WORKSHOP: ANOREXIA DURING DISEASE—FROM

RESEARCH TO CLINICAL PRACTICE Editor: Wolfgang Langhans, DVM, PhD

Neural–Immune Gut–Brain Communication in the

Anorexia of Disease
Gary J. Schwartz, PhD
From the Edward W. Bourne Behavioral Research Laboratory, Weill Medical College of
Cornell University, White Plains, New York, USA
Peripheral administration of toxic bacterial products and cytokines have been used to model the
immunological, physiological, and behavioral responses to infection, including the anorexia of disease.
The vagus nerve is the major neuroanatomic linkage between gut sites exposed to peripheral endotoxins
and cytokines and the central nervous system regions that mediate the control of food intake, and thus has
been a major research focus of the neurobiological approach to understanding cytokine-induced anorexia.
Molecular biological and neurophysiologic evidence demonstrates that peripheral anorectic doses of
cytokines and endotoxins elicit significant increases in neural activation at multiple peripheral and central
levels of the gut– brain axis and in some cases may modify the neural processing of meal-related
gastrointestinal signals that contribute to the negative feedback control of ingestion. However, behavioral
studies of the anorectic effects of peripheral cytokines and endotoxins have shown that neither vagal nor
splanchnic visceral afferent fibers supplying the gut are necessary for the reduction of food intake in these
models. These data do not rule out 1) the potential contribution of supradiaphragmatic vagal afferents or
2) a modulatory role for immune-stimulated gut vagal afferent signals in the expression of cytokine and
enodotoxin-induced anorexia in the intact organism. Nutrition 2002;18:528 –533. ©Elsevier Science
Inc. 2002

KEY WORDS: visceral afferents, vagotomy, feeding, lipopolysaccharide, muramyl dipeptide, cytokines,
interleukins, acute-phase response, food intake

Appearing in this issue of Nutrition is a new paper in the special
series highlighting work presented at the Anorexia During
Disease—From Research to Clinical Practice Workshop held re-
cently in Ascona, Switzerland. The workshop was organized by
Wolfgang Langhans, DVM, PhD. Professor Langhans is also
Guest Editor of this series.
—Editor
INTRODUCTION
Infection and inflammation can elicit a common set of physiologic,
neuroendocrine, and behavioral responses collectively known as
the acute-phase response1 and characterized by fever, increased
sleep, and a cluster of somatic effects known as sickness behav-
ior2: reduced social exploration and locomotion, decreased groom-
ing, and reduced food and water intake. Prolonged anorexia during
disease can reduce fat stores and lean muscle mass and thus
represents a significant health risk.
Experimental work on the neurobiological basis of anorexia
during infection has focused on the examination of neural, phys-
iologic, and behavioral changes in rodent models after systemic
administration of bacterial endotoxins and cytokines as potential
mediators of the acute-phase response. Peripheral administration
of components of both gram-positive (muramyl dipeptide, MDP)
and gram-negative (lipopolysaccharide, LPS) bacteria have been
This study was supported by NIH grant DK 47208.
Correspondence to: Gary J. Schwartz, PhD, Edward W. Bourne Behavioral
Research Laboratory, Weill Medical College of Cornell University, 21
Bloomingdale Road, White Plains, NY 10605 USA. E-mail:
gjs2001@med.cornell.edu
used to evaluate anorexia during disease from the standpoint of a
peripheral infection process.3 Peripheral LPS administration at
doses that produce anorexia also elicits increases in plasma levels
of several cytokines believed to mediate LPS anorexia, including
tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤).4 LPS
and MDP primarily inhibit food intake by reducing meal fre-
quency, with no significant effect on meal size.5,6 In contrast,
intraperitoneal administration of IL-1␤ at doses that inhibit food
intake reduce meal size and meal frequency, suggesting that the
anorectic effects of cytokines and toxins that promote their release
do not completely share the same mechanisms of action.6 The
reduction in meal size after IL-1␤ administration also suggests that
anorexia-producing cytokines act by modulating food-elicited neu-
ral negative feedback signals that contribute to meal termination
(see NEUROPHYSIOLOGIC STUDIES).
Because the central nervous system ultimately determines the
somatic responses that comprise appetitive (approach and food
seeking) and consummatory (chewing, drinking, and swallowing)
ingestive behaviors, peripheral signals that arise from conse-
quences of infection or inflammation must reach and interact with
brain regions that control ingestion to produce anorexia. Lang-
hans3 described three pathways of information flow that may
account for anorexia after peripheral endotoxin or cytokine admin-
istration: 1) a humoral pathway, where endotoxins elicit a release
of cytokine mediators that reach the central nervous system via the
blood; 2) a pathway that involves immunomodulator transport
across the blood– brain barrier and central de novo synthesis of
cytokines; and 3) a direct neural pathway from the gut to the brain,
via sensory vagal or non-vagal, splanchnic afferents (Fig. 1). The
vagus nerve is the primary neuroanatomic linkage between the gut
and the central nervous system sites that mediate feeding behav-
ior.7 Consequently, the majority of experimental work on the
peripheral neurobiology of anorexia during disease has focused on

Nutrition 18:528 –533, 2002 0899-9007/02/$22.00

©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved. PII S0899-9007(02)00781-5
Nutrition Volume 18, Number 6, 2002
FIG. 1. Schematic illustration of neural gut– brain pathways that may
mediate anorexia during infection. Peripheral bacterial products stimulate
the production of peripheral cytokines that may stimulate vagal and non-
vagal sensory visceral afferents in the gut. These peripheral neural afferents
carry cytokine-elicited signals to central nervous system regions of the
gut– brain axis, including the area postrema (AP), the nucleus of the
solitary tract (NTS), and the parabrachial nucleus in the caudal brainstem
(PBN), and the hypothalamus (HYP), the central nucleus of the amygdala
(CeA), and the bed nucleus of the stria terminals (BST) in the forebrain.
