Journal of Internal Medicine 2005; 258: 301–327
doi:10.1111/j.1365-2796.2005.01553.x
REVIEW
Brain regulation of food intake and appetite: molecules and
networks
C. BROBERGER
From the Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
Abstract. Broberger C (Karolinska Institute,
Stockholm, Sweden). Brain regulation of food
intake and appetite: molecules and networks
(Review). J Intern Med 2005; 258: 301–327.
In the clinic, obesity and anorexia constitute
prevalent problems whose manifestations are
encountered in virtually every field of medicine.
However, as the command centre for regulating food
intake and energy metabolism is located in the
brain, the basic neuroscientist sees in the same
disorders malfunctions of a model network for how
integration of diverse sensory inputs leads to a
coordinated behavioural, endocrine and autonomic
response. The two approaches are not mutually
exclusive; rather, much can be gained by combining
both perspectives to understand the pathophysiology
of over- and underweight. The present review
summarizes recent advances in this field including
the characterization of peripheral metabolic signals
Introduction
Few tasks executed by the brain hold greater
survival value than keeping us fed and in adequate
nutritional state. It is not surprising then that the
This paper builds partly on presentations made at a
Nobel Conference on ‘Brain Control of Feeding Behaviour’
organized at the Karolinska Institute, Stockholm, Sweden,
in September 9–11, 2004.
2005 Blackwell Publishing Ltd
to the brain such as leptin, insulin, peptide YY,
ghrelin and lipid mediators as well as the vagus
nerve; signalling of the metabolic sensors in the
brainstem and hypothalamus via, e.g. neuropeptide
Y and melanocortin peptides; integration and
coordination of brain-mediated responses to
nutritional challenges; the organization of food
intake in simple model organisms; the mechanisms
underlying food reward and processing of the
sensory and metabolic properties of food in the
cerebral cortex; and the development of the central
metabolic system, as well as its pathological
regulation in cancer and infections. Finally,
recent findings on the genetics of human obesity
are summarized, as well as the potential for novel
treatments of body weight disorders.
Keywords: brainstem, cerebral cortex,
hypothalamus, metabolic, reward.
feeding,
central nervous system has developed a meticulously interconnected circuitry to meet this challenge. A consequence of this organization is that an
energy-dense environment favours the development
of obesity, whilst overcompensation may shut down
the drive to feed. In today’s society where evolving
disease demographics and lifestyle allow for a
greater diversity of metabolic phenotypes than
perhaps ever before [1] disorders of both extremes
of energy intake are common in health care.
301
302
C. BROBERGER
Obesity is increasing at an alarming rate in
industrialized and developing countries alike [2]
and is associated with a wealth of conditions
afflicting virtually all organ systems [3, 4]. Examples diverge widely to include cholelithiasis [5],
osteoarthritis [6], infertility [7], stroke [8], cutaneous infections [9], wound healing deficiencies [10],
as well as a general increase in mortality [11]
and social and professional stigmatization [12].
The urgency of the problem is illustrated dramatically by the previous rarity of paediatric obesityassociated type 2 diabetes, which is increasing to
the point of taking over as the leading cause of
childhood diabetes [13]. The opposite extreme of
anorexia and hypophagia includes not only anorexia nervosa [14] but is also a common and
potentially fatal complication of infections [15],
malignancies [16] and ageing [17].
Unlike many other common diseases, these disorders have an obvious solution: adjusting food intake
and exercise until normal body weight has been
restored. However, it is no great revelation that this
solution is as simple as it has repeatedly proved
elusive [18]. Experimental studies confirm the common knowledge that weight loss almost always is
followed by a rapid return to initial weight once the
anorexigenic regimen is terminated [19]. Notably,
the same applies to humans subjected to voluntary
overfeeding [20], supporting the concept of a tightly
regulated set-point for body weight. Treatment of
eating disorders has been remarkably unsuccessful –
a consequence possibly of that we are battling
ancient systems maintained by ‘thrifty genes’ that
favour the preservation of energy stores [21]. Available options for pharmacological therapy leave much
to be desired, and compounds that have been
introduced for obesity management have subsequently often been withdrawn due to intolerable
side-effects [22]. The most effective obesity treatment
at present is bariatric surgery, but this is a
complicated procedure not without adverse effects
[23]. Preventive measures have frustratingly limited effect. It has proved even more difficult to
devise strategies for increasing food intake in cases
of anorexia. Although some success has been
reported with behavioural approaches for anorexia
nervosa [24], the more common forms of cancerand inflammation-associated anorexia remain a
major therapeutic challenge. Novel treatments are
greatly needed.
