinin 58. Yoshimatsu, on sympathetic activity to interscapular brown adipose tissue. Brain Res (in press). 59. Young, J. B.; Landsberg, L. Stimulation of the sympathetic nervous system during sucrose feeding. Nature 269:6 15-6 17: 1977. 60. Young. J. B.; Landsberg, L. Suppression of sympathetic nervous svstem during fastine. Science 196: 1473-1475: 1977. 61. Yukimura, Y, Bray. G. Effects of adrenalectomy on thyroid function and insulin levels in obese (ob/ob) mice. Proc. Sot. Exp. Biol. Med. I59:364-367: 1978. 62. Yukimura. Y.; Bray. G. A.; Wolfsen, A. Some effects of adrenalectomy in the fatty rat. Endocrinology 103:1924-1928; 1978. 63. Y ukimura, Y .: Bray, G. A. Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker rat. Endocrinol. Res. Commun. 5:189-198: 1978.
1993 Copyright
Printed in the USA. All rights reserved.
036 l-9230/93 $6.00 + .OO (LI 1993 Pergamon Press Ltd.
Food Intake, Sympathetic Activity, and Adrenal Steroids GEORGE
A. BRAY
PenrzingfonBiomedical Research Center, Departmenf i~~~edicine, Louisiana State University, School qf Medicine, 6400 Perkins Rmd, Baton Rouge, LA ~08~~-4~~4 BRAY, G. A. Food intake, .~~vlnputh~ti~~ activity and adrenul simids. BRAIN RES BULL 32(5) 537-541. 1993.--Food intake is reciprocally related to the activity of sympathetic nerves to brown adipose tissue. This reciprocal or feedback relation is shown for hypothalamic lesions, drugs, and many peptides. These peptides also modulate intake ofspecific nutrients. Galanin and opioids increase fat intake, whereas enterostatin decreases fat intake, NPY increases carbohydrate intake and growth hormone releasing hormone decreases protein intake. The activity of the sympathetic nervous system is low in obesity and adrenalectomy reverses this decrease in sympathetic activity and reverses or stops the progression of obesity. One mechanism for this effect of adrenal steroids is through a transacting substance which is involved in steroid actions and the production of obesity. Food intake
Sympathetic activity
Adrenal glucocorticoids
SYMPATHETIC
Hypothaiamus
Genetics
Obesity
activity (28). 2-Deoxy-D-glucose, an analog of glucose that blocks intracellular metabolism of this metabolite, stimulates food intake and reduces sympathetic activity (3) (Table 2). The site of action on the sympathetic nervous system for some of these substances has been identified (Fig. 1). The dosedependent reduction in firing rate following the injection of norepinephrine into the paraventricular nucleus was blocked by phentolamine, an alpha adrenergic blocking drug (40), but not by propranolol, a beta adrenergic blocking drug, suggesting the involvement of cu-adrenergic receptors. In contrast to the decreased firing rate produced by injecting NE into the PVN, injection of NE into the ventromedial hypothalamus produced a dose-dependent increase in firing rate but the quantities required were iO-100 times greater than those injected into the PVN (40). This effect of norepineph~ne was also blocked by phentolamine but not propranolol. Serotonin increased sympathetic firing rate when injected into either the ventromediai or paraventricular nucleus and the doses were similar (40). Glucose increased sympathetic firing rate when injected into the ventromedial nucleus but decreased firing when injected into the LHA (38). When injected into the paraventricular nucleus, glucose produced an increase in sympathetic activity to IBAT, which was considerably smaller than when injected into the VMH (4 I ). Insulin reduced sympathetic firing when injected into the ventromedial nucleus, (39) but produced a small increase when injected into the lateral hypothalamus (38), and a small decrease when injected into the paraventricular nucleus (41). It is conceivable that the effects of insulin and glucose in the paraventricular nucleus were the result of their diffusion to the ventromedial hypothalamus where the effects of these two substances were much more robust. Corticotropin releasing hormone (CRH) increases sympathetic activity when injected into the third ventricle of the brain (4,20) or into the medial preoptic area, but not when injected into the lateral hypothalamus, the ventromedial hypothalamus, or the paraventricular nucleus (19). Neuropeptide-Y reduced
