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Endocrinology Vol. 142, No. 3 1050-1056
Copyright © 2001 by The Endocrine Society

ARTICLES

Immediate and Prolonged Patterns of Agouti-Related Peptide-(83–132)-Induced c-Fos Activation in Hypothalamic and Extrahypothalamic Sites1

Mary M. Hagan, Stephen C. Benoit, Paul A. Rushing, Laurel M. Pritchard, Stephen C. Woods and Randy J. Seeley

Department of Psychology (M.M.H.), University of Alabama, Birmingham, Alabama 35294-1170; Department of Psychiatry, University of Cincinnati Medical Center (S.C.B., P.A.R., L.M.P., S.C.W., R.J.S.), Cincinnati, Ohio 45267-0559

Address all correspondence and requests for reprints to: Mary M. Hagan, Ph.D., 415 Campbell Hall, Department of Psychology, University of Alabama, Birmingham, Alabama 35294-1170. E-mail: mhagan{at}uab.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Several lines of evidence substantiate the important role of the central nervous system melanocortin 3- and 4-receptor (MC3/4-R) system in the control of food intake and energy balance. Agouti-related peptide (AgRP), an endogenous antagonist of these receptors, produces a robust and unique pattern of increased food intake that lasts up to 7 days after a single injection. Little is known about brain regions that may mediate this powerful effect of AgRP on food intake. To this end we compared c-Fos-like immunoreactivity (c-FLI) in several brain sites of rats injected intracerebroventricularly with 1 nmol AgRP-(83–132) 2 and 24 h before death and compared c-FLI patterns to those induced by another potent orexigenic peptide, neuropeptide Y (NPY). Although both NPY and AgRP induced c-FLI in hypothalamic areas, AgRP also produced increased c-FLI in the accumbens shell and lateral septum. Although NPY elicited no changes in c-FLI 24 h after administration, AgRP induced c-FLI in the accumbens shell, nucleus of the solitary tract, central amygdala, and lateral hypothalamus. These results indicate that an NPY-like hypothalamic circuit mediates the short-term effects of AgRP, but that the unique sustained effect of AgRP on food intake involves a complex circuit of key extrahypothalamic reward and feeding regulatory nuclei.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MUCH EVIDENCE establishes the central melanocortin (MC) system as an important regulator of food intake and energy balance (1, 2, 3, 4, 5). The endogenous melanocortin, {alpha}MSH, binds to MC3 and MC4 receptors (MC3/4-R) where its agonist actions limit food intake. Central injection of {alpha}MSH (6, 7) or synthetic agonists (1, 8, 9, 10) reduces feeding. {alpha}MSH appears critical in this regard, because blockade of endogenous {alpha}MSH using a synthetic MC3/4-R antagonist, SHU9119, reverses the natural hypophagia in animals overfed to gain weight (2), and SHU9119 potently stimulates feeding in sated animals (1, 9).

Interestingly, there is an endogenous antagonist for MC3/4-R, termed Agouti-related peptide (AgRP). AgRP is synthesized exclusively in the arcuate nucleus of the hypothalamus, projecting to other hypothalamic and extrahypothalamic sites (11, 12, 13). Central administration of the fragment AgRP-(83–132) (14) increases food intake (15). States of energy deficiency increase AgRP expression (16, 17), and transgenic mice overexpressing AgRP are hyperphagic and obese (18).

We recently found that AgRP-(83–132) induces a long-lasting increase in food intake up to 168 h after a single third ventricular injection of 100 pmol in rats. AgRP’s short-term hyperphagia involves competitive MC3/4-R antagonism, whereas the persistent effects engage alternate, as yet unknown, mechanisms (19, 20). Our goal in this study was to begin to elucidate the central nervous system (CNS) circuits that subserve AgRP’s potent and remarkably sustained increase in food intake. We measured changes in neuronal activation induced by AgRP using immunohistochemistry for the protein associated with the immediate-early gene, c-fos (21). We compared the areas activated by AgRP 2 h after administration with the areas activated a full 24 h after administration. Additionally, we compared the pattern of AgRP-induced neuronal activation to that elicited by another potent stimulator of food intake, neuropeptide Y (NPY). Given that NPY is extensively colocalized with AgRP (16, 22), our hypothesis was that these two peptides might engage similar circuits in the short term. However, given that NPY does not stimulate intake for long periods like AgRP, we hypothesized that the circuits engaged by NPY and AgRP would be different after 24 h.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and housing
Male Long-Evans rats (350–390 g at the time of surgery) maintained in individual cages with a 12-h light, 12-h dark cycle (lights off at 1300 h) were implanted with a cannula aimed at the third cerebral ventricle (i3vt). Coordinates were midline, 2.2 mm posterior to bregma, and 7.5 mm ventral to dura (23). A minimum 10-day recovery period was followed by confirmation of cannula placement by i3vt infusion of 10 ng angiotensin II in saline. Only animals drinking in excess of 5 ml over 1 h after AII infusion were included in the study (n = 26). This protocol was approved by the University of Cincinnati animal care committee.

