Dissociated feeding and hypothermic effects of neuropeptide Y in the paraventricular and perifornical hypothalamus

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Peptides, Vol. 16. No. 4, pp. 599-604, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0196-9781/95 $9.50 + Ml

0196-9781(95)00020-8

Dissociated Feeding and Hypothermic Effects of Neuropeptide Y in the Paraventricular and Perifornical Hypothalamus PAUL

J. CURRIE*t’

AND

DONALD

V. COSCINA*1_$

*Clarke Institute of Psychiatry, and Departments of tpsychiatry and $Psychology, University of Toronto, Toronto, Ontario, M5T lR8 Canada Received

27 October

1994

CURRIE, P. J. AND D. V. COSCINA. Dissociatedfeeding and hypothermic effects of neuropeptide Yin the paraventricular and perifornical hypothalamus. PEPTIDES 16(4) 599-604, 1995.-The present study investigated the effects of neuropeptide Y (NPY) on food intake and body temperature (Tbo) in free-feeding unrestrained rats following injection into the medial hypothalamic paraventricular nucleus (PVN) or the lateral perifomical hypothalamus (PFH). NPY (78-235 pmol) or saline was infused unilaterally into the PVN or PFH in a volume of 0.4 ~1 and simultaneous measures of food intake and Tbo were taken every 30 min for 3 h. Results indicated that NPY evoked changes in eating behavior and Tbo that were dependent upon the site of hypothalamic injection. Although PVN and PFH administration of NPY both increased food intake dose dependently within 30 min of treatment, PFH NPY-injected rats (n = 9) showed a stronger behavioral response compared to rats (n = 9) receiving NPY injections into the PVN. In PVN-treated rats, however, the increased eating was associated with a significant decline in Tb evident within the first 30-min test interval. A mean maximal decline of 0.92 + 0.26”C occurred within 90 min of PVN treatment of the highest dose, which produced a reduction in Tbo that was maintained for 2.5 h. In contrast, NPY infusion into the PFH failed to reliably alter Tb at any of the doses tested. These findings are consistent with evidence that NPY in the PVN and PFH may have distinct functions and suggest that although PFH NPY acts to stimulate a robust and relatively specific ingestive response, PVN NPY may participate in the complex integrative mechanisms responsible for the simultaneous regulation of feeding, thermoregulatory, and metabolic processes. Neuropeptide

NEUROPEPTIDE

Y

of

Food intake

Hyperphagia

a 36-amino acid polypeptide horin the mammalian brain (2,4), is a potent

ingestive

behavior

and

energy

metabolism

(12,17,29,35,38,64). Infusion of this peptide into the anterior hypothalamic/preoptic area (AIWPOA) evokes a concomitant hyperphagia and reduction in body temperature (r,) (46), whereas NPY injection into the paraventricular nucleus of the hypothalamus (PVN) has been reported to stimulate eating and rapid weight gain (43,5 1,54,55). PVN NPY also promotes a selective increase in carbohydrate appetite (34,53,62) and a shift in energy balance towards an increased utilization of carbohydrate as an energy substrate (27,39). In addition to the feeding-stimulant action of NPY, tissue content and extracellular levels of NPY in the PVN, and, in particular, its medial parvocellular division, have been shown to vary as a function of nutritional state (7-9,30,47). There is a strong positive correlation between carbohydrate ingestion and NPY levels in the PVN (26). Since the PVN is a primary site mediating the feeding and metabolic effects of norepinephrine (NE) (18,31,36,49), with which NPY is colocalized (48), this suggests that this nucleus may also be of primary importance in mediating I Requests MI 48202.