activity is affected by food intake. Young and Landsberg (60) first showed that fasting lowered sympathetic activity and, subsequently, that ingesting sucrose solutions increased sympathetic activity (59). Following this lead, Yoshida et al. (56) found that food intake in the dark increased sympathetic activity more than when food was eaten in the light. When Sakaguchi et al. (42) explored this phenomenon further they observed a highly significant inverse relationship between sympathetic activity and spontaneous food intake. The inverse relationship between sympathetic nervous system firing rate to brown adipose tissue and food intake was of particular interest because it suggested a potential feedback loop between sympathetic activity and food intake (10). Several studies on the reciprocal relationship of food intake and sympathetic activity are summa~zed in Table I. VMH lesions increase food intake and decrease sympathetic activity (43,54). Conversely, LH-lesions reduce food intake and produce an increase in sympathetic activity (2,57). One exception to this relationship appears to be a lesion of the paraventricular nucleus, which increases food intake but does not decrease SNS activity. However, for the level of hyperphagia in PVN-lesioned rats the level of SNS activity might be lower than anticipated. Neurotransmitters, such as norepinephrine and serotonin, show a reciprocal relationship between food intake and sympathetic activity (40). This reciprocal association is also noted for several peptides (9,141, including neuropeptide Y (NPY) (20,2 I), P-endorphin ( 18). cholecystokinin (CCK) (58), corticotropin releasing hormone (CRH) (4%19,20), anorectin (I), and MSH (52), which are found in the hypothalamus or pituitary (Table 1). A reciprocal relationship between food intake and sympathetic activity has also been found with several drugs. Fenfluramine ($30) amphetamine and mazindol(28) decrease food intake and increase sympathetic activity. Nicotine slightly decreases food intake but significantly increases sympathetic activity (29). Diethylpropion is an exception, which reduces food intake but does not show a measurable increase in sympathetic
537
538
TABLE RELATIONSXIP
OF FOOD
INTAKE
1
1 SYMPATHETIC NERVOUS ACTIVITY 1
AND SYMPATHETIC Effects
Procedure
Lesion or Injection Site
Lesion Lesion ~~repinephrine Serotonin Neuropeptide Y &Endorphin CRH Cholecystokinin Glucagon Anorectin
VMH 1-H VMH VMH PVN 3rd ventricle 3rd ventricle 3rd ventricle LH 3rd ventricle
Experimental
Food Intake
ACTIVITY
of Treatment
on
Sympathetic Nervous System Activity
c s : r
;
?
:
!
f
4 i
?
t = increased: 4 = decreased: --+ = no change PVN = Paraventricular nucleus. VMH = Ventromedial hypothalamus. LH = Lateral hypothalamus. C‘RH 7 Corticotropin releasing hormone.
. . . . . . . . . . Par8SyIIIpathetiC BAT
sympathetic activity when injected into the third ventricle (20) or into the PVN (21). Interestingly. NPY, like CRH, increased sympathetic firing when injected into the MPOA. CRH increases SNS activity after injection into the VMH or LH, but not other areas. PEPTIDES
AFFECT
THE INTAKE
OF SPECIFIC
NUTRIENTS
has been known for more than a decade that peptides located in the gut and brain can either selectively increase or decrease food intake (32). For example, the opioid peptides. neuropcptide Y, pancreatic peptide YY, galanin, and growth hormone releasing hormone can increase food intake (27). On the other hand, cholecystokinin, bombesin, anorectin, enterostatin, corticotrophin releasing hormone, glucagon, neurotensin, calcitonin, and TRH decrease food intake (32). As noted above. there is a reciprocal relationship between the effect of food intake and the activity of the sympathetic nervous system for a number of these peptides (12). Many of these peptides It
TABLE EFFECT
2
OF DRUGS ON FOOD INTAKE SYMPATHETIC ACTIVITY
AND
Effect of Treatment
Injection Food intake
Site
Treatment
on
Pancreas
rm
Symp8theti~
Ly
FIG. I A model of the hypothalamic control of sympathetic function. This model shows the sites at which several peptides have been shown to affect sympathetic activity. Solid lines refer to sympathetic connections; dashed lines to parasympathetic connections.