Peptide infusions
The animals were assigned to six groups matched by body weight and baseline food intake and were infused with 1.0 nmol AgRP-(83–132) [a gift from Merck & Co. (Rahway, NJ) or purchased from Phoenix Pharmaceuticals, Inc. (Mountain View, CA)], 5 µg NPY (American Peptide Co., Sunnyvale, CA), or physiological saline (vehicle) in equal volume (2 µl). Groups infused with AgRP, NPY, or saline were killed 2 h (2 h) or 24 h (24 h) after injection. The possibility that feeding could influence AgRP-induced c-Fos-like immunoreactivity (c-FLI) patterns was minimized by removing all food for a period of 6 h before the time of death for animals killed at both the 2 and 24 h periods. Although we cannot completely rule out a possible influence of AgRP-induced food intake on c-FLI patterns in rats killed 24 h after injection (who had 18-h access to food before it was removed for 6 h), a feeding effect is unlikely because feeding-induced Fos patterns observed by others (24) differed from those observed here after AgRP. The selected doses of NPY and AgRP lie within ranges that elicit a similar magnitude of increased food intake over 2 h when injected intraventricularly in rats (15, 19, 25). Water was available at all times. In counterbalanced order for drug received, rats were infused between 0900–1100 h and were killed either 2 or 24 h later to the corresponding minute of infusion.

Tissue processing and c-Fos-like immunohistochemistry
At the time of death, animals were anesthetized with 60 mg/kg sodium pentobarbital and intracardially infused with 0.9% PBS, followed by 4.0% paraformaldehyde in 0.1 M phosphate buffer. Brains were postfixed for at least 4 h and stored in 30% sucrose PBS for a minimum of 2 weeks. Forebrains were frozen and sectioned at 40-µm thickness in a coronal plane, and hindbrains were sectioned in a horizontal plane to visualize sites of interest. For each of the 12 sites examined, one section was selected representing each plane, and care was taken to closely match that plane across rats. The sections were chosen by an experimenter blind to group treatments. The same procedure was followed for sections taken 24 h after injection. With the exception of two rats contributing sections from forebrain regions in the 24-h NPY condition, sections were taken from a total of three rats in the 2-h saline, four rats in the 24-h saline, three rats in the 2-h NPY, four rats in the 24-h NPY, four rats in the 2-h AgRP, and five rats in the 24-h AgRP condition. Immunohistochemical procedures were conducted and quantified as previously described (8). Bilateral sections were quantified for each brain site of interest, except in the accumbens shell that was counted unilaterally. Neuroanatomical boundaries (23) are given in Table 1Go.


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  		Table 1. Rat atlas coordinates from Bregma in millimeters for the centermost area of neuroanatomical sites quantified for c-Fos-like immunoreactivity (23 )

