NEUROBIOLGIAI SSZEFOGLAL

HYPOTHALAMIC REGULATION OF THE FOOD INTAKE

Mikls Palkovits
Hungarian Academy of Sciences and Semmelweis University, Laboratory of Neuromorphology, Budapest

A TPLLKFELVTEL HYPOTHALAMICUS
SZABLYOZSA
Palkovits M, MD, PhD, DSc

The central regulation of the food intake is organized by a
long-loop mechanism involving humoral signals and afferent
neuronal pathways to the hypothalamus, obligatory
processing in hypothalamic neuronal circuits, and
descending commands through vagal and spinal neurons to
the body. Receptors sensitive to glucose metabolism, body
fat reserves, distension of the stomach, as well as
neuropeptide and cannabinoid receptors have been
identified and localized in the hypothalamus. Five groups of
cells in the hypothalamus arcuate, paraventricular,
ventromedial and dorsomedial nuclei, and the dorsolateral
hypothalamic area contain neurons with either anorexic
actions (-MSH, CART peptide, corticotropin-releasing
hormone, urocortin III, cholecystokinin, glucagon-like
peptides) or that stimulate food intake (neuropeptide Y,
agouti-related peptide, orexins, melanin concentrating
hormone, galanin). Intrahypothalamic neuronal circuits exist
between these peptidergic neurons including the
arcuate-paraventricular and arcuate-dorsolateral
hypothalamic projections. Circulating substances carrying
signals connected to changes in body food homeostasis and
energy balance (leptin, ghrelin, insulin, glucose) enter the
hypothalamus mainly through the arcuate nucleus. Neurons
in the medulla oblongata that express leptin and insulin
receptors, as well as neuropeptide mediators project to the
hypothalamus. Vica versa, hypothalamic neurons give rise to
projections to autonomic centers in the brainstem and the
spinal cord with potential for stimulation or inhibition of food
intake, energy balance and ingestion behavior.
Clin Neurosci/Ideggy Szle 2003;56(910):288302.
A tpllkfelvtelnek a kzponti idegrendszer ltal trtn
szablyozsa egy szmos idegsejt ltal alkotott krplyn
(neuronal circuit) t trtnik. A tpllkfelvtellel kapcsolatos
ingereket idegi s humorlis plyk szlltjk
a hypothalamusba. Itt tbb, a tpllkfelvtel szempontjbl
specifikus receptor (inzulin-, leptin-, ghrelin-), tovbb szmos
neuropeptid- s kannabinoid receptor tallhat.
A hypothalamus egyes sejtjei informcit kapnak a vr
cukorszintjrl, a test zsrtartalmnak vltozsrl, a gyomor
teltsgi llapotrl. Az eminentia mediana s a nucleus
arcuatus nyitott kapuknt mkdik a vrplyban kering
inzulin, leptin s ghrelin szmra. A nyltvelben is tallunk
hasonl, a vr-agy gton kvli terletet (area postrema-
nucleus tractus solitarii), ahol leptin- s inzulinreceptorok
vannak, s ahonnan a felszll idegplykon t jut az
ingerlet a hypothalamusba. A hypothalamuson bell t
sejtcsoportot klntnk el (nucleus arcuatus, paraventricularis,
ventromedialis, dorsomedialis, valamint a dorsolateralis
hypothalamus area), ahol az idegsejtek egy csoportja
tpllkozst serkent (neuropeptid Y, agouti-related peptid,
orexinek, melaninkoncentrl hormon, galanin), msik
csoportja gtlanyagokat (-MSH, CART peptid,
corticotropin-releasing hormon, urokortin III, kolecisztokinin,
glkagonszer peptidek), neurohormonokat termel.
Az idegplykon t az egyes sejtcsoportok egymssal
kapcsolatban llnak, kzlk az arcuatus-paraventricularis s
az arcuatus-dorsolateralis hypothalamus kztti kapcsolat
klnsen jelents, ltaluk biztostott a tpllkfelvtel
finoman szablyzott egyenslya. A hypothalamusbl
leszll idegplyk futnak a nervus vagus paraszimpatikus
s a gerincvel szimpatikus sejtjeihez, ahonnan az ingerlet
a szervezet klnbz rszeihez jutva szablyozza
a tpllkfelvtelt, s hosszabb tvon a testslyt, valamint
a szervezet energia-egyenslyt.

Keywords: food intake, hypothalamic neuropeptides, Kulcsszavak: tpllkfelvtel, hypothalamicus neuropeptidek,

obesity, neuronal pathways elhzs, idegplyk

Levelezsi cm/Correspondent: Dr. Palkovits Mikls, Semmelweis Egyetem, Anatmiai Intzet,

H-1094 Budapest, Tzolt utca 58. Telefon: (1) 216-0488; fax: (1) 218-1612, e-mail: palkovits@ana.sote.hu
Kzlsre rkezett: 2003. augusztus 26. Elfogadva: 2003. augusztus 26.

A szerz a szerkesztbizottsg felkrsre rta a tanulmnyt.