Note also that peripheral cytokines may affect central gut– brain regions via
a humoral pathway involving the blood– brain barrier and/or circumven-
tricular organs. IL-1␤, interleukin-1␤; LPS, lipopolysaccharide; MDP,
muramyl dipeptide; TNF-␣, tumor necrosis factor-␣, DMX, dorsal vagal
nucleus.
the potential role of vagal afferent traffic from the gut to the brain.
Primary sensory cell bodies of subdiaphragmatic vagal afferent
neurons are in the nodose ganglion, whose central projections
terminate in the caudal brainstem nucleus of the solitary tract
(NST). Spinal afferent information also from the gut ascends to the
NST via the spinosolitary tract. From the NST, ascending projec-
tions reach multiple hindbrain and forebrain sites involved in the
processing of gut visceral afferent information and the control of
food intake, including the area postrema, the parabrachial nucleus,
the hypothalamic paraventricular nucleus (PVN), the bed nucleus
of the stria terminalis, and the central nucleus of the amygdala
(CeA). This article focuses on current, limited evidence for the
existence and likely function of gut– brain afferent neural path-
ways in the mediation of anorexia in disease models from molec-
ular genetic, neurophysiological, and biobehavioral perspectives.
Gut–Brain Communication in Anorexia 529
MOLECULAR GENETIC EVIDENCE
Immunocytochemical and in situ hybridization studies have re-
ported cytokine signaling capacity in or activation of multiple
levels of the gut– brain axis after peripheral administration of
endotoxin and proinflammatory mediators. Using autoradiographic
binding and immunocytochemical approaches, IL-1 or IL-1 recep-
tors have been localized to vagal paraganglia, nodose ganglia
neurons, brainstem terminations of gut vagal afferent fibers, in-
cluding the nucleus of the solitary tract (NTS) and area postrema,
and forebrain regions of the gut– brain axis, including the hypo-
thalamic PVN and arcuate nuclei.8 –10 Peripheral administration of
LPS at anorectic doses and tissue harvesting at postinjection times
consistent with anorexia increase mRNA levels of cytokines and
orexigenic and anorexigenic neuropeptide mRNA at several levels
of the gut– brain axis. Peripheral LPS increases IL-1␤ and IL-1␤
receptor protein expression in abdominal but not in cervical vagus
as soon as 60 min after peripheral LPS administration,8 suggesting
a primary gut vagal afferent pathway for cytokine-to-brain infor-
mation flow in LPS anorexia models. Turin et al. showed that
anorectic doses of intraperitoneal LPS upregulate mRNA expres-
sion of several proinflammatory cytokines (IL-1␤ and/or TNF-␣)
in liver, spleen, and adipose tissue, and in homogenates from
several brain regions,11 including hippocampus and cortex. Intra-
peritoneal LPS also increases pro-opiomelanocortin and cocaine-
amphetamine–related transcript mRNA in the hypothalamic arcuate
nucleus, and melanin-concentrating hormone, cocaine-
amphetamine–related transcript, and galanin in the lateral hypo-
thalamus.12 Of these, central administration of cocaine-
amphetamine–related transcript and the pro-opiomelanocortin
product ␣-melanocyte–stimulating hormone (␣-MSH) reduce food
intake,13,14 whereas galanin and melanin-concentrating hormone
increase feeding.15 It is not known whether LPS-induced eleva-
tions in mRNA are reflected in greater neuropeptide expression,
and the functional significance of these increases for LPS anorexia
remains to be demonstrated.
C-FOS EXPRESSION STUDIES
Intraperitoneal IL-1␤ and LPS at feeding inhibitory doses induce
c-fos proto-oncogene expression in vagal primary afferent neurons
at times when their anorexic effects can be observed (1.5 to 3 h
postinjection).16 –18 Indomethacin, a prostaglandin E2 synthesis
inhibitor, significantly attenuates but does not completely block
vagal IL-1␤-induced c-fos mRNA expression, suggesting that IL-
1␤–stimulated prostaglandins represent a more proximal stimulus
to nodose neurons than IL-1␤ itself.18 Peripheral administration of
LPS and IL-1␤ at anorectic doses and time points (2 h) also
stimulates c-fos expression in a wide range of central gut– brain
axis regions, including the NST, area postrema, parabrachial nu-
cleus, hypothalamic PVN, bed nucleus of the stria terminalis, and
CeA.19 –24 In time course studies, peripheral IL-1␤-stimulated
brainstem and hypothalamic c-fos mRNA, and protein expression
appears to be maximal at 2 to 3 h and decline thereafter in the
hypothalamus but increases in brainstem gut-recipient sites such as
the NTS.20 This prolonged brainstem activation is consistent with
persistent reductions in food intake at times longer than 3 h after
peripheral IL-1␤ injections. Importantly, peripheral IL-1␤ pro-
duces significantly more expression in several non-hypothalamic
regions of the gut– brain axis than does central administration,
including the NST, the lateral parabrachial nucleus, the bed nu-
cleus of the stria terminalis, and the CeA.24 These data suggest that
peripheral IL-1␤’s anorectic effects are mediated by distinct non-
hypothalamic targets along the gut– brain axis that are different
from those that stimulated by central cytokine injections.