 
Comparisons between time points were not conducted because the two time points differed in their proximity to the injection procedure. Rather, we compared each time point to its own saline-injected control to determine changes in c-FLI associated with the treatment. Therefore, data were analyzed by one-way ANOVAs to specifically examine differences between treatment groups (saline vs. NPY vs. AgRP injected at each brain site and for each time point, 2 or 24 h postinfusion). Significant main effects were further analyzed using either Bonferroni or least significant difference post-hoc tests, and significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Distribution and comparison of c-Fos-like immunoreactivity induced 2 h after NPY and AgRP infusions
As depicted in Fig. 1AGo, saline-induced c-FLI was most notable in hypothalamic regions. Increased NPY-induced c-FLI relative to saline occurred in the caudal accumbens shell, lateral septum, paraventricular nucleus of the hypothalamus (PVN), dorsal region of the dorsomedial nucleus (DMN), the nucleus solitary tract (NTS) and commissural NTS with c-FLI at 300%, 590%, 460%, 240%, 1500%, and 360% of saline-induced levels, respectively (Fig. 1AGo). However, only in the PVN was NPY-induced c-FLI statistically different from saline-induced levels. AgRP elicited a similar c-FLI pattern to NPY (Table 2Go), except that AgRP elicited higher c-FLI in the rostral accumbens shell and DMN (300% and 180% greater than NPY-induced c-FLI, respectively) and lower c-FLI than NPY in the commissural NTS and NTS proper. The only statistically significant differences between NPY and AgRP-provoked c-FLI occurred in the commissural NTS (Fig. 1AGo). Comparisons between NPY- and AgRP- induced c-FLI could not be made in the amygdala and lateral hypothalamus due to an artifact in the slicing process that disrupted the morphological integrity of these sections and prevented accurate orientation of these sites to match those taken from other brains. Previous studies led us to predict that NPY, like AgRP, would evoke increased c-FLI expression in these areas (26, 27). Representative examples of c-FLI expression in saline-, NPY-, and AgRP-treated animals 2 h after injection are depicted in Fig. 2Go.



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  		Figure 1. Mean c-Fos-like immunoreactive nuclei in brain sites of rats injected in the third ventricle with saline, NPY, or AgRP 2 h before death (A) and 24 h before death (B). Different from saline: a, P < 0.05; b, with P < 0.01; c, P < 0.001; marginally different from saline: d, P < 0.057; different from NPY: e, P < 0.01. In B, NPY-induced c-FLI is not included, because in no area were the numbers above saline-treated levels.

 

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  		Table 2. Density and distribution of central AgRP or NPY-induced c-FLI relative to saline-induced expression at 2 and 24 h postinfusion

 


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  		Figure 2. Representative photomicrographs illustrating c-Fos-like immunoreactive cells 2 h after injection of saline (left column), NPY (middle column), or AgRP (right column) in the caudal accumbens shell (A), paraventricular nucleus (B), and dorsal region of the DMN (C) of the hypothalamus. Surrounding structures: aca, anterior area of the anterior commissure; ACC, nucleus accumbens core; AH, central region of the anterior hypothalamus; 3vt, third cerebroventricle. Magnification of all images, x10.

 
Distribution and comparison of c-Fos-like immunoreactivity induced 24 h after NPY and AgRP infusions
Patterns of c-FLI observed 2 h after NPY injection reverted to saline-like levels 24 h after injection. However, AgRP injection elicited sustained elevations of c-FLI in several brain sites (Table 2Go). In fact, c-FLI in the rostral and caudal accumbens shell, lateral septum, central amygdala, basolateral amygdala, lateral hypothalamus, and NTS were greater at this delayed time point than shortly after AgRP injection (Table 2Go). As depicted in Fig. 1BGo, c-FLI in the rostral and caudal accumbens shell remained elevated at 24 h (1550% and 2400% of control value, respectively), albeit to a lesser degree than observed at the 2 h point. c-FLI in the NTS was considerably elevated (426% of control value) compared with c-FLI expression there at 2 h, and whereas no significant c-FLI changes were observed in the central amygdala and lateral hypothalamus at 2 h after AgRP, after 24 h these areas displayed 14- and 128-fold increased c-FLI over that with saline treatment, respectively. Representative brain regions depicting the most salient c-FLI differences between AgRP and saline treatment 24 h after injection are presented in Fig. 3Go.



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  		Figure 3. Representative photomicrographs illustrating c-Fos-like immunoreactive cells 24 h after injection of saline (left column) or AgRP (right column) in the caudal accumbens shell (A), central amygdala (B), lateral hypothalamus (C), and nucleus solitary tract (D). Surrounding structures: aca, anterior area of the anterior commissure; ACC, nucleus accumbens core; 4vt, fourth cerebroventricle. Magnification of all images, x10.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
AgRP is distinct in being a naturally occurring antagonist in the brain, binding to MC3/4-R presumably to inhibit the melanocortin ligand, {alpha}MSH (4, 18). Also unique is AgRP’s ability to stimulate food intake in rats for a prolonged interval, up to 7 days after a single central picomolar dose (19). We observed that whereas the acute increase in intake seen after AgRP involves intrinsic action at the MC3/4-R, the sustained hyperphagia relies on alternate and unique mechanisms (19).