288 Palkovits: Central regulation of the food intake

 he hypothalamus has long been considered
T essential in the regulation of the food intake
and energy homeostasis. The role of the hypothala-
mus in this mechanism was established by lesioning
of the different parts of the hypothalamus1, 2. Large
lesions of the ventromedial hypothalamus (ventro-
medial and arcuate nuclei) produced hyperphagia
and obesity. Lesions in the lateral hypothalamus
resulted in decreased food intake, even aphasia that
could lead to death by starvation. These observa-
tions established the dual center concept in food
intake: the lateral hypothalamic area could serve as
a feeding center and the ventromedial hypothala-
mus as a satiety center. Later, by using more de-
licate electrolytic lesions and transactions of the
neuronal pathways to these areas, the validity of the
dual center model has been questioned. Although
the early lesion studies were crude and they
destroyed a variety of different cell groups and neu-
ronal pathways, the original observations were fair
and valid. Their data were reproducible by using
cell-specific lesions: lateral hypothalamic lesions
produced by kainic acid resulted in hypophagia3, 4,
ventromedial lesions after gold thioglucose5, arcu-
ate nucleus lesions after monosodium glutamate6
applications produced increased food intake and
obesity. It is not to be questioned that these
hypothalamic areas are crucial in the regulation of
the food intake, but this regulatory mechanism is
more complex. Studies by investigating the effects
of various centrally administered substances on
food intake, discovery of a number of feeding-rela-
ted neuropeptides and hormones and the demonstra-
tion of their presence in hypothalamic neurons indi-
cate that food intake is controlled by highly comp-
lex neuronal circuits. In addition to the hypothala-
mus, the central control of appetite and energy ba-
lance involve other neuronal systems in the cerebral
cortex, limbic system and the lower brainstem.
Hypothalamic nuclei (both feeding and satiety
centers) are bidirectionally connected with these
brain areas. Thus, the concept of functional centers
has been replaced by a concept of feeding-related
neuronal circuits. These circuits, including orexi-
genic and anorexigenic neuronal cell groups in the
hypothalamus, their neuronal and humoral input
signals, as well as their interconnections and effe-
rent projections are summarized in this brief review.
This review is basically a neuroanatomical
summary of our present knowledge about the
topography and chemical nature of hypothalamic
neurons and pathways that participate in the regu-
lation of the food intake. In addition, the basic
activities and significance of feeding-related subs-
tances are summarized in the Appendix. For a
more general discussion of factors affecting fee-
ding, the reader is referred to a number of excel-
lent recent reviews711.

AN

Figure 1. Hypothalamic nuclei and cell types involved in the central regulation of the food intake. A, B Coronal sec-
tions of the rat brain 1.5 and 2.5 mm caudal to the level of the bregma, respectively. (The cross-sectional planes are
indicated on Figure 1C.) C Sagittal section of the hypothalamus
AgRP: agouti-related peptide, AN: arcuate nucleus, CRH: corticotropin-releasing hormone, DLHA: dorsolateral hypothalamic area, DMN: dorso-
medial nucleus, ME: median eminence, POMC: pro-opiomelanocortin, MCH: melanin concentrating hormone, NPY: neuropeptide Y, PVN: para-
ventricular nucleus, VMN: ventromedial nucleus

Clin Neurosci/Ideggy Szle 2003;56(910):288302 289

 Table 1. Hypothalamic neuropeptides in the regulation and body weight downstream of peripheral signa-
of food intake
ling by leptin, insulin, glucose and ghrelin (Figure
Orexigenic neuropeptides 2). The most potent orexigenic neurons that co-
Neuropeptide Y AN express neuropeptide Y (NPY) and agouti-related
Agouti-related peptide AN peptide (AgRP) are mainly located in the medial
Orexins (hypocretins) DLHA part of the midportion of the nucleus1117. The -
Melanin concentrating hormone DLHA
Galanin/galanin-like peptide AN, PVN
melanocyte-stimulating hormone (-MSH) that are
Nociceptin PVN, LH cleaved from pro-opiomelanocortin (POMC) pre-
Dynorphins AN, VMN, LH cursor molecule and CART (cocain- and amphe-
Anorexigenic neuropeptides tamine-regulated transcript) peptide that partly co-
-melanocyte stimulating hormone AN expressed by POMC neurons inhibit food intake.
CART peptide AN, PVN, DMN These cells mainly occupy the lateral part of entire
Corticotropin-releasing hormone PVN length of the nucleus from the retrochiasmatic area
Urocortin III JFA
Cholecystokinin
back to the ventral premamillary nucleus18, 19 (Fi-
Glucagon-like peptides gure 1C). All of these arcuate neurons express lep-
tin and insulin receptors2025. Neurons expressing
AN: arcuate nucleus, DMN: dorsomedial nucleus, DLHA: dorsola- NPY and AgRP are inhibited by leptin and
teral hypothalamic area, JFA: juxtaformical area, LH: lateral insulin2631, stimulated by ghrelin32, 33. In contrast,
hypothalamus, PVN: paraventricular nucleus, VMN: ventromedial
nucleus POMC and CART neurons are activated by leptin
and insulin19, 3437 and inhibited by ghrelin38. In addi-
tion, galanin and galanin-like peptide (GALP) are
Hypothalamic neurons also expressed by some of the arcuate neurons39, 40
that are also stimulated by leptin41.
During the past decade, informations about the to- The recently discovered hormone, ghrelin, that
pography and transmitter character of hypothalamic is predominantly produced by the stomach, also
neurons involved in the regulation of the food intake synthesized by hypothalamic neurons, in the hig-
increased substantially (Figure 1 and Table 1). hest concentration in the arcuate nucleus32, 38. The
primary targets of both circulating and brain-born
ARCUATE NUCLEUS ghrelin are NPY/AgRp neurons33.
The ventral portion of the arcuate nucleus is out
The arcuate nucleus (AN) consists of both orexi- of the blood-brain barrier: capillaries of this area
and anorexigenic neurons (Table 1). These peptides arise in the subependymal plexus of the median
are implicated in the normal control of food intake eminence42, 43.
The arcuate neurons receive a number of intra-
and extrahypothalamic neuronal inputs (Figure 2)
Table 2. Orexigenic and anorexigenic peptide and and, vica versa, they project to other hypothalamic
cannabinoid receptors in hypothalamic nuclei nuclei (mainly to the paraventricular nucleus and
dorsolateral hypothalamic area, see below), and to
Orexigenic peptide receptors the autonomic centers in the lower brainstem and
Ghrelin receptors AN the spinal cord (see reference44 for review). In addi-
NPY Y1 and Y5 receptors AN, PVN
Orexin-1 and 2 receptors PVN, VMN tion, intranuclear connections, like NPY-POMC45
CB1 receptor DMN, DLHA, PVN and GALP-NPY40, GALP-CART40 interactions in
NOP (nociceptin) receptor PVN, DLHA the arcuate nucleus have also been reported.
Galanin GAL-1 receptor AN
Anorexigenic peptide receptors VENTROMEDIAL NUCLEUS
Leptin receptors (Ob-Rb) AN, PVN, VMN,
DMN, DLHA Chemical5, 46 or electrolytical1, 2 lesions of the vent-
MC-3 and MC-4 receptors DLHA
GLP-1 receptor PVN romedial nucleus (VMN) produce hyperphagia and
Insulin receptors NA obesity. However, not only neurons, but different
CRH-1 receptor NA feeding-related neuronal pathways that pass the
CRH-2 receptor VMN nucleus (arcuato-paraventricular, arcuato-dorsola-
CCK-B receptor PVN, VMN teral hypothalamic pathways) are also damaged by
AN: arcuate nucleus, DMN: dorsomedial nucleus, DLHA: dorsola-
these lesions. There is no evidence yet of produc-
teral hypothalamic area, PVN: paraventricular nucleus, VMN: vent- tion of either orexigenic or anorexigenic peptides or
romedial nucleus hormones in VMN neurons, but several findings