for reprints

should be addressed

Body temperature

Thermoregulation

similar effects of NPY. The PVN’s involvement in various neuroendocrine and autonomic processes, closely related to eating behavior, energy homeostasis, and thermogenesis is well documented (5,32,33,37,61). Because the hypothalamus contains high concentrations of presynaptic NPY and the PVN is particularly dense with NPY terminals (15,20) that originate largely from noncatecholaminergic neurons of the arcuate nucleus (6,20), it is believed that this NPY projection constitutes the major substrate in the control of NPY feeding (26). Other evidence exists that indicates multiple hypothalamic sites are responsive to the feeding effects of NPY (40,52,56,58). Injection of NPY into the ventromedial hypothalamus potentiates feeding whereas NPY antibody inhibits food intake (63). Neuroanatomical mapping studies aimed specifically at determining the loci of this peptide’s feeding effects indicate that the perifornical hypothalamus (PFH), posterolateral to the PVN, is the major focus of its feeding-stimulant action within the hypothalamus (52,58). Therefore, the PVN is only one of several hypothalamic feeding sites capable of responding to NPY, suggesting that the peptide provides input to a variety of eating control, metabolic, and thermogenic subsystems distributed throughout

Y (NPY),

mone widely distributed modulator

Hypothalamus

to Dr. P. J. Currie, Department

599

of Psychology,

Wayne State University,

7 1 West Warren Ave.. Detroit,

600

CURRIE AND COSCINA

the hypothalamus. Despite these data, we know of no evidence that suggests NPY in the PFH participates in the types of integrative mechanisms responsibie for the control of feeding and energy metabolism as demonstrated in the PVN. Based on the above findings indicating that hypothalamic NPY evokes changes in eating behavior and core Tbo,the present investigation characterized and compared the ingestive and temperature responses that occur in the rat following PVN and PFH administration of NPY.

Histology

At the end of the experiment animals were perfused transcardially with saline followed by 10% buffered formalin and were then decapitated. Brains were removed and cut in 40-pm coronal sections through the site of implantation and then stained with Cresyl violet. Cannula placements were verified using the stereotaxic atlas of Paxinos and Watson (44). RESULTS

METHOD

Animals

Adult male Sprague-Dawley rats (n = 18) were purchased from Charles River laboratory (St. Constant, QC, Canada). The rats, weighing 275-300 g at the start of the experiment, were housed in separate stainless steel cages in a temperature-controlled colony room (22 + 2°C) illuminated on a 12: 12 h 1ight:dark cycle (lights off at 1900 h). Throughout the study rats had ad lib access to lab chow pellets (Purina) and water. Design and Procedure

Rats were anesthetized with sodium pentobarbital (Somnotol, 50 mg/kg, IP), and chronic 22-ga stainless steel cannulae (Plastics One, Roanoke, VA) aimed at either the PVN or PFH were implanted. The following coordinates relative to bregma and with the incisor bar set 3.6 mm below interaural zero were used. For the PVN the coordinates were 1.8 mm posterior to bregma, 0.4 mm lateral to the midsagittal sinus, and 4.2 mm ventral to the skull surface. Stereotaxic coordinates for the PFH were posterior 2.1 mm, lateral 1.4 mm, and ventral 4.6 mm. Guide cannulae terminated 4 mm above the target site and were fitted with 28ga inner stylets to maintain patency. Behavioral testing began 1 week after surgery. All testing was conducted during the light phase of the 1ight:dark cycle between 1300 and 1600 h. One hour prior to treatment fresh food was placed in the home cage of each rat to promote satiation and minimize spontaneous eating. Rats were then infused with saline vehicle or NPY (78, 156, and 235 pmol) using a 28-ga microinjector (Plastics One) attached to a 5+1 Hamilton syringe. Synthesized NPY was kindly provided by Dr. R. D. Myers of the Departments of Pharmacology and Psychiatric Medicine, East Carolina University School of Medicine (Greenville, NC). The injector cannula extended 4 mm beyond the indwelling guide cannula. A volume of 0.4 ~1 was administered into either the PVN (n = 9) or PFH (n = 9) over a period of 1 min with the injector left in place for an additional 30 s to permit peptide diffusion. Rats were then returned to their home cages with preweighed amounts of fresh food. Changes in Tboand food intake were recorded every 30 min over the next 3-h period. Body temperature was determined using a YSI 401 temperature probe attached to a YSI telethermometer (Model 43TA, Yellow Springs Instruments, Yellow Springs, OH) inserted 4 cm into the colon. Data Analyses The amount of food consumed and change in Th after NPY treatment were subjected to separate three-way analyses of variance (ANOVA) with one between factor (hypothalamic site) and two within factors (dose and time after NPY injection). Individual means were compared using post hoc Tukey tests following significant main effects or interactions. Significance was defined at the 0.05 (Ylevel.

