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. 2002 Jun 15;22(12):5091-9.
doi: 10.1523/JNEUROSCI.22-12-05091.2002.

Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia

Teresa M Reyes  1 , Paul E Sawchenko
Affiliations

Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia

Teresa M Reyes et al. J Neurosci. .

Abstract

Cytokine-mediated anorexia is a component of "sickness behavior" and presents a significant obstacle in the treatment of chronic illnesses. We hypothesized an involvement of the hypothalamic arcuate nucleus (ARH) in mediating the anorexic effects of a systemic interleukin-1 (IL-1) challenge based on its content of peptidergic neurons involved in feeding, its expression of IL-1 receptors and its sensitivity to systemic IL-1. IL-1 (6 microg/kg, i.v.) was found to induce Fos expression in both pro-opiomelanocortin- and neuropeptide Y-expressing neurons in and around the ARH. Contrary to expectations, rats that had sustained lesions of the arcuate nucleus, produced by neonatal monosodium glutamate treatment, displayed a more pronounced suppression (by 25%) of food intake than nonlesioned controls when treated with IL-1 after a 20 hr fast. To confirm and further characterize this unexpected result, a second ablation method was used in a similar paradigm. Animals bearing knife cuts designed to sever major ARH projections displayed an even more accentuated loss of appetite (by 60%, relative to controls) in response to systemic IL-1. This effect exhibited at least some degree of specificity, because the knife cuts did not alter either IL-1 effects on another centrally mediated acute phase response (fever) or the anorexia produced by an alternate agent, fenfluramine. These results fail to support the hypothesized ARH mediation of IL-1-induced anorexia and may suggest rather that the net output of this cell group may serve normally to restrain cytokine-induced reductions in food intake.

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Figures

Fig. 1.
Fig. 1.
IL-1 suppression of deprivation-induced feeding.Top, Mean ± SEM cumulative food intake over 24 hr after intravenous administration of IL-1β (6 μg/kg) (open squares, vehicle; filled squares,IL-1-injected). Bottom, Food intake per time bin. IL-1-induced suppression of food intake was manifest primarily during the 2 hr immediately after injection. n = 4; *differs significantly from vehicle-treated values,p < 0.005.
Fig. 2.
Fig. 2.
IL-1-induced Fos expression in the arcuate nucleus. Left, IL-1-induced Fos-IR (brown nuclei) was seen reliably in the arcuate nucleus and the POMC-rich region laterally adjoining it (bottom). Saline-injected animals (top) showed little to no Fos-IR in the arcuate. Both photomicrographs, 45×. Center andright, Chemical characterization of IL-1-responsive neurons of the ARH. Polarized epifluorescence (top) and higher magnification bright-field photomicrographs (bottom) of the ARH, showing dual localization of Fos-IR (brown nuclei) with POMC (center) or NPY (right) mRNAs (aqua or black grains). Substantial proportions of Fos-IR neurons displayed positive hybridization signals for each transcript (arrowheads), although cells labeled singly for either marker were also apparent. Doubly-labeled cells are seen throughout the longitudinal extent of the ARH but were most prominent rostrally. Rats were killed 3 hr after intravenous injection of 6 μg/kg rat IL-1. Magnifications: top, 35×; bottom, 220×.AHA, Anterior hypothalamic area; fx, fornix; me, median eminence; mp (pm), medial parvocellular (posterior magnocellular) part of the paraventricular nucleus; VMH, ventromedial nucleus.
Fig. 3.
Fig. 3.
Evaluation of MSG lesions. Sections through the ARH of representative control (top) and MSG-lesioned (bottom) animals. Left, Examination of Nissl-stained material revealed substantial cell loss in the ARH of MSG-lesioned animals, with the most substantial sparing seen in the dorsomedial aspect of the nucleus. Middle, Dark-field photomicrographs showing POMC mRNA expression. MSG lesions virtually eliminated POMC cells from the ARH proper, although positively hybridized neurons lateral to the ARH were spared.Right, NPY mRNA expression in the ARH of lesioned animals was markedly attenuated, but not abolished, with sparing seen reliably in the ventromedial aspect of the nucleus. All photomicrographs, 50×. me, Median eminence;VMH, ventromedial nucleus; v3, third ventricle.
Fig. 4.
Fig. 4.
Accentuation of IL-1-induced feeding suppression in MSG-lesioned rats. Mean ± SEM cumulative food intake of control (open squares) and MSG-lesioned rats (filled squares) after an injection of IL-1, expressed as percentage of each animal's own response to vehicle injection. MSG-lesioned animals (n = 10) displayed a significantly greater suppression of feeding at 4 hr after injection compared with control animals (n = 8). Beyond 8 hr, lesioned animals' food intake did not differ reliably from control values. *Differs significantly from vehicle-treated values,p < 0.05.
Fig. 5.
Fig. 5.
Reduction of IL-1-induced Fos expression in MSG-lesioned rats. Intravenous IL-1 induced robust Fos expression in the paraventricular nucleus in a representative control animal (A), concentrated in the medial parvocellular region (mp). Sections from two ARH-lesioned animals (B, C) illustrate the reduced Fos expression seen in these animals, which ranged from an obvious attenuation (B) to a nearly total elimination of the response (C). Also apparent in the lesioned animals is the enlargement of the third ventricle that was characteristic of MSG-treated rats. Dashed line outlines the approximate border of the paraventricular nucleus. All photomicrographs, 60×.pm, Posterior magnocellular part (paraventricular nucleus).
Fig. 6.
Fig. 6.
Evaluation of knife cuts. A,Schematic drawing of a midsagittal section through the hypothalamus to show the approximate extent and position of horizontal knife cuts (red) designed to sever the vertically directed ARH projections. Such transections are expected to compromise projections from the ARH to such feeding-related targets as the paraventricular nucleus (PVH) and lateral hypothalamic area (LHA). B, Nissl-stained section through the ARH region of a knife cut animal. Black arrowsindicate placement and extent of the cut, dorsal to the ARH and roughly bisecting the ventromedial nucleus (VMH). Magnification, 20×. C, Immunofluorescence localization of glial fibrillary acidic protein- (GFAP; top) and α-MSH-IRs (bottom) reveals a glial scar at the site of the lesion (top), with significant pile-up of immunoreactive material in fibers on the side proximal to it (bottom). Dashed lines schematically indicate knife placement. Magnification, 60×.
Fig. 7.
Fig. 7.
Knife cut effects on IL-1-induced appetite suppression. Mean ± SEM cumulative food intake of knife cut (filled squares) and control (open squares) rats after intravenous injection of IL-1, expressed as percentage of each animal's own response to vehicle injection. Animals bearing an ARH knife cut (n = 9) displayed a significantly potentiated suppression of feeding at 2 hr after injection compared with control animals (n = 6). Beyond 8 hr, their food intake scores did not differ reliably from those of controls. *Differs significantly from control values,p < 0.05.
Fig. 8.
Fig. 8.
Temperature and activity measurements in knife cut animals. Intra-abdominally implanted telemeters were used to monitor core body temperature (top) and gross activity (bottom) in sham (open squares) and knife cut (filled squares) animals. Shaded areas represent the mean ± 1 SD of pooled baseline values from sham and knife cut animals. Both groups mounted similar febrile responses to an injection of IL-1 given at 10:00 A.M. (arrow). The trends toward a mild hypoactivity exhibited by both groups after IL-1 injection were not statistically reliable. *Differs significantly from baseline values, p < 0.01.
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