290 Palkovits: Central regulation of the food intake

raise the possibility that this nucleus
represents a receptive field for se-
veral appetite-regulating signal
molecules.
The VMN can be divided into to
major parts: dorsomedial and vent-
rolateral subdivisions. The dorso-
medial part of the nucleus is con-
nected to feeding responses. Neu-
rons here are sensitive to glucose47
and contain a variety of food intake
related receptors, like leptin23, 48,
corticotropin-releasing hormone-2
(CRH-2)49 and nociceptin NOP50
receptors (Table 2). This part of the
nucleus is connected to the dorsola-
teral hypothalamus bilaterally, and
receives orexin (ORX) and uro-
cortin immunoreactive fibers49. Uro-
cortins, potent inhibitors of the food
intake have a high affinity for
CRH-2 receptors in the VMN49, 51, 52.
Intranuclear injections of orexigenic
substances, like galanin53, noci-
ceptin54 or anandamide55 stimulate
feeding while anorexigenic chole-
cystokinin56 produces satiety.
The VMN projects to both
intrahypothalamic and lower brain- Figure 2. Afferent and efferent signal routes to/from the hypothalamus
stem nuclei (see below). Projections related to the regulation of the food intake
to the paraventricular nucleus are Red: humoral signal routes (plasma leptin, insulin, glucose, ghrelin) to the arcuate nucleus
and the nucleus of the solitary tract (through the area postrema). Black: ascending neuronal
activated by leptin57. pathway from the stomach to the nucleus of the solitary tract, and further up to the hypotha-
lamus, the limbic system and the cerebral cortex. (The hypothalamus-nucleus accumbens-
PARAVENTRICULAR NUCLEUS limbic cortex connections are also labeled by black.) Yellow: efferent pathways from hypotha-
lamic nuclei to vagal (DVN) and spinal cord preganglionic neurons. Green: vagal fibers to
the stomach and the pancreas (preganglionic fibers pass the celiac ganglion). Blue: afferent
The paraventricular nucleus (PVN) route of the gastric-spinal cord sympathetic reflex loop. Orange: efferent fibers from the sym-
occupies a central position in the pathetic preganglionic neurons in the intermediolateral cell column to the gastrointestinal sys-
tem (signals are relayed in the celiac ganglion).
regulation of food intake and energy A: nucleus accumbens, AN: arcuate nucleus, AP: area postrema, CC: cholecystokinin, CG:
homeostasis. It receives a number of celiac ganglion, D: duodenum, DM: dorsomedial nucleus, DVN: dorsal vagal nucleus,
input signals from other feeding- GLP-1: glucagon-like peptide-1, IML: intermediolateral cell column, NTS: nucleus of the
solitary tract, PVN: paraventricular nucleus, VG: intramural ganglia in the pancreas, VM:
related hypothalamic and brainstem ventromedial nucleus
nuclei, and PVN neurons project to
lower brainstem and spinal auto-
nomic centers (see reference44 for review). Para- nervous system through descending fibers from the
ventricular lesions are followed by increased food PVN to the spinal cord9, 61, 62. Paraventricular CRH
intake and obesity5860. neurons are jointly regulated by NPY and me-
A great variety of neuropeptides are synthesized in lanocortins. NPY/AgRP and -MSH fibers converge
the PVN. Some of them are closely involved in the on the medial parvicellular PVN and terminate on the
central regulation of the food intake. Corticotropin- same neurons62, 63. They express Y1 and Y5 NPY
releasing hormone (CRH) neurons in the PVN have receptor subtypes which are involved in mediating of
been implicated in the regulation of food intake and feeding responses elicited by NPY released from
energy balance mediating via binding to CRH recep- nerve terminals of arcuate nucleus origin64, 65. NPY in
tors. These cells are present in the mid-lateral portion the PVN stimulates feeding behavior and carbohyd-
of the parvicellular PVN. CRH decreases food intake rate intake in rats8, 66, 67. PVN neurons express leptin
and increases the activity of the central sympathetic receptors23, 29, 68. Leptin stimulates CRH mRNA