But what systems should such treatments target?
Early clinical observations that patients with pituitary tumours and accompanying injury to the base of
the brain develop obesity [25–28], inspired experimental lesion studies [29–33], which demonstrated
that damage to particular regions of the hypothalamus and brainstem lead to profound, often fatal,
alterations of feeding behaviour. It also became
apparent that signals from the peripheral energy
stores [34] and gastrointestinal canal [35] provide
essential cues for appetite and satiety. Based on
these and other findings, Stellar [36] half a century
ago proposed a dual centre hypothesis for the
initiation of motivated behaviour. The hypothesis
included both mechanisms for sensing peripheral
cues, separate nuclei (i.e. the ‘dual centres’) for
stimulating and inhibiting behaviour, and connections between the hypothalamus and higher brain
regions to allow for internal states to determine the
threshold for initiating behaviour. Of all motivated
behaviours, the model is perhaps most applicable for
food intake. Yet, for all its heuristic value, the dual
centre hypothesis was as low on specifics as it was
laden with theory. Research dating in particular
from the last decade has changed this. Today, we
have an understanding of the circuitry and neuropharmacology of feeding behaviour that can be
probed for therapeutic targets. The present article is
not an exhaustive review of the central control of
energy metabolism [37, 38], but summarizes recent
advances, which have brought new insight into the
peripheral signals describing the metabolic state to
the brain; the input stations in the hypothalamus
and brainstem sensitive to these signals, the organization of feeding behaviour in simple and complex
organisms; the link between food intake and energy
expenditure; the neural framework for integrating
metabolic cues and reward properties; the mechanisms of infection- and cancer-associated anorexia;
developmental and genetic causes of obesity and
novel therapeutic strategies.
A central framework for sensing and
orchestrating energy metabolism
The regulation of energy metabolism presents a
prototypical homeostatic system, with the brain
acting as the central coordinator and rectifier
(Fig. 1). It is one of the great wonders of the brain
that body weight stays remarkably fixed (as a
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
NPY
POMC
ARC
IN
GHREL
LIN
INSU
Y
PY
S
GU
VA
X
nTS
IML
LEP
T
IN
DM
A
OE
Fig. 1 The central metabolic circuitry is regulated by numerous
endocrine and neural inputs. Schematic illustration of how brain
networks regulating ingestive behaviour communicate with peripheral organs. Hormones supplying information about the peripheral metabolic state to the brain include the gastrointestinal
peptides ghrelin and PYY(3-36), insulin from the pancreas and
leptin from adipose tissue. Ghrelin and leptin act both on the
hypothalamus (Arc) and the brainstem (nTS). The afferent portion of the vagus nerve innervates most of the gastrointestinal
tract where it collects information about the immediate alimentary state, and terminates in the nTS. The lipid mediator OEA is
produced in the duodenum and activates the brainstem, possibly
via the vagus nerve. Both the Arc (via antagonistic NPY- and
POMC-expressing cells) and the nTS project further into the brain
in parallel pathways to engage higher brain regions into ingestive
behaviour. Outputs from the brain regulating energy expenditure
include both branches of the autonomic nervous system; the
sympathetic system whose preganglionic neurones are located in
the intermediolateral cell column (IML), which is directly innervated by POMC neurones from the Arc, as well as the parasympathetic system with preganglionic neurones for the efferent
portion of the vagus nerve located in the dorsal motor nucleus of
the vagus (DMX). The efferent autonomic innervation regulates,
e.g. glucose homeostasis via actions in liver and skeletal muscle.
See text for details.
‘set-point’) most of the time in most people [39]. The
first step in maintaining this homeostasis is for
the brain to inform itself of the metabolic status of
303
the individual, which it does through two main
channels. First, hormonal signals reflecting the
availability and demand for metabolic fuel is relayed
via neurones in the hypothalamus. The receptors for
these signals are primarily expressed on two neurochemically distinct sets of neurones located in the
arcuate nucleus (Arc) in the mediobasal hypothalamus, alongside the third ventricle [40]. One neurone
group expresses neuropeptide Y (NPY); increasing
NPY release or activation of these neurones by a
variety of approaches results in increased food
intake and decreased energy expenditure. The other
group expresses the neuropeptide precursor proopiomelanocortin (POMC), which is processed to
melanocortin peptides; activation of these neurones
has the opposite effect of triggering the NPY cells, i.e.