affect the intake of specific nutrients ( 12) (Table 3). Of part&tar interest in a circulating satiety factor is a pentapeptide derived from enzymatic cleavage of pancreatic procolipase into colipase the pentapeptide Val-Pro-Asp-Pro-Arg (VPDPR) (22). This pentapeptide, VPDPR is released by trypsin hydrolysis during activation of the colipase which is involved in digestion of triglycerides. Enterostatin was found to reduce food intake and to specifically reduce the intake of fat (23,45). Galanin, on the other hand, stimulates fat intake. Neuropeptide Y stimulates carbohydrate intake, and cycle-his-pro reduces carbohydrate intake. Recently, glucagon has been shown to reduce protein intake (12). Thus, there are now peptides that can selectively reduce or stimulate the intake of each of the macronut~ents. Because
Sympathettc Nervous System Activity
TABLE 7-deoxy_D-glucose Fenlluramine Nicotine Mazindol d-Amphetamine Diethylpropion t = increased;
ICV IP SC IP IP IP
4 = decreased:
ICV = intracerebroventricle. IP = intraperitoneal. SC = subcutaneous.
i
-,
I *
T
i 4
F +
= no change
PEPTIDES
AFFECTING
3
SPECIFIC
NUTRIENTS
Nutrient
1ncreasc
Decrease
Carbohydrate Protein Sodium
Galanin Opioids p-Casomorphin Neuropeptide Y Growth hormone RH Angiotensin
Enterostatin Vasopressin Corticotropin RH Cholecystokinin Glucagon
Fat
FOOD
INTAKE
AND
SYMPATHETIC
539
ACTIVITY
of its long half life, VPDPR (enterostatin) is a prime candidate for a circulating satiety factor for fat intake.
FATIY
RECIPROCAL RELATIONSHIP OF SYNAPTOSOMAL UPTAKE OF NOREPINEPHRINE
Uptake of norepinephrine by hypothalamic synaptosomes is reciprocally related to sympathetic activity (46). An inverse relationship between synaptosomal uptake of norepinephrine and sympathetic activity was found in rats and mice under a variety of experimental conditions. When sympathetic activity was low there was a high reuptake of norepinephrine and, thus, probably low extracellular norepinephrine concentration as compared to states of high sympathetic activity where reuptake of norepinephrine was low and. thus, the extracellular concentration of norepinephrine was probably high. These data would suggest that hypothalamic norepinephrine concentration directly modulates the sympathetic nervous system. An anatomic model of the hypothalamus and its adrenergic controls (see Fig. I) show that the ventromedial, lateral, and paraventricular areas interact with each other primarily through the dorsomedial hypothalamus. The ventromedial hypothalamus has an important input into the sympathetic nervous system through the periaqueductal gray matter in the medulla, and, hence. into the dorsal motor nucleus (DMH) of the vagus. The lateral hypothalamus also has an input into the vagal complex in the hindbrain and, in turn, modulates the sympathetic nervous system. Sympathetic activity is reduced in most known forms of obesity. Following the classical work of Rothwell and Stock (36) who showed that sympathetically innervated brown adipose tissue responded to overeating by an increase in thermogenic activity, Himms-Hagen and Desautels (24) measured the thermogenic activity of brown adipose tissue in genetically obese mice. They observed a reduction in sympathetic activity in these animals as had been observed in animals with hypothalamic obesity (14). Subsequent work by York and his colleagues (25.3 1). as well as Vander Tuig (53) and Knehans and Romsos (26). demonstrated a reduced level of sympathetic activity to brown adipose tissue in all of the recessively inherited forms of genetic obesity. Thus, reduced sympathetic activity exists in both hypothalamic and genetic forms of obesity. ADRENAL
DEPENDENCE
OF OBESITY