Clin Neurosci/Ideggy Szle 2003;56(910):288302. 291

 expression and CRH release in the PVN29, 48 and lep-
tin and insulin inhibit the release of NPY from the
nerve terminals7, 69 which could be antagonizes by
ghrelin38. In addition, leptin activates ventro- and dor-
somedial hypothalamic projections to the PVN57.
Thyrotropin-releasing hormone (TRH) is synt-
hesized by parvicellular PVN neurons. Some of
these cells co-express CART peptide15. TRH supp-
resses food intake and play an important role in
regulating the energy balance of the body70. Galanin
inhibits the release of TRH in the PVN71.
Galanin in the PVN is identified as a neuro-
chemical marker for fat ingestion. Galanin is synt-
hesized by local PVN neurons and it is also present
in fibers that arise in the arcuate nucleus. Galanin
contributes to the natural appetite for fat41, 72. Its
release from nerve terminals is inhibited by
insulin31, 69.
Various nerve fibers with orexi- or anorexigenic
peptides terminate and act in the PVN. Orexin73-
and nociceptin-containing50 fibers from dorsolateral
hypothalamic neurons stimulate food intake.
Galanin-like peptide (GALP)40, 41, 74 that synthesized
by arcuate neurons also exerts orexigenic action in
the PVN: it stimulates the release of NPY and
blocks the release of the CART peptide from fibers
arising in the arcuate nucleus. In contrast, CART
peptide blocks NPY action in the PVN75, like chole-
cystokinin56, 76 and glucagons-like peptides7779 that
synthesized in the nucleus of the solitary tract and
project to the PVN produce satiety.
PVN neurons project to the lower brainstem and
the spinal cord (Figure 2 and 3).
DORSOMEDIAL NUCLEUS
The dorsomedial nucleus (DMN) is consisted by
three major subdivisions. Although the nucleus
contains leptin and insulin receptors20, 23 and arcuate
NPY/AgRP axons terminate there8, only few orexi-
genic or anorexigenic peptides are expressed in this
nucleus. The dorsal and the lateral borders of the
nucleus are continuous to the dorsolateral hypotha-
lamic area. Orexin- and melanin-concentrating hor-
mone-containing cells do not respect these borders,
few of them are located in the DMN80. Galanin-like
peptide mRNA expressing neurons are present in
the caudal DMN39.
DMN lesions inhibit feeding81, which may relate
to a partial damage of the dorsolateral hypothala-
mic area (DLHA), or transecting of feeding-related
fibers from or to the nucleus, or lesioning of tran-
sient fibers from the brainstem to the PVN, or from
the arcuate nucleus to the DLHA. The role of the
DMN in ingestive behavior may be connected to
292 Palkovits: Central regulation of the food intake
the extended projections of DMN neurons. They
project to the ventromedial and paraventricular
nuclei81, 82, these projections are activated by lep-
tin57. Descending DMN axons innervate several
brainstem areas8284.
DORSOLATERAL HYPOTHALAMIC AREA
The lateral hypothalamic area has long been con-
sidered essential in regulating food intake and body
weight (feeding center). Lesions of this area
result in depleted food intake or even aphagia2. The
DLHA covers a relatively large but poorly outlined
area in the middle and caudal parts of the hypotha-
lamus. It extends rostrocaudally from the level of
the retrochiasmatic area to the premamillary region,
and from the top of the third ventricle to the medial
edge of the internal capsule/cerebral peduncle,
mediolaterally. This area includes the rostral medi-
al part of the zona incerta, the perifornical nucleus
and the dorsal part of the lateral hypothalamus. The
DLHA is connected with forebrain and hindbrain
areas and the spinal cord by a variety of ascending
and descending neuronal pathways (see reference44
for review) indicating a role in the behavioral and
autonomic aspects of food intake and body weight
regulations85, 86.
Two distinct groups of neuropeptides (orexins and
melanin-concentrating hormone) have been locali-
zed in the DLHA35, 80. Cells express orexins87 (ore-
xin A and B; they are also termed as hypocretin 1 and
288) and melanin-concentrating hormone8991 (MCH),
a functional melanocortin antagonist92, two neu-
ropeptides that stimulate food intake80, 87, 9395. Both
orexin and MCH nerve fibers distribute throughout
the hypothalamus and several other brain regions.
Neurons in the DLHA receive neuronal inputs
from the arcuate nucleus35, 80. NPY/AgRP fibers
surround both orexin and MCH neurons. These
cells seem to be the downstream targets of NPY-
induced feeding80, 96. NPY acts on NPY Y5 recep-
tors in the DLHA80. -MSH of arcuate origin
inhibits feeding by blocking the action of MCH
through competitive binding on central melano-
cortin receptors92. This action is antagonized by
AgRP, an endogenous melanocortin receptor anta-
gonist expressed in the arcuate nucleus, projected to
and released in the DLHA16, 17, 9799.
In the rostral part of the DLHA, at the level of
the caudal edge of the paraventricular nucleus, uro-
cortin III-synthesizing neurons distribute just medi-