Schematic representations of coronal sections of the PVN and PFH identifying the injection sites are shown in Fig. 1. All rats were found to have injector tracts extending into the intended target site. Figure 2 illustrates the mean intake of food recorded every 30 min over the 3-h test period for each dose of NPY. The three-way ANOVA revealed highly significant main effects for dose, F(3,64) = 29.93, p < 0.001, site, F(1, 64) = 7.63, p < 0.005, and time, F(5, 320) = 43.37, p < 0.001. That is, there were dose-dependent increases of feeding, increased eating in PFH vs. PVN groups, and reliable changes in NPY-stimulated eating over time, respectively. Although there was no reliable dose X site interaction, there were significant dose X time, F(15, 320) = 8.48, p < 0.001, and site x time, F(5,320) = 5.01,~ < 0.001, effects. These revealed that NPYinduced feeding diminished over time, with a greater time-dependent change in PFH vs. PVN groups, respectively. Gf particular interest was the finding of a significant dose X site X time interaction, F(15, 320) = 1.94, p < 0.02. This was largely due to the stronger feeding responses at the two highest doses of NPY by PFHtreated rats during the first 30-min time interval. Therefore, NPY elicited dose-dependent eating after injection into either hypothalamic site, although the magnitude of this feeding response was significantly greater following PFH NPY infusion. The enhanced eating behavior induced by PFH compared to PVN infusions of NPY was most evident during the first test interval. In both instances, however, feeding occurred within 30 min of injection and was generally maintained for 90 min postinjection, after which time interval intakes were no longer statistically different from saline values. The relationship between NPY injections into the PVN and PFH and the subsequent impact on Tbais shown in Fig. 3. Data are presented as mean changes in body temperature over 30-min test intervals for the 3 h following treatment. Although baseline values for body temperature were not significantly different between PVN and PFH groups, three-way ANOVA examining changes in T,,,, from preinjection Tbo values revealed significant main effects on all three factors [dose: F(3, 64) = 6.27, p < 0.001; site: F(1,64) = 40.69;~ < 0.001; time: F(5,320) = 15.35, p < O.OOl] as well as two-way interactions for dose X site, F(3, 64) = 8.01, p < 0.001, dose x time, F(15, 320) = 1.71, p < 0.05, and site x time, F(5, 320) = 3.66, p < 0.005. In PVN treated rats, NPY-stimulated eating was associated with a significant decline in Tbothat was also evident within 30 min of injection. A mean maximal Tbodecline of 0.92 ? 0.26”C occurred within 90 min following PVN treatment of the 235 pmol dose. The significant reduction in Tboor NPY-induced hypothermia persisted for 2.5 h postinjection. In contrast, NPY had no apparent effect on Tbowhen injected into the PFH. DISCUSSION The results of the present study are consistent with previous reports (14,34,43,54,55) demonstrating that NPY elicits dose-dependent increases in feeding following administration into the PVN or the PFH. Further, in agreement with recently published data (58), we obtained evidence of an enhanced eating response