Intraperitoneal LPS at anorectic doses activates c-fos expres-
sion in distinct subpopulations of neurons within several of the
gut-responsive regions of the caudal brainstem, including the area
530 Schwartz
postrema, NTS, and the dorsal motor vagal complex.25,26 Of the
c-fos–labeled cells in the NTS, only a subpopulation sends direct
projections to the hypothalamic PVN. In separate studies, intra-
peritoneal LPS produced a similar regional distribution of brain-
stem c-fos–labeled neurons projecting to the CeA, a non-
hypothalamic forebrain region of the gut– brain axis.
Subdiaphragmatic vagotomy eliminated LPS-induced c-fos label-
ing in many of these hypothalamic and amygdaloid-projecting
NTS neurons. These data 1) affirm the role of the subdiphragmatic
afferent vagus in activating hindbrain–forebrain circuits along the
gut– brain axis after peripheral endotoxin administration and 2)
demonstrate how combinations of immunohistochemical and neu-
roanatomic tract tracing methods can show which neural popula-
tions contribute to LPS-induced anorexia more clearly than c-fos
studies alone.
Taken together, these results show that peripheral cytokines
and endotoxins at anorectic doses produce c-fos activation at
multiple levels of the gut– brain axis at times during which an-
orexia is expressed. However, the temporal relations between the
patterns of c-fos expression and the magnitude of anorexia have
not been explored. Such relations might identify which candidate
neural populations mediate LPS-induced anorexia throughout the
24-h period typically assessed in feeding studies. In addition, the
neurochemical phenotypes and projection sites of LPS-induced
c-fos–labeled cells along the gut– brain axis have only begun to be
established. Peripheral LPS administration activates brainstem
cells positive and negative for tyrosine hydroxylase in the NTS and
parabrachial nucleus and hypothalamic PVN neurons immunopo-
sitive for oxytocin, corticotrophin-releasing hormone, and
vasopressin.25–27 Further neurochemical and/or neuropeptidergic
phenotyping of LPS- and IL-1␤–stimulated fos-labeled cells in the
central nervous system will be critical in characterizing the neural
circuits and transmitters that contribute to cytokine and endotoxin-
induced anorexia.
NEUROPHYSIOLOGIC EVIDENCE
In neurophysiologic studies, multiunit recordings from the subdi-
aphragmatic vagus nerves support a role for gut vagal afferents in
mediating LPS and cytokine-induced signaling. Intravenous ad-
ministration of IL-1␤ stimulates gastric branch vagal afferents
after a 15-min response latency, with elevated response rates
lasting at least 60 min.28,29 Hepatic vagal afferent fibers also are
excited by intravenous IL-1␤ administration, but only after laten-
cies longer than 10 to 20 min.29 The relatively long latencies
between IL-1␤ injection and the increased gut vagal afferent
response rate 1) are in sharp contrast with the much shorter latency
response (5 to 15 s) to meal-related feeding inhibitory stimuli, such
as mechanical distension, osmolarity, nutrient content, and gut
peptides,30 and 2) suggest that the endotoxin and cytokines them-
selves are not providing a direct stimulus to the vagal receptors and
transduction elements that mediate the increase in neural discharge
rates. Pretreatment with the prostaglandin synthesis inhibitor in-
domethacin blocks the vagal afferent response to intravenous
IL-1␤, and vagal sensory neurons in the rat nodose ganglion
express mRNA encoding the EP3 subtype of the prostaglandin E2
receptor,18 suggesting that local prostaglandin signaling may be a
more direct mediator of the vagal afferent neurophysiologic re-
sponse to endotoxins than the proinflammatory cytokines elicited
by LPS.
Several methodologic concerns make it difficult to interpret this
collection of neurophysiologic data. Multiunit recordings do not
reveal whether the immunomodulator-induced increases in vagal
afferent activity are due to 1) increased activity in single neurons
over time, 2) recruitment of more single neurons over time, or 3)
both of these processes. The lack of single-unit data hinders
progress in characterizing what types of receptors or transduction
mechanisms might be responsible for vagal afferent activation.
Nutrition Volume 18, Number 6, 2002
These experiments also do not identify the gastrointestinal origin
of the vagal afferent signals, because the gastric and hepatic
branches of the vagus nerves supply multiple gut regions, includ-
ing the stomach, pylorus, and proximal small intestine (gastric
branch) and the liver, stomach, and duodenum (hepatic branch).31
Finally, these studies do not characterize the functional capability
of the vagal sensory fibers in terms of chemosensitivity, mechano-
sensitivity, or gut– brain peptide responsivity, which has been well
established.30 Single-unit recordings would provide data on each
of these fronts by establishing which gut vagal afferent sensors are
stimulated in terms of gastrointestinal region and functional sub-
type, and facilitate experiments designed to show how gut vagal
sensory stimulation might contribute to the anorectic effects of
peripheral cytokines and endotoxins.
