Peptides as central regulators of feeding

Brcrin R~.wcw~~hBulkritz.

Vol. 14, pp. 51l-519. 1985.‘OAnkho

International

Inc. Printed

in the

0361-9230185 $3.00 + .OO

U.S.A.

Peptides as Central Regulators of Feeding J. E. MORLEY,’ A. S. LEVINE, B. A. GOSNELL AND D. D. KRAHN

Neuroendocrine Research Laboratory, VA Medicul Center, Minneapolis, und Departments of Medicine and Food Science and Nutrition University of Minnesota, Minneapolis-St. Paul, MN

MN

MORELY, .I. E., A. S. LEVINE, B. A. GOSNELL AND D. D. KRAHN. Peptides us ccnrrol rcy,wlators of fc’c’ding. BRAIN RES BULL 14(6) 511-519, 1985.-During the past decade there has been an increased awareness of the role peptides play as neuromodulators. In this article we review the available data on peptides as central regulators of food ingestion. We stress the possible problems of non-specific effects. We stress that whereas many peptides decrease feeding after central injection, only two families of peptides have been shown to increase feeding after central injection. These are the opioid family and the pancreatic polypeptide-neuropeptide Y family. The putative role of corticotropin releasing factor as the mediator of norepinephrine and serotonin effects on feeding is discussed. Dynorphin Bombesin

Neuropeptide Food intake

Y

Peptide YY Calcitonin

Corticotropin

PROCESSING of information in the brain involves neuronal communication through the release of neurotransmitters at synapses. Until the 1960’s, the only well known neurotransmitters were the amines, i.e., the catecholamines, acetylcholine and serotonin. Next it was recognized that a number of amino acids, such as gamma amino butyric acid, also served as neruotransmitters. In the last decade it has become apparent that numerous peptides also are neurotransmitter candidates in the central and peripheral nervous system. Many of these peptides have been localized in areas within the central nervous system that have been classically thought to play a role in the regulation of food intake. Thus, it is not surprising that there has been increasing interest in the potential role of peptides as neuromodulators of the feeding process. At present, with the exception of studies on the opioid peptides, almost all the studies on the central role of neuropeptides in the regulation of feeding have been pharmacological in nature and thus allow only crude extrapolations to the physiological situation. Nevertheless, these pharmacological studies do point the way to potential physiological studies and in the history of science, pharmacological endeavors have often been parents to the birth of physiological understanding. In addition, for those interested in the treatment of eating disorders, it is the pharmacology that is of overriding importance. In 1980, Morley [57] developed a peptidergic hypothesis of appetite regulation in which he suggested that the final integration of food intake is brought about by maintaining a delicate balance in the concentration of a number of interacting peptides and monoamines. At that time it was also suggested that a number of other peptides would be discovered to play a role in food intake regulation. In this re-

releasing factor

Cholecystokinin

view, we will provide a historical approach to the growing number of peptide candidates involved in the central regulation of feeding. We will not discuss the role of peptides as putative peripheral regulators of feeding but rather, concentrate on those peptides that appear to have a central locus of action. Before reviewing the available data on peptides as feeding regulators, it is necessary to briefly discuss the major problem plaguing the study of the role of neurotransmitters as feeding regulators, i.e., the specificity of the effect. After administration of a neurotransmitter, feeding can be produced either by a specific increase in hunger or secondarily to an increase in the general activation of the organism with a consequent increased utilization in energy or by an alteration in the nutrient homeostasis of the milku intc>ricwr,e.g., a neurotransmitter could increase insulin release which in turn would lower the blood glucose and activate feeding. Even greater problems exist with neurotransmitters that decrease feeding. Decreases in feeding can be due to a specific decrease in hunger, or due to a decrease in the ability to chew and/or swallow or due to a decrease in arousal or due to the production of a generalized aversion. In general, our ability to discriminate between which of these factors is playing a role is rudimentary at best. For instance, multiple problems exist with the interpretation of the tests for aversion (see Billington et d. [6] for a review). Further, most studies on neuropeptides and feeding have involved intracerebroventricular injection and it is quite clear that most neuropeptides are involved in the modulation of more than one process and their specificity comes as much from the anatomical site of release as it does from the peptide itself.