al to the fornix. The major target of these neurons is
the ventromedial nucleus where they bind to
CRH-2 receptors49.
Both ascending and descending pathways pass the
lateral hypothalamic area interconnecting the
hypothalamus, the cerebral cortex, various limbic
and lower brainstem areas, as well as the spinal cord.
Many of them directly related to the food intake,
feeding behavior and energy homeostasis. Recently,
a functional relationship has been reported between
the nucleus accumbens and the lateral hypothalamus
subserving the control of feeding behavior100.
Feeding-related signal routes
to the hypothalamus
Signals from the energy homeostasis and feeding
behavior may reach the hypothalamus through
humoral and neuronal pathways (Figure 2).
HUMORAL SIGNAL ROUTES
Circulating leptin and insulin each function as
afferent signals to the hypothalamus in a feedback
loop that regulates body adiposity. Leptin is an adi-
pose tissue-derived hormone that inhibits food
intake and stimulates energy expenditure101104.
These effects have been attributed to activation of
leptin receptors in the brain. Leptin receptor gene
(Ob-Rb) expression has been localized to several
hypothalamic nuclei that have been implicated in
the regulation of food intake and energy balance21, 23.
NPY/AgRP and POMC/CART peptide neurons
in the arcuate nucleus are the principal sites of lep-
tin receptor expression that lead to acute decreases
of food intake, marked reduction of body fat while
it increases energy expenditure, an action that
appears to be mediated by the activation of the sym-
pathetic nervous system19, 37, 62. Leptin activates
arcuate CART peptide neurons projecting to the
spinal cord19. The expression of leptin receptors in
the arcuate nucleus is upregulated during fasting24.
Leptin has been shown to downregulate NPY
expression in the arcuate neurons2730.
Insulin is a long-term regulator of food intake,
energy balance and adiposity. Central insulin
reduces food intake by acting through insulin recep-
tors that are synthesized by arcuate neurons20, 25, 105.
Insulin inhibits NPY mRNA expression in the arcu-
ate nucleus26, 31 and the release of NPY from nerve
terminals in the PVN69. In contrast, insulin increa-
ses POMC expression25.
Marked changes in blood glucose levels can
modulate short-term food intake. Lowering of
blood glucose levels triggers sensation of hunger.
Neurons in the hypothalamus that respond to
change in glucose levels may be the same as
respond to leptin.
Ghrelin is a peptide with 28 amino acid residues,
synthesized mainly in the stomach, but also in the
brain, especially in the hypothalamus32, 33, 38, 106. Ghre-
lin stimulates food intake107109. It antagonizes leptin
action through the activation of the arcuate-paravent-
ricular NPY pathway38, 106, 108, 109. The arcuate
NPY/AgRP neurons are the primary targets of ghre-
lin. It increases NPY and AgRP mRNA expression in
the arcuate nucleus and NPY and AgRP levels in the
hypothalamus33. It is more likely, that both circulat-
ing and brain-born ghrelin106 are involved in this reg-
ulatory mechanism of the energy homeostasis.
Circulating leptin and insulin may gain access to
the brain via a specific and saturable transport sys-
tem110, 111. Furthermore, brain microvessels have an
ability to bind and internalize leptin, thus, it may gain
access to the brain by receptor-mediated transcyto-
sis112. To the hypothalamus, especially to the target
site, arcuate nucleus, leptin110, insulin and most pro-
bably circulating ghrelin108, 113 enter through the medi-
an eminence (Figure 2). The median eminence, as
other circumventricular organs is outside the blood-
brain barrier. Capillaries arise in the subependymal
plexus of the median eminence supply the arcuate
nucleus42, 43 lack tight junctions, and thereby large
molecules gain access to the arcuate nucleus114.
Leptin, ghrelin and insulin may also enter the
brain through another circumventricular organ, the
area postrema that serves as an open gate for the
nucleus of the solitary tract (Figure 2). Neurons in
the area postrema and the nucleus of the solitary
tract (NTS) express leptin115 and insulin116 receptors
that enhance the satiety actions of circulating gut
hormones, like cholecystokinin (CCK) and
glucagon-like peptide-1 (GLP-1). CCK is released
from the gut during the course of meal ingestion76.
It acts as a satiety hormone, it tells us when we
have had enough to eat. The circulating CCK exerts
its effect on the NTS through CCK-A receptors.
NEURONAL PATHWAYS
Feeding-related signals from the gastrointestinal
system may also reach the NTS via the vagus nerve
(Figure 2). NTS neurons are activated by stomach
distension. The activation of stretch- and mechano-
receptors trigger afferent neuronal signals to the
commissural part of the nucleus. Leptin and insulin
receptors are highly concentrated in this part of the
NTS. The chemical nature of gastrointestinal affe-
rents to the NTS is not known. Vagotomy reduces