Cytokine modulation of neural signaling in central and periph-
eral regions of the gut– brain axis may mediate LPS and IL-1␤-
induced anorexia. Central administration of IL-1␤ receptor antag-
onists partly block peripheral IL-1␤–induced reductions in food-
motivated behavior32 and completely block peripheral LPS
anorexia in mice.33 In the brainstem NTS, where gut vagal affer-
ents terminate, local pressure injection of femtomole doses of
TNF-␣ stimulate gastric load-sensitive neurons and increases the
subsequent neurophysiologic response to gastric distention,34 a
potent inhibitor of food intake.35 In the periphery, recent work has
focused on how immunomodulators interact with signaling mech-
anisms for cholecystokinin (CCK), a gut– brain peptide released
from duodenal endocrine cells during meals that acts via the
subdipahragmatic afferent vagus to inhibit food intake.36 Two
functional subtypes of CCK receptors have been identified, CCKA
and CCKB, and exogenous and endogenous CCK’s feeding inhib-
itory effects rely on its interactions with CCKA receptors.37 CCKA
receptors are localized to several regions of the gut– brain axis,
including the afferent vagus and the brainstem NTS.38,39 Gastric
branch vagal afferents are stimulated by CCK and IL-1␤, and
intravenous administration of IL-1␤ enhances the gastric vagal
afferent excitatory responses to CCK,40 suggesting a neuromodu-
latory role for IL-1␤ in gut vagal afferent signaling. These data
support the idea that peripheral endotoxins and proinflammatory
cytokines produce anorexia by amplifying gut neural signals im-
portant in the negative feedback control of ingestion.
Neurophysiologic responses to intravenous IL-1␤ are attenu-
ated in part by pretreatment with the CCKA receptor antagonist
devazepide.28 However, CCKA receptor blockade does not con-
sistently block cytokine- or LPS-induced reductions in appetitive
and consummatory ingestive behaviors. In rats, devazepide partly
blocks the reduction in food intake produced by intraperitoneal
injections of IL-1␣41 but does not block peripheral intraperitoneal
LPS- and IL-1␤–induced reductions in instrumental bar pressing
for 20-mg pellet food rewards.42 These data may reflect species
differences in CCKA receptor modulation of infection anorexia
and demonstrate that CCKA receptors are not essential for LPS-
and IL-1␤–induced reductions in feeding behavior in these models.
There is limited recent evidence that vagal efferent outflow may
mediate some of the immunologic effects of peripheral cytokine
and endotoxin administration. Intravenous administration of IL-1␤
activates vagal efferent fibers supplying the thymus and inhibits
gastric branch vagal efferent neurophysiologic activity.43,44 Pe-
ripheral vagal efferent nerve stimulation after bilateral cervical
vagotomy in rats attenuates the systemic inflammatory response to
intravenous LPS, reduces TNF-␣, IL-1␤, and IL-6 in human mac-
rophage cultures, and reduces serum TNF-␣ and mortality after a
lethal LPS dose in mice.45 Bilateral cervical vagotomy also in-
creases IL-1␤– elicited sympathetic activity in lumbar, renal, and
splenic efferents, suggesting that vagal afferent responses to pe-
ripheral IL-1␤ tonically inhibit sympathetic outflow.46 Although
these are intriguing demonstrations of neural–immune communi-
cation from an efferent perspective, the relationships between
these effects and food intake have not been addressed and cur-
Nutrition Volume 18, Number 6, 2002
rently do not support a role for such communicatin in the anorexia
of disease.
BIOBEHAVIORAL EVIDENCE
Nerve Transection Studies
Chemical lesions or surgical transactions have been used to eval-
uate the role of gastrointestinal vagal afferents in mediating the
neuronal activation and anorectic effects of peripheral endotoxins
and proinflammatory cytokines. Subdiaphragmatic vagotomy at-
tenuates the ability of anorectic doses of peripheral LPS to increase
IL-1␤ mRNA in hypothalamic extracts47and inhibits intraperito-
neal IL-1␤–stimulated IL-1 mRNA expression in the central ner-
vous system.48 Subdiaphragmatic vagotomy also prevents hypo-
thalamic PVN and supraoptic nucleus c-fos activation produced by
intraperitoneal but not by intravenous injections of anorexia-
producing doses of LPS,23 demonstrating that the patterns of
LPS-induced c-fos activity in the gut– brain axis are sensitive to
the route of immunomodulator administration, and suggesting that
intraperitoneal administration selectively stimulates vagal afferent
pathways. However, vagotomy does not block the ability of intra-
peritoneal anorectic doses of LPS to stimulate plasma and brain
elevations in IL-1␤,49 –50 suggesting that LPS-induced proinflam-
matory mediators do not require an afferent vagus to mediate their
feeding-inhibitory effects.