‘Present Address: Director, Geriatric Research Education and Clinical Center, VA Medical Center, 16111 Plummer 91343.

St.,

Sepulveda, C,b,

512

MORLEY E7 AI.. TABLE

1

ENDOGENOUS PEPTIDES DEMONSTRATED TO INCREASE FOOD INTAKE IN THE RAT AFTER CENTRAL ADMINISTRATION

Opioid Peptide Family /3-endorphin Dynorphin cr-neo-endorphin Pancreatic Polypeptide Human pancreatic polypeptide Neuropeptide Y Peptide YY

lllll~~llllll Saline *xNPY

---• RPP o---OPYY

o*

l

1

,I’

Grandison & Guidotti, 1977 [27] Morley & Levine, 1981 [63] Morley & Levine, 1982 [59] Family Clark et al. 1984 [13] Clark et ~11.1984 [13] Morley et al. 1984 [68]

Bearing these caveats in mind, we will now turn to a discussion first of the role of neuropeptides as feeding stimulators and then to the studies on inhibition of food intake.

-0

I

2

4

(Hours) PEI’TIDES AS STIMULATORS

OF FOOD INTAKE

Surprisingly few endogenous peptides have been demonstrated to increase food intake. In fact, only two families of peptides have been demonstrated to consistently produce food intake after central administration (Table 1). These are the opioid peptides and the pancreatic polypeptide family. The opioid peptides are reviewed in detail elsewhere in this volume [49] and thus will not be discussed here. The pancreatic polypeptide family consists of pancreatic polypeptide, neuropeptide Y, and peptide YY. The latter two peptides, isolated by Tatemoto et al. [lOO,lOl], are characterized by having tyrosines at both ends of the molecule and hence the designation YY and Y (Y=tyrosine). Neuropeptide Y was isolated from the brain [ 1001 while peptide YY (PYY) was isolated from the gastrointestinal tract [loll. Neuropeptide Y is widely distributed throughout the central nervous system with the highest concentrations occurring in the hypothalamus, nucleus accumbens and the periaqueductal grey region [16]. In 1984, Clark et al. [13] reported that both human pancreatic polypeptide and to greater extent, neuropeptide Y (NPY), increased feeding after injections into the third ventricle of ovariectomized rats. Besides its effects on ingestive behaviors, central NPY has been reported to have a hypotensive action [22], to modulate luteinizing hormone levels [35], and to be a potent vasoconstrictor of cerebral vessels [2]. Studies in our laboratory have confirmed the potent orexigenic effect of NPY in intact male rats [58,68,69]. Not only does NPY increase feeding during the daytime when rats normally don’t eat but it also increases nocturnal feeding and feeding in animals after 24 hour starvation. NPY is inactive after peripheral injection. In addition to the increase in feeding it also causes a major increase in water ingestion and this increase in water ingestion is still present although diminished in the absence of food. NPY has been shown to co-exist with catecholamines in the central nervous system [31,51] and to enhance the binding to a-adrenergic receptors [ 11. Because norepinephrine is also a potent enhancer of feeding [40] we studied the putative of NPY and norepinephrine. cointerrelationship administration of the alpha-blocking agent, phentolamine (60 nMoles) failed to attenuate the feeding effect of NPY. In