decreased food intake and increased energy expenditure. The yin–yang relationship between the two
Arc groups is further underscored by their opposite
regulation by leptin and insulin, hormones signalling metabolic affluence, which decrease the expression of NPY, whilst they increase the expression of
POMC. The second main input for information
pertaining to energy balance is the brainstem,
classically viewed as a channel for visceroceptive
information as cranial nerves, in particular the
vagus nerve, carrying information from the alimentary organs enter the brain here. Vagal afferents
synapse onto [41, 42] and excite [43] neurones in
the brainstem nucleus tractus solitarii (nTS). From
both the hypothalamus and the brainstem, projections fan further into the brain to engage other brain
regions in the initiation and organization of food
intake. As in all homeostatic systems, the brain has
at its disposal three effector pathways to activate
when the controlled variable (i.e. body weight)
needs to be adjusted: behaviour (i.e. food intake), the
endocrine system and the autonomic nervous system [44]. Importantly, all three of these systems are
engaged downstream of the Arc and nTS stations to
provide a synchronized response to fluctuations in
energy balance; the first primarily in the volitional
control of intake, the latter two regulate energy
expenditure.
Peripheral control of feeding behaviour
Metabolic state is reflected in a diverse array of
signals of the brain. Recent investigations have shed
light on some of the key hormones and the vagal
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
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C. BROBERGER
mechanisms that shape the central response to
nutritional challenges (Fig. 1).
The vagus nerve
The gastrointestinal canal is equipped with a myriad
of sensory receptors along its full crown-rump
extension [45]. Thus, the taste, texture and
mechanic stress of food is reported to the brain to
provide an online description of the immediate
alimentary state. This information is routed to the
nTS primarily via the afferent portion of the vagus
nerve, so that vagal activation causes satiation and
meal termination. (Parallel neural feedback is also
supplied by sensory neurones innervating the oral
cavity mediating, e.g. taste, and lesser-studied
splanchnic nerves [46].) Vagal afferents are broadly
sensitive to gastrointestinal signals, including gastroduodenal distension, the presence of chemically
distinct nutrients within the gastrointestinal tract as
well as peptides produced by endocrine cells in the
gut wall, most prominently cholecystokinin (CCK), a
well-characterized satiety signal [47, 48]. Importantly, these signals are integrated within the individual vagal sensory neurone prior to the signal
being relayed in the nTS [49, 50]. The neurochemical identity of viscerosensory vagal neurones has
remained enigmatic, but these cells likely signal via
glutamate [51] and the neuropeptide cocaine- and
amphetamine-regulated transcript [52], which
inhibits feeding upon brainstem administration [53].
centrally active feeding-inhibitory messenger, as
restitution of the leptin signal in these animals
normalizes food intake and body weight [56]
(Fig. 2). Serum leptin correlates well to the size of
the body fat deposit, and falls with weight loss [57].
This relationship is seen also in obesity, where the
combination of hyperleptinaemia and hyperphagia
has led to the suggestion that overweight is
characterized by leptin resistance [58]. Central
actions underlie both leptin-mediated feeding suppression as well as the extensive peripheral metabolic effects of this hormone; thus, e.g. replacement
of leptin receptors selectively in the brain of ob/ob
mice is sufficient to prevent hepatic steatosis [59].
Leptin
Insulin
An appetite-regulating endocrine signal from fat
tissue maintaining energy homeostasis had been
hypothesized already with parabiosis experiments
in the 1950s [34]. The seminal discovery of leptin,
the adipocyte-derived protein hormone providing
this signal, by Friedman and collaborators in 1994
[54] was a decisive catalyst for much of the current
investigation on peripheral modulation of central
networks. A little more than a decade later, leptin
has been shown to modulate several aspects of
energy balance through several different mechanisms and across a wide spectrum of timeframes,
alerting the brain to the state of body adiposity [55]
and acting as a ‘fat-o-stat’. It is now well established that the pronounced obesity in genetically
leptin-deficient ob/ob mice is due to the loss of a
Insulin is well recognized as the key glucostatic
regulator. Recent data demonstrate that in addition to
the control of peripheral glucose uptake, this role also
encompasses powerful central effects, in synergism
with leptin. First, intracerebroventricular (i.c.v.)
administration of insulin decreases food intake [60]
via insulin receptors expressed on Arc neurones [61].
The role of insulin in feeding is complicated by the fact
that the hypoglycaemia resulting from elevations in
serum insulin in itself stimulates food intake. However, when blood glucose changes are compensated
for, hypophagia is seen also with increases in peripheral insulin [62, 63], suggesting that the central
effects of insulin are anabolic. (This secondary hypoglycaemia may also explain why the insulin secretion
triggered already at the sight of a palatable-looking
Fig. 2 Genetically leptin-deficient ob/ob mice treated subcutaneously (s.c.) with saline (left) or with leptin (right). The severe
obesity in these animals is abolished with leptin replacement
therapy. Figure generously provided by Dr Jeffrey M. Friedman.