NPY, FEEDING,

601

AND HYPOTHERMIA

-2.30 mm

FIG. 1. Schematic representation of coronal sections of the rat brain depicting the distribution of PVN and PFH microinfusion sites. Sections are taken from Paxinos and Watson (45). Relevant anatomical structures are: AHA, anterior hypothalamic area; Arc, arcuate nucleus; fx, fomix; LH, lateral hypothalamus; mfb, medial forebrain bundle; ox, optic chiasm; PaAP, paraventricular nucleus, anterior parvocellular; PVN, paraventricular nucleus; TC, tuber cinereum; VMH, ventromedial hypothalamus; 3V, third ventricle.

to PFH infusion of NPY compared to PVN treatment. Feeding effective doses of PVN NPY also evoked a simultaneous but more protracted reduction in core Tbo.This effect was not observed in rats receiving NPY injections into the PFH, indicating that the eating-stimulatory and hypothermic effects of NPY depend not only on the dose of peptide infused but also on the anatomical site of injection. The PFH is reported to be the hypothalamic site most sensitive to the feeding-stimulant action of NPY, although multiple hy-

pothalamic areas, including the PVN, are clearly responsive to NPY’s effects on ingestive behavior (14,40,52,58). Therefore, NPY would appear to provide input to a variety of eating control subsystems distributed throughout the hypothalamus. Although previous work has already implicated the PFH as being involved in feeding control mechanisms (41,45), recent findings have further suggested that PFH NPY may interact antagonistically with the catecholamines, and in particular dopamine, to regulate eating behavior (22). With respect to the mechanism of action of NPY,

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FIG. 2. The effects of NPY (78-235 pmol) on food intake after injection into the PVN (n = 9) or PFH (n = 9). Data represent the mean intake of food (2 SEM), measured in 30-min intervals, over a 3-h period following treatment. *p < 0.05 compared to saline values.

it is believed that the Y, receptor or a variant of this subtype mediates the feeding response characteristics (2957). Given the multiple sites of action responsive to NPY, it is unlikely that the peptide would exert identical effects in each region, For example, PVN, but not PFH, NPY-induced feeding exhibits a circadian sensitivity (59,62), and whereas the concentration of NPY in the PVN is reduced in rats refeeding after a period of food deprivation, peptide levels in the PFH actually increase (7). In addition to eliciting eating, PVN NPY has been implicated in energy metabolism. This is supported by biochemical data demonstrating that NPY is found in relatively high concentrations in the PVN (15) and that the levels of peptide are altered by conditions that potentiate food intake and alter body energy balance (47,51,65). PVN NPY also produces endocrine and autonomic effects in association with feeding, although similar effects are not observed after NPY infusion into the PFH (1,21,25,50). Consequently, a primary function of NPY in the PFH may be to mediate the actual eating response, whereas in the PVN NPY may have a more integrative role in coordinating energy intake and metabolism, including, as demonstrated here, NPY-induced hypothermia. This is consistent with the proposal that these brain regions are functionally distinct with respect to their responsiveness to NPY, specifically in relation to the induction of eating and the physiological responses associated with this behavior (50,58). Despite initial reports that NPY exerts minimal effects on core temperature (24), other data have shown that NPY given intracerebroventricularly produces hypothermia (28). In one recent study (46), perfusion of NPY into the AI-I/POA resulted in a perturbation of the neuronal mechanisms underlying body temperature and energy intake. Chronic elevation of NPY at this site spontaneously evoked feeding, a decline in temperature, or both responses. This suggests that temperature and feeding effects of NPY are independent and that separate neuronal populations may exist within AH/POA to subserve these functions. In the present study, PVN NPY injections elicited both feeding and temperature