FIG. 1. Effect of neuropeptide Y (NPY), peptide YY (PYY) and rat pancreatic polypeptide (RPP) on food and water intake. All peptides were given at a dose of 10 pg intracerebroventricularly. Shaded areas represents meancSEM of controls. *p
addition, there was no additive or synergistic effect of NPY and norepinephrine on food intake when co-administered into the ventricle. These studies suggest that the effect of NPY on food intake is independent of norephinephrine. We next studied the area within the central nervous system in which NPY produces its effects (Gosnell et al., manuscript in preparation). NPY at a dose of 230 pmol produced increases in feeding in the paraventricular nucleus (PVN), ventromedial nucleus (VMH), and posterior lateral hypothalamus. It was ineffective in the striatum, anterior lateral hypothalamus and globus pallidus. The effect of the 230 pmols of NPY was greater in the anterior VMH (6.9* 1.2 g in 4 hours) compared to the posterior VMH (3.6% 1.0 g) and the PVN (3.720.9 g). Thus, it would seem that NPY may produce its effect in the anterior VMH or an adjacent area. However, before this can be ascertained with certainty, dose response curves need to be established and lesioning experiments undertaken. In another series of experiments, we compared the potency of NPY to PYY and rat pancreatic polypeptide. We could find no effect of rat pancreatic polypeptide on food or water intake in male rats. PYY, on the other hand, proved to be significantly more potent than NPY (Fig. 1). We then studied the effects of chronic PYY (10 pg ICV every 6 hours for 48 hours) on food intake. Multiple injections of PYY caused a marked increase in food intake (80.5-t2.4 g compared to 3 1.1 k4.6 g in the saline group,p
PEPTIDES

513

AND FEEDING

These studies in our laboratory and those of Clark et al. [ 131 and Stanley et al. (see this issue) suggest that NPY/PYY are among the most potent endogenously occurring orexigenic agents yet to be described. The magnitude of increased food intake following NPY or PYY is far greater than that seen following the central administration of opioid peptides [76]. These findings suggest that consideration should be given to the possibility that either NPY or PYY play a role in the pathophysiology of bulimia. Should one of these peptides prove to be involved, we suggest that the term “bulimin” might be used as a descriptive trivial name. PEYTIDES AS INHIBITORS

OF FOOD INTAKE

In contrast to the few peptides known to increase food intake after central administration, there is a much larger number that have been shown to decrease food intake. The studies on central administration of peptides decreasing food intake in the rat are summarized in Table 2. /tWhl

Insulin became the first peptide demonstrated to decrease feeding, when in 1974, Hatfield et al. [29] demonstrated that direct injection of insulin into the VMH decreased feeding in the rat. The potential physiological role of insulin as a satiety agent was enhanced when Strubbe and Mein [96] showed that insulin antibodies injected into the VMH, but not the LH, stimulate food intake and the observation of Oomura [79] that iontophoresis of insulin onto hypothalamic neurons that are glucose responsive alters their firing rate. Recently, Brief and Davis [7] showed that chronic infusion of insulin into the third ventricle for 7 days decreased food intake and body weight gain. However, the weight loss in the animals infused with insulin could not be explained by the decreased in caloric intake alone, which suggests that central insulin infusion also alters either energy expenditure or water metabolism. This is in contrast to the finding of Woods et al. [ 1071 where the weight loss in baboons receiving central infusion of insulin could be accounted for by the decrease in food intake. Ikeda et ul. [32] found that central insulin infusion reduced feeding in lean but not obese Zucker (fa/fa) rats, which suggests that a deficit in the insulin satiety system may be involved in the pathogenesis of the obesity in these animals. The doses of insulin necessary to alter food intake are in the pharmacological range and this could be explained by the recent finding that a crude preparation of insulin growth factor is an extremely potent inhibitor of feeding in the rat [99]. As high concentrations of insulin cross-react with the receptors for insulin growth factors, it may turn out that one of their insulin growth factors is a physiological modulator of feeding. In view of the fact that insulin growth factors (somatomedins) also modulate growth by stimulating somatostatin release in the hypothalamus [5], it makes teleological sense that they should modulate feeding (supply of energy for growth) as well. Cholecystokinin