The present study was conducted to begin elucidating the CNS mechanisms engaged by AgRP to mediate its effect on food intake. c-FLI was used to identify neuroanatomical sites activated both acutely and after 24 h after AgRP. Two hours after AgRP injection, a time point reflecting the acute induction of food intake, the largest c-FLI response occurred in the hypothalamic PVN and the DMN and in the accumbens shell and lateral septum outside the hypothalamus. In the PVN and DMN, sites dense with MC3/4-R (28), c-FLI is probably due to competitive binding at MC3/4-R. PVN injection of MTII, a MC3/4-R agonist, suppresses intake in fasted rats, an effect reversible by SHU9119, a MC3/4-R antagonist (29). AgRP acts in an inhibitory manner, decreasing {alpha}MSH- induced cAMP activation (4, 11, 15), and MC3/4-R agonists potentiate {gamma}-aminobutyric acid (GABA)-mediated inhibition of postsynaptic PVN neurons (29). Because c-FLI is induced at the transcriptional level with extracellular stimulation and not inhibition (21), c-FLI observed in the PVN may reflect AgRP inhibition of GABA to release PVN neurons from their inhibitory signals.

To further understand AgRP’s actions, we compared its c-FLI pattern to that induced by NPY. Both peptides induce potent hyperphagia in animals (5, 30, 31), and both are extensively coexpressed and colocalized in the arcuate nucleus (16, 22). AgRP and NPY activated common neuroanatomical targets 2 h after infusion, including the ACSh, lateral septum, PVN, anterior hypothalamic area, DMN, and NTS. The largest c-FLI response occurred in the PVN after both AgRP and NPY.

The PVN is critical in regulating energy intake and metabolism, and NPY mediates many of these actions (31, 32). The colocalization and density of NPY and melanocortin receptors in the PVN (28) suggest that AgRP, like NPY and perhaps in concert with NPY, has a prominent role in the control of energy homeostasis. The DMN also had high levels of c-FLI after AgRP and NPY injection. Morphologically linked to the PVN, the DMN is also important in energy regulation (33). DMN-lesioned rats are hypophagic (33), and a high level of NPY expression specifically in the DMN is associated with obesity in MC4-R-deficient mice (34). Given that both NPY and AgRP impact activity in the DMN, the current results implicate the DMN as one area where NPY and AgRP may interact in coordinating the response to negative energy balance. Like AgRP, NPY is also an inhibitory peptide; its stimulation of receptors promotes inhibition of adenylate cyclase (35). Hence, the expression of c-FLI observed after NPY injection in these nuclei probably reflects NPY inhibition of catabolic signals produced by peptides known to interact with NPY, such as leptin and {alpha}MSH (1, 17, 29).

Outside of the hypothalamus, AgRP evoked c-FLI in the accumbens shell and lateral septum. Similar c-FLI increases have been observed in the lateral septum after lateral ventricular injection of NDP-{alpha}MSH, a MC3/4-R agonist (36). The nucleus accumbens contains MC4-R, but no AgRP-containing fibers, whereas the lateral septum is moderately innervated by AgRP fibers (22). The accumbens shell is innervated by viscero-endocrine circuits and integrates reward signals from the lateral hypothalamus with food intake (37). The accumbens is largely innervated by GABA neurons and enkephalin terminals are abundant in the shell (38). Inhibition of accumbens shell neurons by GABA agonists elicits a powerful lateral hypothalamus stimulation-like feeding response (37). The lateral hypothalamus also had nonsignificant, but 8-fold, increases in c-FLI after AgRP relative to that after saline treatment. It is tempting to speculate that AgRP may activate an opioid or other reward regulatory circuit as it elicits feeding, possibly via interaction with MC3/4-R that may inhibit accumbens GABA neurons, as proposed for AgRP’s action in the PVN (29). Consistent with this observation that NPY-induced hyperphagia is suppressed by an opioid antagonist (39), we recently found that the same opioid antagonist suppresses the hyperphagia induced after the injection of AgRP (40). Activation of an accumbens opioid system, however, is only one potential mediator of AgRP hyperphagia. In the hindbrain, NPY, but not AgRP, increased c-FLI in the NTS. Others have reported increased c-FLI in medial areas of the NTS after fourth ventricular injection of NPY and in the absence of food (41), and neuronal activation in the NTS is generally associated with feeding (27, 41).