Data from behavioral studies using total subdiaphragmatic va-
gotomy have demonstrated a role for the intact vagus in mediating
1) the inhibition of food intake produced by gastric, duodenal, and
hepatic meal-related stimuli,7 2) peripheral LPS- and IL-1␤–
induced sickness behavior,51–52 3) cytokine-induced taste aver-
sions,53 and 4) instrumental bar pressing behaviors to acquire
food.54 However, these studies do not specifically address the
discrete role of gut vagal afferents in peripheral endotoxin and
proinflammatory cytokine-induced anorexia because total subdia-
phragmatic vagotomy interrupts ascending vagal sensory fibers
and descending efferent fibers. Thus, it fails to discriminate be-
tween the contribution of vagal afferents and vagal efferents to the
reduction in food intake. Systemic capsaicin treatment, which
selectively destroys a subpopulation of unmyelinated primary af-
ferent axons, does not block LPS- and IL-1␤–induced reductions
in instrumental responding to obtain food, suggesting that capsa-
icin sensitive vagal afferents do not contribute to LPS- and IL-
1␤–induced anorexia.55 With a more direct test of the role of
gastrointestinal vagal afferents, selective surgical transection of all
subdiaphragmatic vagal sensory axons also failed to block the
anorectic effects of intraperitoneal LPS and IL-␤, demonstrating
that gut vagal sensory input is not necessary for the reduction of
food intake in this model.56 The combination of gut vagal deaf-
ferentation with splanchnic nerve transection also failed to atten-
uate anorexia produced by LPS, MDP, and IL-1␤,59 demonstrating
that the extrinsic innervation of the upper gut is not necessary for
peripheral cytokine- and endotoxin-induced anorexia. These find-
ings were surprising, given the ability of subdiaphragmatic vagot-
omy to block LPS- or IL-1␤–induced increases in central neuronal
activation, social exploration, and food-motivated instrumental bar
pressing (see above).51–54 However, there are some exceptions;
subdiaphragmatic vagotomy does not block intraperitoneal LPS-
induced fever49 or IL-1␤–induced fever at doses that are sub-
threshold for inhibiting food intake.57–58 Surgical vagal deafferen-
tation has not been used systematically to determine which aspects
of the acute-phase response to peripheral cytokines and endotoxin
administration (fever, sleep, reduced locomotion and grooming)
rely on gut vagal afferents, and would clarify this contribution.
Central Neuropeptide Mediation
Results from two recent studies suggested that pharmacologic
blockade of neuropeptide signaling in central gut– brain regions
Gut–Brain Communication in Anorexia 531
involved in feeding may attenuate LPS- and IL-1␤–induced an-
orexia. Central third ventricular or hypothalamic PVN administra-
tion of ␣-MSH, a peptide product of the pro-opiomelanocortin
gene, produces potent feeding-inhibitory effects in rats, and brain
melanocortin-3/4 receptors mediate this inhibition.60 – 61
Melanocortin-4 receptor mRNA is expressed in brainstem and
forebrain regions of the gut– brain axis, including the dorsal motor
vagal nucleus (DMX), the NTS, the PVN, the CeA, and the bed
nucleus of the stria terminalis.62 Further, central third intracere-
broventricular ␣-MSH administration activates c-fos in multiple
regions of the gut– brain axis, including the lateral parabrachial
nucleus, the PVN, and the CeA.61 Central administration of the
melanocortin-3/4 receptor antagonist SHU9119, at doses that do
not alter food intake and body weight when administered alone
blocked the anorectic effects of central IL-1␤.63 Complementary
work showed that ␣-MSH exacerbates intraperitoneal LPS-
induced anorexia and that pretreatment with central SHU9119 at
doses that are ineffective when given alone block the anorectic
action of LPS. These data demonstrate a central melanocortinergic
mediation of the anorectic effects of LPS and IL-1␤, but do not
address whether central portions of the gut– brain axis are involved
in this mediation.
LPS anorexia also may be mediated by stimulation of gut–
brain neurons immunopositive for glucagon-like peptide-1 (GLP-
1), a gut– brain peptide whose central administration has been
shown to reduce feeding in rats.65 GLP-1–immunoreactive neurons
have been localized to regions of lateral and medial NST, where
gut vagal afferents terminate.66 Peripheral LPS administration at
anorectic doses and tissue processing at time points during which
anorexia would be expressed produce c-fos protein expression in
GLP-1–imunopositive cells in the gut vagal recipient and PVN-
projecting regions of the NTS.66 Central administration of GLP-1
receptor antagonists at doses that do not alter body temperature or
food intake when given alone reduces LPS anorexia.67 Given this
GLP-1–mediated enhancement of LPS-induced anorexia, it would
be helpful to determine whether 1) vagotomy blocks LPS-induced
c-fos in GLP-1 brainstem neurons and 2) brainstem application of
GLP-1 antagonists would also reduce peripheral LPS- or cytokine-
induced c-fos production in other central regions of the gut– brain
axis.
CONCLUSIONS
The ineffectiveness of extrinsic gut deafferentation demonstrates
that the sensory gut– brain neuraxis is not a necessary mediator of
the anorectic response to peripheral cytokine and endotoxin ad-
ministration. However, this result does not rule out the possibility
that vagal and non-vagal afferents contribute to anorexia in these
models. Supradiaphragmatic vagal afferents are spared by the gut
vagal deafferentation procedure, and cytokines and endotoxins
may act on these vagal afferents to promote anorexia. C-fos
immunoreactivity has not yet been probed in nodose neurons after
gut vagal deafferentation and would show whether the vagal
sensory pathway was still activated in this case and might then
contribute to the persistence of LPS-, IL-1␤–, and MDP-induced
anorexia. In addition, non-vagal visceral afferent fibers outside the
celiac-superior mesenteric plexus may be sensitive to cytokines
and endotoxins, yet their role in these anorexia models would be
difficult to assess because of their widespread distribution. The
ability of peripheral cytokines and immunomodulators to 1) mod-
ify the processing of meal-related negative feedback signals from
the gut and 2) engage the central neuropeptide systems involved in
feeding have only begun to be explored and will be critical to
understanding the role of neural–immune communication in the
control of energy homeostasis.
532 Schwartz
REFERENCES
1. Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav
Immunol 2001;15:7
2. Langhans W. Anorexia of infection: current prospects. Nutrition 2000;16:996
3. Hansen MK, Nguyen KT, Fleshner M., et al. Effects of vagotomy on serum
endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide.