(CCK) and C’aerulein

In 1976, Stern et al. [9.5] reported that caerulein (a frog skin analog of CCK) decreased food intake after microinjection into the VMH. In the same year, Maddison [54] found that intracerebroventricular administration of CCK-33 decreased food intake. Since that time there has been much controversy whether CCK produces its effect directly on the central nervous system or if its effect is secondary to leakage

into the periphery [83]. Recently, a series of studies in which local injections of CCK-8 have been shown to decrease feeding in the low pmole dosage range suggests that CCK does indeed produce its effects within the central nervous system in the rat [20, 55, 861 as well as by peripheral activation of ascending vagal fibers [70,91]. The CCK activation of the satiety system involving the ascending vagal fibers appears to involve relays in the area postrema/nucleus of the solitary tract [105] and the paraventricular nucleus [14]. Thus, CCK may turn out to be the neurotransmitter involved in relaying the satiety message from gut to brain at multiple levels. An unusual paradigm of feeding induction involves mildly pinching the tail of a rat [73]. This so-called stress induced feeding has been shown to involve the activation of endogenous opioids [61]. Central administration of CCK-8 has proved to be a potent inhibitor of this paradigm of feeding behavior [46, 78, 1021. Telegedy et al. [102] showed that both sulfated and unsulfated CCK decrease feeding in this paradigm. Levine and Morley [46] found that the CCK suppression of feeding was due to the hyperglycemia it produced. This is of particular interest in view of the accumulating evidence that glucose modulates opioid receptors [48,90]. CCK has also been suggested to act as an opioid antagonist [19] and it may be due to the modulation of the opioid pain system which is activated by tail pinch that CCK is particularly potent at inhibiting tail pinch feeding. Calcitonin and Calcitonin Gene-Related

Peptide

Freed and his colleagues [21,84], in a series of pionCering studies, demonstrated the potent anorectic effect of salmon calcitonin. Our group confirmed this finding and found that central administration of salmon calcitonin to rats was effective at a dose approximately one-thousandth that of the parenteral dosage [45]. The calcitonin effect is extremely long lasting, with effects being present up to 32 hours after administration. Twery rt al. [103] produced similar findings and showed that salmon calcitonin was more potent than rat calcitonin. DeBeaurepaire and Freed [15] have found that the central site of action of calcitonin appears to be in the paraventricular nucleus. In view of the potent effects of calcitonin on calcium metabolism and the fact that intraventricular calcium increases feeding in a number of speices [77], we investigated whether the calcitonin effects could be secondary to its effects on calcium metabolism. Calcitonin reversed calcium-chloride induced eating and reduced ““Ca’+ -uptake in a hypothalamic explant system [45]. These findings led us to conclude that the mechanism of calcitonin induced food suppression may be related to an alteration in calcium flux by neuronal tissue. The recent discovery by Rosenfeld and colleagues [87] that calcitonin gene is expressed in the central nervous system as calcitonin gene-related peptide (CGRP), and that CGRP is distributed in areas of the central nervous system classically associated with taste and feeding, led us to investigate whether CGRP also reduces food intake in the rat. CGRP decreased food intake after central administration both in rats who had been food deprived for 24 hours and during spontaneous nocturnal feeding [36]. CGRP was less effective than calcitonin at suppressing food intake. Behaviorally, CGRP treated animals rested more, groomed less and ate less. These results suggest that CGRP may be centrally active in regulating consummatory behaviors. However. we have recently found that CGRP produces a taste

MORLEY TABLE PEPTIDES THAT DECREASE

Peptide Insulin Cholecystokinin

Route of Administration VMH ICV

PVN

12 pmole 0.1 pmole 30 pmole 4 pmole

1211 [451 [IO31 1151

ICV

263 pmole

[371

1cvt ICV ICV

62 pmole 62 pmole 154 pmole 3 pmole

[621 [381 [41 [971

Caerulein

VMH

Calcitonin

ICV 1cvt ICV

LH (bilateral) PVN ICV ICV

L301 L5-21 [441

L1f-w [@)I I531 [981

ICV

10,000 pmole

[761

ICV ICV§

3,000 pmole 9,768 pmole

[lo61 [31

VMH/LH

Somatostatin

1,494 pmole 1,973 pmole 5,997 pmole

[541

600 pmole 100,000 pmole 110,369 pmole 8,000 pmole

ICV 1cvt ICV

Cycle HIS-PRO Diketopiperazine

~291 171

[951

LH (bilateral) PVN 4th ventricle

TRH (pGlu-His-ProNH,)