peripheral ghrelin effects on the brain117 and the
density of CART peptide immunoreactive fibers in
the NTS118 indicating the presence of these hor-
mones in vagal afferents. CART peptide released
Clin Neurosci/Ideggy Szle 2003;56(910):288302. 293
 upon CCK stimulation could function as a satiety
transmitter at the level of the NTS119.
The NTS projects various types of sensory sig-
nals to the hypothalamus, the limbic system and the
cerebral cortex. A wide variety of neuropeptides
and neurotransmitters are present in these ascen-
ding fibers (see references44, 120 for review). The fee-
ding-related fibers may reach hypothalamic nuclei
directly, or they are relayed by parabrachial neurons
where gastric and gustatory signals are integrated.
The glucagons-like peptides consist a group of the
neuropeptides that transfer ascending anorexigenic
signals to the hypothalamus. Central GLP-1 synthe-
sizing neurons are restricted to the caudal (commis-
sural) portion of the NTS. In the hypothalamus, the
PVN is the primary site where GLP-1 regulates
food intake: it is densely innervated by ascending
GLP-1 fibers from the NTS, and possesses a high
density of GLP-1 receptors. GLP-2 fibers, also
from NTS neurons, terminate in the dorsomedial
hypothalamic nucleus that express GLP-2 recep-
tors79. CCK is another neurotransmitter that carries
satiety signals from the NTS to the hypothalamus
(CCK-B receptors are expressed in the paraventri-
cular and ventromedial neurons).
Ascending fibers from brainstem biogen aminer-
gic (noradrenaline, dopamine, serotonin) nuclei
innervate hypothalamic nuclei that are involved in
the regulation of food intake. They exert effects
both on feeding and energy homeostasis (see refe-
rence9 for review).
Increasing number of evidence (see Appendix)
indicate that endocannabinoids are involved in the
central regulation of food intake121, 122. The cannabi-
noid receptor type 1 (CB1) receptor mRNA is co-
expressed with CRH, CART and MCH neurons in
the hypothalamic nuclei122. No specific, feeding-
related endocannabinoid neuronal pathways have
been yet localized.
Intrahypothalamic neuronal circuits
PROJECTIONS FROM THE ARCUATE NUCLEUS
Arcuate neurons express both orexigenic
(NPY/AgRP) and anorexigenic (-MSH/CART)
peptides. Both types of neurons are regulated by
leptin and project to the PVN and the DLHA (Fi-
gure 3A) where they exert opposite actions on CRH,
as well as orexin and MCH neurons, respectively.
In the parvicellular PVN, NPY/AgRP and -MSH
fibers terminate on the same neuron62. NPY/AgRP
has complementary actions at inhibiting synapses
on CRH neurons, simultaneously inhibiting GABA
294 Palkovits: Central regulation of the food intake
input and preventing -MSH actions. Both
NPY/AgRP and -MSH receptors regulate GABA
release62. In the DLHA, fibers of both cell popula-
tions terminate on orexin and MCH neurons. NPY
has a strong effect on orexin, -MSH on MCH neu-
rons. AgRP here blocks -MSH action on MCH
neurons by binding on MCH-4 receptors23, 25.
Arcuate neurons also project brainstem and spinal
autonomic centers. -MSH neurons innervate para-
sympathetic preganglionic neurons in the dorsal va-
gal nucleus123, while CART peptide neurons project
to sympathetic preganglionic neurons in the interme-
diolateral cell column of the thoracic spinal cord19.
PROJECTIONS TO THE PARAVENTRICULAR NUCLEUS
Paraventricular neurons receive feeding-related neu-
ronal inputs from NPY/AgRP and POMC/CART
neurons from the arcuate nucleus, inputs from ore-
xin neurons in the dorsolateral hypothalamic area73,
and CCK and GLP-1 containing fibers from the
nucleus of the solitary tract (Figure 3B).
The PVN is a major source of input to autono-
mic neurons controlling the gastrointestinal tract and
the pancreas (Figure 2). Two distinct cell groups in
the PVN project to the dorsal vagal nucleus and the
thoracic (segments 8 and 9) intermediolateral cell
column124.
PROJECTIONS TO THE VENTROMEDIAL NUCLEUS
The dorsomedial part of the ventromedial nucleus
receives some inputs from the arcuate nucleus,
more orexin fibers from the DHLA (Figure 3C).
The VMN is massively innervated by the amygdala
through the stria terminalis (fibers terminate in and
around the VMN). The amygdala is implicated in
emotional aspects of feeding behavior. It has been
suggested that CRH projections from the central
nucleus of the amygdala influences CRH-2 recep-
tors that are densely located in the VMN. Urocortin
III neurons located between the PVN and the fornix
(Figure 3C) also project to the dorsomedial part of
the VMN and act on CRH-2 receptors.
Ascending (GLP-1) fibers from the NTS, and
CCK fibers from the NTS and the lateral para-
brachial nucleus terminate in the VMN.
Ventromedial neurons send descending nerve
fibers to the lower brainstem (Figure 3C).
PROJECTIONS FROM THE DORSOLATERAL HYPOTHALAMIC AREA
Lateral hypothalamic neuropeptides, orexins and
MCH (almost completely co-localized with CART
peptide80) may regulate both cognitive and auto-