Am J Physiol 2000;278:R331
4. Langhans W, Harlacher R, Balkowski G, et al. Comparison of the effects of
bacterial lipopolysaccharide and muramyl dipeptide on food intake. Physiol
Behav 1990;47:805
5. Langhans W, Salvodelli D, Weingarten H. Comparison of the feeding responses
to bacterial lipopolysaccharide and interleukin-1␤. Physiol Behav 1993;53:643
6. Schwartz GJ. The role of gastrointestinal vagal afferents in the control of food
intake: current prospects. Nutrition 2000;16:866
7. Goehler LE, Gaykema RPA, Nguyen KT, et al. Interleukin-1␤ in immune cells
of the abdominal vagus nerve: a link between the nervous and immune systems?
J Neurosci 1999;19:2799
8. Ericsson A, Liu C, Hart RP, Sawchenko PE. Type 1 interleukin-1 receptor in the
rat brain: distribution, regulation, and relationship to sites of IL-1-induced cel-
lular activation. J Comp Neurol 1995;361:681
9. Goehler LE, Relton JK Dripps D, et al. Vagal paraganglia bind biotinylated
interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain
communication. Brain Res Bull 1997;43:357
10. Turrin NP, Gayle D, Ilyin SE, et al. Pro-inflammatory and anti-inflammatory
cytokine mRNA induction in the periphery and brain following intraperitoneal
administration of bacterial lipopolysaccharide. Brain Res Bull 2001;54:443
11. Sergeyev V, Broberger C, Hökfelt T. Effects of LPS administration on the
expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat
hypothalamus. Mol Brain Res 2001;90:93
12. Aja S, Schwartz GJ, Kuhar MJ, Moran TH. Intracerebroventricular CART
peptide reduces rat ingestive behavior and alters licking microstructure. Am J
Physiol 2001;280:R1613
13. Wirth MM, Olsewski PK, Yu C, et al. Paraventricular hypothalamic alpha-
melanocyte-stimulating hormone and MTII reduce feeding without causing aver-
sive effects. Peptides 2001;22:129
14. Crawley JN. The role of galanin in feeding behavior. Neuropeptides 1999;33:369
15. Tritos NA, Maratos-Flier E. Two important systems in energy homeostasis:
melanocortins and melanin-concentrating hormone. Neuropeptides 1999;33:339
16. Goehler LE, Gaykema PRPA, Hammack SE, et al. Interleukin-1 induces c-Fos
immunoreactivity in primary afferent neurons of the vagus nerve. Brain Res
1998;804:306
17. Gaykema RPA, Goehler LE, Tilders FJH, et al. Bacterial endotoxin induces Fos
immunoreactivity in primary afferent neurons of the vagus nerve. Neuroimmu-
nomodulation 1998;5:234
18. Ek M, Kurosawa M, Lundeberg T, et al. Activation of vagal afferents after
intravenous injection of interleukin-1␤: role of endogenous prostaglandins.
J Neurosci 1998;18:9471
19. Brady LS, Lynn AB, Herkenham M, et al. Systemic interleukin-1 induces early
and late patterns of c-fos mRNA expression in brain. J Neurosci 1994;14:4951
20. Sagar SM, Price KJ, Kasting NW, et al. Anatomic patterns of Fos immunostain-
ing in rat brain following systemic endotoxin administration. Brain Res Bull
1995;36:381
21. Konsman JP, Kelley K, Dantzer R. Temporal and spatial relationships between
lipopolysaccharide -induce expression of fos, interleukin-1␤ and inducible nitric
oxide synthase in rat brain. Neuroscience 1999;89:535
22. Wan W, Wetmore L, Sorensen CM, et al. Neural and biochemical mediators of
endotoxin and stress-induced c-fos expression in the rat brain. Brain Res Bull
1994;34:7
23. Zhang YH, Lu J, Elmquist JK, Saper CB. Lipopolysaccharide activates specific
populations of hypothalamic and brainstem neurons that project to the spinal
cord. J Neurosci 2000;20:6578
24. Day HEW, Akil H. Differential pattern of c-fos mRNA in rat brain following
central and systemic administration of interleukin 1-beta: implications for mech-
anism of action. Neuroendocrinology 1996;63:207
25. Yang ZJ, Rao ZR, Ju G. Evidence for the medullary visceral zone as a neural
station of neuroimmunomodulation. Neurosci Res 2000;38:237
26. Ge X, Yang Z, Duan L, Rao Z. Evidence for involvement of the neural pathway
containing the peripheral vagus nerve, medullary visceral zone and central
amygdaloid nucleus in neuroimmunomodulation. Brain Res 2001;914:149
27. Gaykema RP, Dijkstra I, Tilders FJ. Subdiaphragmatic vagotomy suppresses
endotoxin-induced activation of hypothalamic corticotropin-releasing hormone
neurons and ACTH secretion. Endocrinology 1995;136:4717
28. Kurosawa M, Uvnas-Moberg K, Miyasaka K, et al. Interleukin-1␤ increases
activity of the gastric vagal afferent nerve partly via stimulation of type A CCK
receptor in anesthetized rats. J Auton Nerv Syst 1997;62:72
Nutrition Volume 18, Number 6, 2002
29. Niijima A. The afferent discharges from sensors for interleukin-1 beta in the
hepatoportal system of the anesthetized rat. J Auton Nerv Syst 1996;61:287
30. Schwartz GJ, Moran TH. Integrative gastrointestinal actions of the brain– gut
peptide cholecystokinin in satiety. In: Morrsion AD, Fluharty SF, eds. Progress
in physiological psychology, Vol 17. New York: Academic Press, 1998:1
31. Berthoud HR, Carlson NR, Powley TL. Topography of efferent vagal innervation
of the rat gastrointestinal tract. Am J Physiol 1991;260:R200
32. Kent S, Bluthe RM, Dantzer R, et al. Different receptor mechanisms mediate the
pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci USA
1992;89:9117
33. Laye S, Gheusi G, Cremona S, et al. Endogenous brain IL-1␤ mediates LPS-induced
anorexia and hypothalamic cytokine expression. Am J Physiol 2000;279:R93
34. Emch GS, Hermann GE, Rogers RC. TNF-alpha activates solitary nucleus
neurons responsive to gastric distension. Am J Physiol 2000;279:G582
35. Phillips RJ, Powley TL. Gastric volume rather than nutrient content inhibits food
intake. Am J Physiol 1996;271(3 pt 2):R766
36. Smith GP, Jerome C, Norgren R. Afferent axons in abdominal vagus mediate
satiety effect of cholecystokinin in rats. Am J Physiol 1985;249:R638.