5 mu/day

Vasoactive Intestinal Peptide

ICV

3 pmolett

Insulin Growth Factor

ICV

106 Equlnsulin

[991

CRF

ICV ICV PVN

150 pmole 214 pmole 107 pmole

[91 1671 [371

Sauvagine

ICV ICV

1,086 pmole 109 pmole

Glucagon

ICV

1 pmole;’

IN

Reference

18 pmole

1cv*t

Neurotensin

Dose

1781 1551 1461 I1021 [lo81 WI WI

PVN** ICVi

Bombesin

ADMINISTRATION

.10 IDU 875 pmole 131 pmole 218 pmole 800 pmole 88 pmole 28 pmole 87 pmole

ICV (CCK-33) 1cvt

Calcitonin GeneRelated Peptide

2

FEEDING AFTER CENTRAL THE RAT

[IO71

v51 PI [331

tTail-pinch induced eating. *Sulfated and non-sulfated form. **Decreased norepinephrine induced feeding. ttNo effect with higher doses, minimal data reported. lBiphasic effects dependent on fed state of rat. “Preliminary data in our laboratory failed to find an effect of a large range of glucagon doses given into the lateral ventricle on food intake in rats starved for 24 hours.

t‘7’ A 1.

PEPTIDES

51s

AND FEEDING

aversion, which calls into question the specificity CGRP effect (unpublished observations).

of the

Bombrsin

Bombesin is a tetradecapeptide originally isolated from the skin of the frog, Bombina bombina. Besides decreasing feeding after peripheral administration [24,72,94], it also has been shown to slow gastric emptying [85] and decrease gastric a&d secretion (741. Morley and Levine [62] showed that bombesin administered into the lateral ventricle decreased feeding in the mild tail pinch model of stress induced eating. Although centrally administered bombesin produced hyperglycemia, its satiety inducing effect was independent of the glucose rise, as bombesin still suppressed stress-induced animals. Adrenalectomy eating in adrena1ectomized abolished the bombesin induced hyper~ycemia. The following year, Kdkosky ?I al. [381 and Avery and Calisher [4] confirmed that bombesin reduced food intake in free feeding animals. Stuckey and Gibbs [97] found that bilateral injections of very small amounts of bombesin (3 pmole) into the lateral hypothalamus was also effective at reducing food intake. Kyrkouli rt a/. [39] found that bombesin reliably reduced food intake when microinjected into a variety of medial hypothalamic areas, the periaqueductal grey and the amygdala. These injections enhanced grooming, whereas drinking behavior was unchanged. Central administration of bombesin appears to reduce food intake by decreasing meal size rather than meal frequency [28].

Neurotensin is an undecapeptide which has been shown to decrease feeding in a number of situations. Hoebel rt ul. [30] found that administration of neurotensin bilaterally into the PVN decreased feeding without altering drinking. In addition, neurotensin antagonized the feeding induced by an injection of norepineph~ne into the PVN. Ipsilateral injections of neurotensin were more potent than contralateral injections, which suggests that the effect was not simply the result of malaise. Behavioral specificity was suggested by the finding that centrally administered neurotensin did not alter grooming, rearing, sleeping. resting or locomotor activity in their paradigm [93]. Luttinger et al. 1521confirmed that centrally administered neurotensin inhibited food intake following starvation. They also found that it did not produce an aversion to a novel flavor, further supporting a specific effect on food intake. Levine et al. [44] found that administration of neurotensin into the lateral ventricle inhibited starvation inspontaneous, norepinephrine-induced and dyduced, no~hin-induced feeding. It was ineffective at inhibiting muscimo1-induced and insulin-induced feeding. Thyrotropin Releasing Hormone Histidyl-Proline-Diketopiperazine