NPY/AgRP
CART
-MSH/CART
NPY/AgRP
-MSH/CART
orexins
GLP-1
-MSH: -melanocyte-stimulating hormone, AgRP: agouti-related peptide, AN: arcuate nucleus, BS: brain stem, CART: cocaine- and amphetamine-regu-
lated transcript peptide, CCK: cholecystokinin, CRH: corticotropin-releasing hormone, DLHA: dorsolateral hypothalamic area, DVN: dorsal vagal nucleus,
GLP-1: glucagon-like peptide-1, LPbN: lateral parabrachial nucleus, NPY: neuropeptide Y, NTS: nucleus of the solitary tract, PVN: paraventricular nucle-
us, VMN: ventromedial nucleus
nomic aspects of food intake and body weight regu-
lation96. MCH has been implicated in computing the
hedonic properties of food80. Both orexin and MCH
cells are under NPY/AgRP and -MSH control by
arcuate neurons125127. MCH and orexins neurons
that constitute two distinct, separate groups of cells
in the DLHA, provide diffuse innervation of the
neuraxis, including monosynaptic projections to the
entire cerebral cortex and the limbic system96.
Although, the lateral hypothalamus has modest
input to autonomic centers relative to the PVN,
MCH and orexin neurons innervate both sympathe-
tic and parasympathetic cells in the medulla and the
spinal cord. These sites are critical for gastric moti-
lity, gastric acid secretion and the regulation of the
secretion of pancreatic hormones. In addition, late-
ral hypothalamic cells project to brainstem reticular
formation and sensorimotor nuclei84. MCH neurons
innervate the basal forebrain, certain parts of the
extrapyramidal system and rostral midbrain areas90.
For further details, see references44, 8486, 120, 128.
There is a neuronal feedback circuit between the
arcuate nucleus and the DLHA. Orexin-immunore-
BS
LPbN
NTS
CRH
urocortin III.
orexins
CCK
Figure 3. Intrahypothalamic connections between
hypothalamic nuclei involved in the regulation of the
food intake with some extrahypothalamic afferent and
efferent projections. A Connections of the arcuate
nucleus. Humoral signal routes (afferents) and pro-
jections to paraventricular and dorsolateral hypotha-
lamic neurons and to sympathetic preganglionic neu-
rons in the thoracic spinal cord. B Neuronal afferents
to the paraventricular nucleus and paraventricular
efferent pathways to parasympathetic (dorsal vagal
nucleus) and spinal sympathetic preganglionic neu-
rons. C Neuronal inputs to the hypothalamic ventro-
medial nucleus and ventromedial efferents to the
lower brainstem and the spinal cord
active terminals from DLHA neurons make direct
synaptic contact with arcuate NPY/AgRP neurons
that project, vica versa, to the DLHA. Both cell
types also express leptin receptors. Thus, the exci-
tatory actions of orexin could increase NPY release,
resulting in enhanced feeding behavior127.
Hypothalamic efferents
Efferent pathways from the hypothalamus are car-
rying output signals to the autonomic centers and
the limbic system (Figure 2).
PATHWAYS TO THE SYMPATHETIC AND PARASYMPATHETIC
PREGANGLIONIC NEURONS: CONTROL OF THE ENERGY
EXPENDITURE
All of the hypothalamic nuclei that participate in
the control of food intake project to the lower brain-
stem and/or the spinal cord44, 84, 120. The major por-
tion of these hypothalamic efferent fibers arises in
the PVN. CRH from the PVN decreases food intake
Clin Neurosci/Ideggy Szle 2003;56(910):288302. 295
 and increases the activity of the central sympathe-
tic system through descending fibers to the spinal
cord. CART peptide containing neurons from the
arcuate nucleus19 and projections from the lateral
hypothalamus128, 129 also terminate here. In the ener-
gy-spending, catabolic state of the body, the sym-
pathetic nervous system is predominant.
Paraventricular fibers also terminate in the dor-
sal vagal nucleus innervating parasympathetic pre-
ganglionic neurons124, 130, 131. These cells are also
innervated by POMC fibers from the arcuate123, and
other fibers from the dorsomedial nucleus83, 130.
HYPOTHALAMO-LIMBIC CONNECTIONS: ORGANIZATION OF
THE FEEDING BEHAVIOR
Motivation to eat involves the nucleus accumbens
in the basal forebrain. The shell portion of the
nucleus, which receives input from the medial pre-
frontal cortex and the hippocampus send outputs to
the hypothalamus. The nucleus accumbens is
thought to be involved in the rewarding aspects of
feeding. By enhancing activity in the accumbens
nucleus, the MCH neurons from the DLHA may
play an unique role enhancing the hedonic value of
food (for further details about the mechanism of
action, see reference11). There is evidence for func-
tional relationships between the accumbens nucleus
and the lateral hypothalamus, as well as the PVN
subserving the control of feeding behavior. Injec-
tions of orexin into the accumbens shell increase
food intake100. Activation of accumbens neurons by
a GABA agonist elicits Fos activation in lateral
hypothalamic neurons100. Inhibition of the activity
APPENDIX
The effects of brain-born and peripheral hormones,
neuropeptides, opioid peptides and endocannabi-
noids that participate in the central regulation of the
food intake and energy homeostasis.
AGOUTI-RELATED PEPTIDE (AGRP)
AgRP binds to MC-3 and MC-4 melanocortin
receptors to antagonize the action of -MSH16, 95,
9799, 131
fasting increases AgRP mRNA expression132
AgRP is upregulated in obese and diabetic
mutant mice25
AgRP injections into the paraventricular nucleus
result in a long-lasting food intake
296 Palkovits: Central regulation of the food intake
of accumbens neurons by local injections of GABA
or glutamate antagonists result in intense feeding
response similar to that can be elicited by lateral
hypothalamic stimulations100. It has been suggested
that the PVN may initiate feeding, in part, by acti-
vating the mesolimbic system130. Galanin injected
into the PVN increases food intake and parallel
dopamine release from mesolimbic terminals in the
nucleus accumbens, while injections of CCK and
serotonin that reduce food intake inhibits dopamine
release in these terminals.
Conclusions
Recent progress in neuroanatomy, neuropharmaco-
logy and molecular biology has greatly advanced
understanding of the central regulatory mechanisms
of food intake and the energy homeostasis. There is
emerging evidence that neuropeptides in the
hypothalamus keep a fine balance of the food intake
and feeding behavior through delicate orexi- and
anorexigenic neuronal circuits. It is likely, the new
genes, new feeding-related molecules and new re-
gulatory pathways will be further identified. It is
hoped that new information will clarify the patho-
logical and clinical aspects of these regulatory
mechanisms and facilitate therapeutic strategies for
eating disorders and obesity.
ACKNOWLEDGEMENTS
This work was supported by the Hungarian Natio-
nal Science Foundation (OTKA), grants T 034496
and TS 040771.
leptin inhibits AgRP expression in arcuate neurons
AgRP fibers terminate on MCH and ORX cells
in the dorsolateral hypothalamic area1
-MELANOCYTE STIMULATING HORMONE (-MSH)
melanocortinerg neurons exert a tonic inhibition