37. Moran TH, Ameglio PJ, Schwartz GJ, et al. Blockade of type A, not type B, CCK
receptors attenuates satiety of exogenous and endogenous CCK. Am J Physiol
1992;262:R46
38. Moran TH, Norgren R, Crosby RJ, McHugh PR. Central and peripheral vagal
transport of cholecystokinin binding sites occurs in afferent fibers. Brain Res
1990;526:95
39. Corp ES, McQuade J, Moran TH, Smith GP. Characterization of type A and type
B CCK receptor binding sites in rat vagus nerve. Brain Res 1993;623:161
40. Bucinskaite V, Kurosawa M, Miyasaka K, Funakoshi A, Lundeberg T.
Interleukin-1beta sensitizes the response of the gastric vagal afferent to chole-
cystokinin in rat. Neurosci Lett 1997;229:33
41. Daun JM, McCarthy DO. The role of cholecystokinin in interleukin-1-induced
anorexia. Physiol Behav 1993;54:237
42. Bret-Dibat JL, Dantzer R. Cholecystokinin receptors do not mediate the suppres-
sion of food-motivated behavior by lipopolysaccharide and interleukin-1 beta in
mice. Physiol Behav 2000;69:325
43. Niijima A, Hori T, Katafuchi T, et al. The effect of interleukin-1␤ on the efferent
activity of the vagus nerve to the thymus. J Auton Nerv Syst 1995;54:137
44. Bucinskaite V, Kurosawa M, Lundeberg T. Effect of interleukin-1beta on sub-
diaphragmatic vagal efferents in the rat. Auton Neurosci 2000;85:93
45. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates
the systemic inflammatory response to endotoxin. Nature 2000;405:458
46. Saindon CS, Blech F, et al. Effects of cervical vagotomy on sympathetic nerve
responses to peripheral interleukin-beta. Auton Neurosci 2001;87:243
47. Laye S, Bluthe RM, Kent S, et al. Subdiaphragmatic vagotomy blocks induction
of IL-1␤ mRNA in mice brain in response to peripheral LPS. Am J Physiol
1995;268:R1327
48. Hansen MK, Taishi P, Chen Z, et al. Vagotomy blocks the induction of
interleukin-1 beta mRNA in the brain of rats in response to systemic IL-1␤.
J Neurosci 1998;18:2247
49. Hansen MK, Daniels S, Goehler LE, et al. Subdiaphragmatic vagotomy does not
block intraperitoneal lipopolysaccharide-induced fever. Auton Neurosci 2000;85:83
50. Hansen MK, Nguyen KT, Goehler LE, et al. Effects of vagotomy on
lipopolysaccharide-induced brain interleukin-1beta protein in rats. Auton Neuro-
sci 2000;85:119
51. Bluthé RM, Michaud B, Kelley KW, et al., Vagotomy attenuates behavioral
effects of interleukin-1␤ injected peripherally but not centrally. Neuroreport
1996;7:1485
52. Bluthé RM, Walter V, Parnet P, et al. Lipopolysaccharide induces sickness
behavior in rats by a vagal mediated mechanism. C R Acad Sci 1994;317:499
53. Goehler LE, Busch CR, Tartaglia N, et al. Blockade of cytokine induced condi-
tioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal
mediation of immune-brain communication. Neurosci Lett 1995;185:163
54. Bret-Dibat JL, Bluthe RM, Kent S, et al. Lipopolysaccharide and interleukin-1
depress food motivated behavior in mice by a vagal-mediated mechanism. Brain
Behav Immunol 1995;9:242
55. Bret-Dibat JL, Creminon C, Couraud JY, et al. Systemic capsaicin pretreatment
fails to block the decrease in food-motivated behavior induced by lipopolysac-
charide and interleukin ⫺1␤. Brain Res Bull 1997;42:443
56. Schwartz GJ, Plata-Salaman CR, Langhans W. Subdiaphragmatic vagal deaffer-
entation fails to block feeding-suppressive effects of LPS and IL-1␤ in rats. Am J
Physiol 1997;273:R1193
57. Luheshi GN, Bluthe RM, Rushforth D, et al. Vagotomy attenuates the behav-
ioural but not the pyrogenic effects of interleukin-1 in rats. Auton Neurosci
2000;85:127
58. Hansen MK, O’Connor KA, Goehler LE, et al. The contribution of the vagus
nerve in interleukin-1beta-induced fever is dependent on dose. Am J Physiol
2001;280:R929
Nutrition Volume 18, Number 6, 2002
59. Porter MH, Hrupka BJ, Langhans W, et al. Vagal and splanchnic afferents are not
necessary for the feeding suppressive effects of peripheral IL-1␤, LPS, and MDP.