(TRH) nnd C.y&(cHIS-PRO)

Originally, Vijayan and McCann [ 1061 showed that TRH (600 pmole) decreased feeding after central injection. Subsequent studies [53,58] have found much higher concentrations of TRH to be necessary to decrease feeding (-100,000 PmOk). Suzaki ef al. [98] found that local injections of TRH into the VMH and LH decreased feeding at approximately a ten fold lower dose. TRH decreased feeding in hypophysectomized animals, which suggests that the effect is independent of the release of thyrotropin from the pituitary or of the release of thyroid hormones [60]. TRH failed to inhibit norepinephrine-and muscimol-induced feeding 163,713.

Evidence for a physiological role of TRH in the central modulation of feeding comes from studies showing that chronic starvation produced a decrease in hypothalamic TRH content 1591. Zinc deficiency, a condition in which there is marked anorexia [ 171, was ibund to significantly decrease hypothalamic TRH content [59]. cHis-Pro is a cyclic depeptide derived from TRH by its limited proteolysis by the enzyme pyroglutamate aminopeptidase. cHis-Pro produces a long lasting inhibition of food intake in rats [65]. it is, in our taboratory, a more effective inhibitor of feeding than TRH when compared on a molar basis. This suggests that cHis-Pro may be the metabolically active compound responsible for the TRH inhibition of food intake. Concentrations of cHis-Pro in the hypothalamus have been found to fluctuate with feeding, which indicates a possible appetite regulatory role of cHis-Pro in the rat. Somatostatin

and Glucugon

Somatostatin, a tetradecapeptide, produces a vagally dependent inhibition of food intake after peripheral administration [47]. High concentrations of centrally administered somatostatin were reported to reduce food intake [IOS]. More recently, Aponte et al. [3] showed that centrally administered somatostatin produced biphasic effects on food intake that appeared to be dependent on the fed state of the animal. Like somatostatin, glucagon has been shown to produce a vagally dependent inhibition of food intake after peripheral administration in the rat 1231. Direct glucagon application by microelectrophoresis selectively suppresses gluco-sensitive neurons in the lateral hypothalamus [Sl]. These neurons have been postulated to play a key role in feeding behavior [80]. Inokuchi rt al. [33] found that administration of pancreatic glucagon into the third cerebral ventricle of rats suppressed feeding with a potency 1000 times greater than that seen after peripheral administration. In view of the low effective dose of gfucagon reported in this study, further confirmatory studies are indicated. Corticwtropin R&using

Factor and Suuvmgine

Corticotropin releasing factor (CRF) is a 41 amino acid polypeptide which was characterized from extracts of the bovine hypothal~us 1921. This peptide stimulates the pituitary secretion of both ACTH and P-lipotropin-P-endorphin [ 1041. When administered centrally, CRF produces a variety of stress-like responses such as increased plasma levels of catecholamines, glucose, vasopressin and elevated mean arterial pressure, heart rate and oxygen consumption [1 l]. Selye [89] suggested that CRF may be the first mediator of the stress response, and the experimental evidence so far obtained is compatible with the concept that CRF plays a central role in co-ordinating the physiological responses to stressful stimuli. Clinical and laboratory studies have indicated that stress may result in either increased or decreased food consumption [76]. Britton CI af. [9] and our group [66] have reported that CRF administered into the lateral ventricle decreased food intake and increased grooming. The decreased food intake was still present in hypophysectomized animals, which indicates that the effects of CRF on food intake were not secondary to release of any of the peptides associated with the pro-opio-melanoco~in precursor molecule 1661. In further studies on CRF, we examined the ability of CRF to suppress feeding induced by a variety of phar-