Adrenal glucocorticoids are essential for the development of hypothalamic obesity whether from VMH or PVN lesions (9). Bruce et al. ( 16) Debons et al. ( 17) and, subsequently, Tokunaga et al. (5 I) all showed that adrenalectomy reverses hypothalamic obesity and that in such animals treatment with corticosterone restores the hyperphagia and obesity. Thus, adrenal glucocorticoids play a critical role in the development of hypothalamic obesity. Circulating adrenal glucocorticoids are also essential for the development of all forms of genetic obesity, [fatty rat (62,63). obese mouse (33,37,61), diabetes mouse (48) and yellow mouse (48)] and for dietary obesity (34) and castration-induced obesity (8). Adrenalectomy profoundly influences the expression of obesity in genetically obese animals as it does in those with hypothalamic obesity (8.9). Solomon et al. (50) and Naeser (33) have shown that adrenalectomy improved glucose tolerance. However, it was the work of Yukimura and his colleagues (61-63) Bray ( 15) and Saito and Bray (37) that clearly demonstrated the role of adrenalectomy in the phenotypic expression for almost all of the defects in genetically obese animals. Following adrenalectomy, insulin and glucose levels fall (6,6 l), food intake returns
FA GENE Protein
& -
2% 1
(Steroid Responsive)
I
I Protein (Enzyme)
4 Permissive
1 Steroid Responsive4
FIG. 2. Transacting model for the genetic defect in the fatty rat. The FA gene is depicted as producing a protein that modulate the action of steroid responsive genes.
critical
to normal (37). muscle mass increases (37,44), insulin resistance is reduced (35). growth occurs (62,37), sympathetic activity returns to normal (53,55), and the accretion of body fat occurs only at normal rates (37). Because the adrenal gland and its secretion of glucocorticosteroids plays a key role in modulating the activity of the sympathetic and parasympathetic nervous system, it has been proposed that these two systems act together to regulate nutrient partitioning, and fat storage. One explanation for the effects of adrenalectomy is through modulation of gene expression. Adrenal steroids modulate the expression of genes involved in Iipogenesis after replacement of corticosterone in adrenalectomized genetically obese rats differently from lean rats (7, I I). In fatty rats that are adrenalectomized, the levels of mRNA for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) declines to low levels. This contrasts with the effects in lean animals where little or no change is observed in adrenalectomized animals. With steroid replacement there was an increase in mRNA for GAPDH in the liver from genetically obese rats but little effect in the lean animal. Similar findings were observed in adipose tissue when the mRNA for malic enzyme was studied. Because the mRNA for these two enzymes are transcribed from different genes our observations suggest that the genetically obese animal may have a defect in the synthesis of a peptide in response to corticosteroids which would regulate indirectly the function of other enzymes such as GAPDH and malic enzyme. Such a transacting factor could explain the diverse defects in these genetically obese animals and how steroid hormones modulate these functions, and is diagrammed in Fig. 2. Adrenalectomy reverses not only genetic but hypothalamic and other types of obesity as well. In the absence of a hypothalamic lesion or the genetic defect of the obese animal adrenal steroids do not produce significant obesity. Yamamoto and his group have proposed that steroids modulate some transcription events by interacting with transcription factors. C-fos and c-jun would be two possible examples. If either the steroid or the transacting factor are missing, the genes will be appropriately transcribed. For genetically obese animals this would result from a genetic defect in the production of the factor. For hypothalamic obesity the loss of neuronal stimulation might reduce the production oft-fos or c-jun and, thus, alter gene transcription controlled by steroids. This transcriptional model for steroidal control of obesity can be applied to all of the know defects. ACKNOWLEDGEMENT
Supported in part by Grant No. DK32089.
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2.
3.
4.
5.
6.
7.
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541
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