of feeding behavior95
-MSH exerts anorexic effects by acting on
MC-3 and MC-4 melanocortin receptors in the
dorsolateral hypothalamic area92
-MSH expression from POMC is stimulated by
leptin
POMC and leptin receptors are co-expressed in
arcuate neurons
CART (COCAINE- AND AMPHETAMINE-REGULATED
TRANSCRIPT) PEPTIDE
CART mRNA expression is down-regulated in
food-deprived rats34
icv. administered CART inhibits food intake34
CART peptide blocks NPY-induced feeding
responses in the paraventricular nucleus75
CART is co-expressed with POMC and leptin
receptors in arcuate neurons
CART expression in arcuate neurons is stimula-
ted by leptin19, 34
fourth ventricle injection of CART reduces food
intake118
CART in the nucleus of the solitary tract is a
putative mediator of CCK-induced satiety119
CORTICOTROPIN-RELEASING HORMONE (CRH)
CRH has potent inhibitory effect on food
intake61
CRH influences the energy balance by acting on
the sympathetic nervous system
CHOLECYSTOKININ (CCK)
CCK promotes satiety by inhibition of gastric
emptying76
CCK is acting as a neurotransmitter to produce
satiety in the hypothalamus56
the effect of central CCK to inhibit food intake is
mediated via CCK-A receptors in the nucleus of
the solitary tract56
CCK is activated by leptin
intrahypothalamic injections of CCK inhibit
food intake
ENDOCANNABINOIDS
the endogeneous cannabinoid system affects
energy balance via central orexigenic drive122
both peripheral and central administration of
anandamide stimulate food intake55, 121, 133
anandamide and 2-archidonoyl-glycerol (2-AG)
levels in the hypothalamus are reduced by lep-
tin121
the blockage of cannabinoid receptors produces
large reduction in food intake134
CB1 receptors are present in the arcuate nucleus
and the dorsolateral hypothalamic area122
hypothalamic CB1 mRNA is co-expressed with
CRH, CART, MCH and orexins122, 135
2-AG is present in hypothalamic areas involved
in feeding
GALANIN
endogeneous galanin contributes to the natural
appetite for fat71
paraventricular and ventromedial injections of
galanin produce a strong feeding response53, 61
food deprivation enhances galanin levels selec-
tively in the paraventricular nucleus72
leptin and insulin inhibit galanin mRNA expres-
sion
GALANIN-LIKE PEPTIDE (GALP)
GALP increases food intake by stimulation NPY
and blocking CART in the arcuate nucleus40
GALP mRNA expression in arcute neurons is
increased by leptin39, 41
fasting reduces GALP mRNA expression39
GALP induces Fos expression in the arcuate
nucleus74
GLUCAGON-LIKE PEPTIDES (GLP-1 AND GLP-2)
GLP-1 acts as a satiety factor, it inhibits food
intake
GLP-1 neurons are present in the nucleus of the
solitary tract from where they project to the
hypothalamic paraventricular nucleus
administration of GLP-1 into the paraventricular
nucleus leads to profound anorexia
GLP-2 inhibits food intake79
GLUCOSE
marked changes in blood glucose levels can
modulate short-term food intake: low glucose
level promotes feeding
lowering of blood glucose levels triggers sensa-
tion of hunger
hypoglycemia activates orexin neurons136
GHRELIN
ghrelin stimulates food intake32, 38, 113
centrally administered ghrelin increases NPY
and AgRP mRNA levels in the arcuate nuc-
leus32, 33
ghrelin stimulates NPY and CRH release38
ghrelin antagonizes the action of leptin38
ghrelin in the brain is expressed by arcuate, para-
ventricular, ventromedial and dorsomedial neu-
rons32, 108
ghrelin receptors activates NPY neurons in the
arcuate nucleus38
Clin Neurosci/Ideggy Szle 2003;56(910):288302. 297
 INSULIN
icv. injections of insulin reduce food intake105
insulin stimulates leptin expression and release
down-regulation of insulin receptors in the arcu-
ate nucleus causes hyperphagia25
insulin activates the sympathetic nervous system
and thermogenesis
insulin inhibits NPY expression in the arcuate
nucleus26 and the release of NPY from the nerve
terminals in the paraventricular nucleus69
insulin increases POMC expression in the arcu-
ate nucleus25
central insulin inhibits galanin expression in the
arcuate nucleus31
insulin receptors are expressed in key brain areas
for food intake20
LEPTIN
leptin acts on the brain to inhibit feeding
leptin levels in the plasma fall rapidly in fasting126
the effects of leptin on appetite and energy balance
are mediated by hypothalamic neurons: basal hypo-
thalamic lesions prevent leptin action in the brain
leptin receptors (Ob-Rb) are expressed by
hypothalamic neurons23 (Table 2)
leptin receptors in the arcuate nucleus are up-
regulated by fasting24
leptin reduces NPY levels and blocks NPY
mRNA expression in the arcuate nucleus2730, 35
POMC and leptin receptors are co-expressed in
the arcuate nucleus36
leptin activates anorexigenic POMC expression
in the arcuate nucleus29, 35, 37
leptin stimulates CRH mRNA expression in the
paraventricular nucleus48
leptin activates CART neurons in the arcuate
nucleus that project to sympathetic preganglio-
nic neurons in the spinal cord19
leptin injected into the fourth ventricle inhibits
gastric emptying115
MELANIN CONCENTRATING HORMONE (MCH)
MCH has a stimulatory effect on feeding: icv.
given MCH increases food intake94
MCH mRNA expression is inhibited by leptin
MCH mRNA levels are elevated during fasting94
MCH neurons co-express leptin receptors
NEUROPEPTIDE Y (NPY)
NPY is the most potent orexigenic agent
known12
298 Palkovits: Central regulation of the food intake
central administration of NPY induces food
intake12, 137, 138
NPY released in the paraventricular nucleus
stimulates feeding behavior66, 67
arcuate pre-proNPY mRNA level is increased by
food deprivation126
arcuate NPY neurons express leptin receptors
(Ob-Rb form)22
expression of NPY mRNA in the arcuate nucle-
us is inhibited by leptin and insulin
glucose increases NPY levels and NPY mRNA
expression in the arcuate nucleus
NOCICEPTIN
nociceptin, an endogenous agonist of opioid recep-
tor ORL-1, injected into the accumbens or hypotha-
lamic ventromedial nuclei increases food intake54
food deprived rats exhibit lower mRNA levels
for pro-nociceptin and nociceptin NOP receptors
in the paraventricular nucleus and the lateral
hypothalamus50
OPIOID PEPTIDES
-endorphin stimulates food intake through
receptors
dynorphins acts in the lateral hypothalamus,
facilitate feeding behavior
dynorphin mRNA expression is elevated by food
deprivation139
OREXINS (ORX)
orexins injected into the dorsolateral hypothala-
mus enhance food intake73, 87, 93
orexin levels are markedly elevated during star-
vation and decreased by refeeding
food deprivation upregulates pre-proorexin
mRNA levels in the hypothalamus87, 140
orexin expression is blocked by leptin
PRO-OPIOMELANOCORTINS (POMC)
fasting reduces POMC mRNA expression in the
arcuate nucleus126, 141
UROCORTINS
urocortin is a potent inhibitor of appetite when
injected centrally142, 143
urocortin III has an anorexic effect more potent
than that of CRH or urocortin I
urocortin III acts on CRH-2 receptors in the vent-
romedial nucleus
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