MORLEY

FIG. 2. Postulated role of corticotropin releasing factor (CRF) as a mediator for the effects of norepinephrine (NE) and serotonin on feeding. It is postulated that these effects are localized to the paraventricular nucleus (PVN). In addition, CRF releases P-endorphin from the pituitary and epinephrine from the adrenal medulla secondary to activation of the adrenal medulla. Both peripheral infusions of epinephrine and /3-endorphin have been demonstrated to decrease feeding. Cortisol exerts a negative feedback on CRF in the PVN with CRF levels increasing after adrenalectomy. This increase of CRF in the PVN of adrenalectomized animals could explain the failure of NE to increase feeding in these animals.

macological substances [25,50]. CRF proved to be a potent inhibitor of feeding induced by muscimol, norepinephrine, and insulin. dynorphin-l-13, ethylkeotcyclazocine Sauvagine, a frog skin peptide isolated from the skin of the Phyllomedus sauvagei that has structural similarities to CRF, was found to be a more potent inhibitor of feeding than CRF [8,25]. Both CRF and sauvagine produced a condition aversion when paired to a novel saccharin taste [25]. Coupled with earlier studies, this finding suggests that CRF may have a disruptive effect on feeding.

onoms(liddli.1 D-u.A--ENc

rspnn

WV

-**196(

.we.we3

I:“/’ A 1..

Gosnell rt d. [26] examined the effects of adrenalectomy and vagotomy on CRF suppression of food intake. Vagotomy failed to alter the CRF effect on food intake. On the other hand, adrenal demedullation resulted in a partial blunting of the CRF effect. This is consistent with the known effects of CRF on adrenomedullary discharge [I I] and suggests that the release of epinephrine peripherally may be partially responsible for the CRF inhibition of feeding. These studies could show no role of the adrenal cortex in the CRF feeding effect. Studies in our laboratory have now concentrated on the site of action of CRF within the central nervous system. CRF decreases feeding when microinjected into the PVN but not when injected into a number of other areas including the VMH, striatum, LH and globus pallidus [37]. CRF also inhibits the norepinephrine induced feeding effect when both substances are injected directly into the PVN. CRF tends to produce a greater decrease in carbohydrate than fat intake. Norepinephrine, on the other hand, has been reported to preferentially increase carbohydrate intake [ 181. Lesions of the PVN lead to hyperphagia [41]. Norepinephrine produces its effects on feeding stimulation primarily in the PVN and this effect is attenuated after PVN lesions [42]. This suggests that norepinephrine increases feeding by inhibiting the release of a satiety substance within the PVN. Serotonin, within the PVN, inhibits the feeding effect of norepinephrine [40]. Norepinephrine has been shown to inhibit the release of CRF from the hypothalamus and serotonin releases CRF from the hypothalamus [12]. The largest cell population of CRF is found in the parvocellular sub-units of the paraventricular nucleus [82] and CRF receptors have been demonstrated to be present in the PVN [34]. Adrenalectomy increases CRF content within the PVN [88] and markedly attenuates norepinephrine-induced feeding [43]. In view of our findings and the above cited evidence, it seems reasonable to postulate that CRF represents the feeding inhibitory substance that norepinephrine inhibits to allow feeding to occur (Fig. 2). Clearly, further studies are necessary to substantiate this hypothesis. CONCLUSION

of peptides can alter food intake after administration into the central nervous system. Some of these peptides have been demonstrated to produce It

is now clear that a number

LATERAL

HYPon4ALAwJS

Tmi

stuc*eyL Qbar 1882 sJz*i el at 1983

ccl-8

WLaetalwM

BakeEm

FIG. 3. Summary of the effects of local injections of peptides into various brain areas on feeding. octapeptide; CRF=corticotropin releasing factor: NPY =neuropeptide Y; CCK-I=cholecystokinin TRH=thyrotropin releasing hormone.

PEPTIDES

517

AND FEEDING

their effect after injection into specific areas within the brain (Fig. 3). The specificity of the effects of these peptides remains in doubt, and much work remains to be done before a physiological role in appetite regulation can be clearly attributed to any one of them. However, the next decade

promises to be an neuropeptides (and tools to help dissect a single meal and balanced intake.

extremely exciting period in which the their antogonists) will prove to be useful the central nervous system regulation of of the choices involved in producing a

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