Am J Physiol 1998;275:R384
60. McMinn JE, Wilkinson CW, Havel PJ, et al. Effect of intracerebroventricular
alpha MSH on food intake, adiposity, c-Fos induction, and neuropeptide expres-
sion. Am J Physiol 2000;279:R695
61. Wirth MM, Olsewski PK, Yu C, et al. Paraventricular hypothalamic alpha-
melanocyte-stimulating hormone and MTII reduce feeding without causing aver-
sive effects. Peptides 2001;22:129
62. Mountjoy KG, Mortrud MT, Low MJ, et al. Localization of the melanocortin-4
receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.
Mol Endocrinol 1994;8:1298
CALENDAR OF EVENTS
June
20 –22 Practical Aproaches to the Treatment of Obesity.
Sponsored by Harvard Medical School and endorsed by
the North American Association for the Study of Obe-
sity and the Boston Obesity Nutrition Research Center.
To be held at the Royal Sonesta Hotel, Cambridge,
MA. To view course information or to register online,
visit www.cme.hms.harvard.edu. To receive a course
brochure, please contact Susan Branco Sidell at 617-
677-2651 or e-mail ssidell@caregroup.harvard.edu.
June
24 –26 9th World Congress on Clinical Nutrition. To be held
at the Church House Conference Center, Westminster,
London. For more information, please contact Dr. Heema
Shukla, Secretary General, 9th WCCN, at 44 20 7911
5752. E-mail: shuklah@wmin.ac.uk. website: www.
wmin.ac.uk/9thwccn2002/
Aug 31–
Sept 4 Annual Meeting of the British Association for Par-
enteral and Enteral Nutrition (BAPEN). To be held
in conjunction with the ESPEN 2002 Congress in Glas-
gow, Scotland. For more information contact Prof. C.
R. Pennington, Chairman of the Steering Committee
for ESPEN 2002, Dept. of Digestive Diseases and
Clinical Nutrition, Ninewells Hospital and Medical
School, Dundee DD1 9SY, Scotland. Tel: 44-01382-
632307. Fax: 44-01382-425504. BAPEN website: www.
bapen.co.uk
Aug 31–
Sept 4 24th (2002) Congress of the European Society for
Parenteral and Enteral Nutrition (ESPEN). To be
held at the Scottish Exhibition and Conference Center
Gut–Brain Communication in Anorexia 533
63. Lawrence CB, Rothwell NJ. Anorexic but not pyrogenic actions of interleukin-1
are modulated by central melanocortin-3/4 receptors in the rat. J Neuroendocrinol
2000;13:490
64. Huang QH, Hruby VJ, Tatro JB. Role of central melanocortins in endotoxin-
induced anorexia. Am J Physiol 1999;276:864
65. Tang-Christensen M, Larsen PJ, Goke R, et al. Central administration of GLP-
1-(7-36) amide inhibits food and water intake in rats. Am J Physiol 1996;271(4
pt 2):R848
66. Rinaman L. Interoceptive stress activates glucagon-like peptide-1 neurons that
project to the hypothalamus. Am J Physiol 1999;277:R582
67. Comer J, Rinaman L. Role of central glucagon-like peptide-1 receptor signaling
in lipopolysaccharide-induced fever and anorexia. FASEB J 2000;14:A87
in Glasgow, Scotland. For more information, please
contact: MCI Congress, Rue de Lyon 75, 1211 Geneva
13, Switzerland, or call 41 22 33 99 580 or e-mail
espen@mci-group.com. ESPEN website: www.espen.
org.
Oct
25–27 27th Annual Scientific Meeting of the Australian
Society for Parenteral and Enteral Nutrition
(AuSPEN). “Challenges in Longterm Feeding.” To be
held at the Peppers Fairmont Resort, Blue Mountains,
New South Wales, Australia. For more information,
contact Paul Woods at paul.woods@health.wa.gov.au.
2003
Feb
23–27 IX Asian Congress of Nutrition, New Delhi, India.
“Nutrition Goals for Asia-Vision 2020.” For informa-
tion, contact Dr. C. Gopalan, President, IX Asian Con-
gress of Nutrition, Nutrition Foundation of India, C-13
Qutab Institutional Area, New Delhi-110016, India.
Tel: 91-11-6857814, 6962615. Fax: 91-11-6560106,
6857814. E-mail: acn2003@yahoo.com. Website:
www.nutritionfoundationofindia.org
May 5th European Forum for Dieticians, Budapest, Hun-
gary. For scientific information, contact Izabelia
Henter, Dietitian, HDA delegate to EFAD, H-1051
Budapest, Arany J. U. 31. IV/65. Tel: 361-311-8947.
Mobil: 3630-274-7643. E-mail: mdosz@mail.externet.
hu. For congress information, contact Zsombor Papp,
Head of Office, Convention Budapest Ltd., H-1461
Budapest, P.O.B.: 11. Tel: 361-216-1121 or 361-216-
3421. Fax: 361-456-0888. E-mail: convention.
budapest@mail.datanet.hu