effects simultaneously and so it is unclear whether or not these effects are mediated by separate mechanisms. To demonstrate the independence of the feeding and thermoregulatory responses, it would be necessary to show that local NPY infusion could evoke a decline in TbOunder conditions where food is not available. This possibility warrants further investigation. The medial aspect of the preoptic area is also sensitive to the feeding and hypothermic effects of NE, suggesting that NPYinduced hypothermia may be attributed, at least in part, to a local modulatory action of the peptide on catecholaminergic neurons (42,46). Within the anterior hypothalamus, cells implicated in thermoregulatory mechanisms for heat loss are principally noradrenergic (42). Because NPY releases NE in the rat hypothalamus (66), it is possible that feeding concomitant with the thermal displacement of core temperature results in part from the activation of noradrenergic receptors. Although the mechanism of NPY-induced hypothermia in the PVN is not known, the coexistence of NE and NPY in hypothalamic neurons (48) and the feeding elicited by both NPY and NE in the PVN (19,31,43,62) suggest some degree of functional overlap. It has been shown that a,-adrenoceptor stimulation enhances the binding of NPY in hypothalamic and cortical membranes and that NPY itself increases the affinity of a-adrenoceptors (3,23X In addition, the (Y*antagonist yohimbine attenuates NPY-stimulated eating following administration into the third ventricle (16). NPY acting on receptors localized within the PVN could also directly or indirectly modulate neuroendocrine and autonomic systems, thereby altering energy metabolism. Cells projecting from the parvocellular region of the PVN terminate in the median eminence whereas the posterior pituitary receives direct inputs from neurosecretory cells originating from the PVN magnocellular division (61). The parasympathetic cell groups in the motor vagus nucleus and the nucleus ambiguus both receive direct inputs from the PVN, and it has been demonstrated that the activity of neurosecretory cells in the PVN is influenced by thermosensitive neurons in the preoptic area (37,60). Through these and

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FIG. 3. The effects of NPY (78-235 pmol) on Tbo after PVN (n = 9) or PFH (n = 9) infusion. Values represent mean (? SEM) changes in Tbo from baseline recorded every 30 min for 3 h postinjection. *p < 0.05 compared to saline.

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other projections, it is possible that NPY acts within the PVN to influence both ingestive and thermoregulatory processes. Given the physiological interrelationship between the control of Tboin an animal and its energy intake (13,46), it is reasonable to assume that this interdependence is reflected in overlapping or closely related neural systems within the hypothalamus, including the PVN. In fact, several lines of evidence now suggest that NPY in the PVN may coordinate various aspects of energy metabolism in addition to appetite control. NPY has been reported to decrease brown fat therrnogenesis and increase white fat lipoprotein lipase activity (IO,1 1). In the PVN, NPY stimulation reduces gene expression for the critical brown fat thermogenic moiety, uncoupling protein, and increases gene expression for the white fat storage enzyme lipoprotein lipase (11). NPY injected into the PVN also increases respiratory quotient, indicating an increase in car-

bohydrate oxidation in favor of fat storage (27,39). The anabolic state involving carbohydrate utilization as an energy substrate is consistent with the selective enhancement of carbohydrate appetite induced by acute injection of NPY into the PVN (34,53,62) and with the potent effect of this peptide on fat deposition and body weight (5 1,54). Our findings provide further support for the role of PVN NPY in the integrative mechanisms controlling energy intake and metabolism. This contrasts with the effects of NPY in the PFH where the peptide is a potent stimulator of ingestive behavior but may have less of a direct impact on several metabolic indices. ACKNOWLEDGEMENTS

This research was supported by funds from the Natural Sciences and Engineering Research Council and the National Institute of Nutrition of Canada. We thank Dr. R. D. Myers for generously providing the NPY.

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was in press, another report appeared (Jolicceur, F. B.; Boulai, S. M.; Fournier, A.; St.-Pierre, S. Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake. Brain Res. Bull. 36: 125-129; 1995) which also examined the feeding and temperature-altering effects of NPY after local infusion into discrete hypothalamic regions. Although a number of ptocedural and dose-response differences exist between that report and the current one, two major findings of our work were confirmed by that study: (1) the PFH is the most sensitive site at which NPY can stimulate feeding, and (2) the PFH is insensitive to the potential temperature-altering effects of this peptide. Therefore, both studies are in agreement that dissociation can exist between the feeding and body temperature effects of NPY depending on its apparent locus of action within the hypothalamus. this

paper

COSCINA

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