Although a powerful tool, c-FLI data are limited, in that they cannot describe the neurochemical phenotype of neurons being activated or the critical connections to other nuclei to affect feeding. Fos data are also limited, in that they cannot identify neurons that have been inhibited by the treatment. Furthermore, the absence of c-FLI expression in nuclei does not mean these are not activated, as some brain cells do not express c-FLI when stimulated. Therefore, future dual labeling studies are warranted to identify the neurochemical phenotype of activated neurons with, for example, serotonin, glutamate, and dopamine as possible candidates in accumbens shell neurons (37, 38). Another limitation of the current study is that ventricular injection is expected to distribute NPY and AgRP in a pattern that is not identical to that of the endogenous secretion of these peptides. Hence, these data indicate which circuits can be recruited by these peptides rather than determine exactly which ones are engaged during endogenous secretion. Complementary studies using peptide injection into discrete sites will help determine the neuroanatomical origin of the observed effect on c-FLI expression or possibly elucidate divergent patterns. As AgRP produces hyperphagia for as long as 7 days after injection (20), it will also be of future interest to observe whether c-FLI patterns produced by AgRP beyond 24 h after injection are recapitulated or are different from the patterns observed at 24 h after injection.

The other intriguing aspect of AgRP’s effect on behavior is its ability to stimulate increased intake for up to 7 days with a single picomolar injection (19), a behavior not observed after NPY. Based on our previous data suggesting that mechanisms other than competitive binding at the MC3/4-R mediate AgRP’s long-term effects (19), and on the discovery that AgRP elicits hyperphagia in MC4-R-deficient mice (42), we hypothesized that AgRP would recruit additional neuroanatomical substrates 24 h after injection. At no site examined was c-FLI increased 24 h after NPY injection. However, the extended CNS actions of AgRP were evident from increased c-FLI in 10 of the 12 sites studied compared with that after saline treatment. Accumbens shell activation was even greater than that observed at 2 h, whereas activity in the PVN, anterior hypothalamus, and dorsomedial nucleus decreased or returned to control levels. Nonsignificant c-FLI elevations in the central amygdala, lateral hypothalamus, and NTS at 2 h became significant after 24 h. It is unlikely that AgRP-stimulated feeding before the 6-h fast induced these patterns, as others have found opposite patterns of c-Fos expression in the dorsomedial nucleus and NTS in response to ingestion (24).

A functional link between the accumbens shell and the lateral hypothalamus in the control of feeding is well established (37, 43). Both the accumbens and lateral hypothalamus are innervated by and functionally interconnected with the amygdala (44). The central amygdala has a key role in integrating food intake with learned, hedonic, and emotional inputs (45, 46). Projections from the central amygdala to the NTS (44, 47) have been implicated in the control of food intake (48, 49). In summary, the strong c-FLI expression evoked by AgRP in the ACSh, lateral hypothalamus, central amygdala, and NTS 24 h after injection suggests that these nuclei form a functional circuit through which AgRP may mediate long-lasting changes in food intake.

These long-lasting orexigenic effects may involve modulation of the release or expression of other orexigenic peptides localized within these nuclei, such as hypocretin and melanin-concentrating hormone. AgRP may stimulate hypocretin release, which is contained in the lateral hypothalamus, is surrounded by AgRP-containing cell bodies (22), and elicits a extrahypothalamic c-FLI pattern very similar to that induced by AgRP when injected in the lateral hypothalamus (49). AgRP may have similar effects on melanin-concentrating hormone, which is also contained in the lateral hypothalamus and is expressed in some of the extrahypothalamic sites that were c-Fos reactive to AgRP (50). AgRP may also induce transcriptional changes leading to altered synaptic efficacy in hypothalamic and extrahypothalamic proteins involved in the regulation of energy balance.

Depletion of an organism’s caloric stores results in strong behavioral changes to find and ingest calories. Consistent with this survival function, AgRP elicits the most long-lasting effect to increase food intake of any acute pharmacological manipulation of the CNS. AgRP apparently accomplishes this by recruitment of anatomical sites inside and outside of the hypothalamus, sites that integrate and relay gustatory, sensory, and reward properties of food.


   Footnotes
 
1 This work was supported by several grants from the NIH (DK-54080, DK-54890, and DK-17844). Back

Received September 14, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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