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
meal stimulates appetite (‘the cephalic phase’ [64]),
an indication that direct sensory input relayed via the
cortex can set off powerful appetitive mechanisms.)
Secondly, and again similar to leptin, insulin also
modulates peripheral energy metabolism via central
effects by inhibiting liver gluconeogenesis [65, 66].
Thus, whilst the brain does not depend on insulin for
glucose uptake, it is very much interested in what
insulin has to say about the metabolic state of the
body.
Peptide YY (3-36)
In addition to CCK, several gut-derived peptides
provide alimentary feedback to the central metabolic
circuits [67]. Peptide tyrosine-tyrosine (3-36)
[PYY(3-36)], a member of the NPY peptide family
produced by enteroendocrine cells [68], has recently
been shown to act as an important feedback signal
from the gut to the hypothalamus. Following a
meal, PYY(3-36) is released into the circulation
[69], specifically stimulated by the presence of lipids
and carbohydrates in the lumen of the distal ileum
and colon [70, 71]. Peripheral administration of this
hormone inhibits food intake and causes weight loss
[72, 73]. While some laboratories initially were
unable to replicate this effect [74], this may partly be
due to discrepancies in technique [75] and the
results have since been independently confirmed
[76, 77]. The satiety effect of PYY(3-36) is comparatively modest but, importantly, is observed also in
humans, including obese patients [73, 78]. Plasma
levels of PYY(3-36) rise markedly following ileal
resection [79, 80], an observation that has been
linked to the weight loss observed in patients
undergoing this procedure (S.R. Bloom and C. Le
Roux, personal communication).
Ghrelin
Thus, the gastrointestinal-brain axis has long been
viewed as a key channel subserving meal termination with CCK and PYY(3-36) as prime mediator
examples. Novel findings on the hormone ghrelin
(produced in stomach and small intestine epithelia
[81], see [82]) are challenging this doctrine. Ghrelin
is unique as the first gut hormone shown to
stimulate food intake [67]. Both peripheral and
central injections of ghrelin result in increased
feeding as well as fat mass [83–86]. Ghrelin levels
305
peak sharply in anticipation of a meal in humans as
well as experimental animals [87], resulting in
stimulation of both feeding and gastric emptying
[88] through actions possibly involving the vagus
nerve [89], and may thus provide a meal initiation
signal. In the hypothalamus, peripherally administered ghrelin mainly activates the NPY neurones
[85, 90] and antagonizing the actions of these cells
inhibits the orexigenic effect of ghrelin administration [85, 91]. In contrast, the melanocortin pathway
does not appear to be primarily involved [90]. Recent
reports have proposed that ghrelin is synthesized also
in hypothalamic neurones, but this issue remains
controversial, in part due to the contradictory claims
of the site of central ghrelinergic neurones and the
failure to demonstrate ghrelin mRNA in the brain (cf.
[92] and [93]).
Importantly, a loss of the hunger message relayed
by ghrelin has been suggested as the mechanism
behind the weight-reducing effects of bariatric surgery [94]. The initial rationale for gastric bypass
[95] was that the procedure would produce weight
loss by means of malabsorption. However, this turns
out to be a transient effect due to the considerable
compensatory potential of the digestive system.
Nevertheless, weight loss persists, caused instead
by a loss of appetite and hypophagia [96]. Concomitant with this effect, a fall in plasma ghrelin is
observed following the bypass procedure, in contrast
to the ghrelin increase associated with nonsurgical
weight reduction, where weight relapse is common
[86, 97]. (Note, however, findings that argue
against such a relationship, see [67].) Furthermore,
clinical data tie the hyperphagia observed in Prader–
Willi syndrome to strikingly high plasma ghrelin
levels [98]. These results, coupled with the discovery
that elevated plasma ghrelin is a marker for future
weight gain (D.E. Cummings and J. Krakoff, personal
communication) indicate that interfering with ghrelin signalling offers a clinically promising approach
to treating eating disorders.
Oleoylethanolamide
A role for endogenous cannabinoids in appetite
regulation has long been suspected from the carbohydrate craving observed in marijuana smoking
[99]; indeed, increased appetite is a diagnostic
criterion for cannabis intoxication [100]. Neuronal
production of cannabinoids is widespread and these
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
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C. BROBERGER
mediators play an important and general role in the
modulation of synaptic transmission [101], with the
orexigenic effects likely mediated via central cannabinoid CB1 receptors [102, 103]. However, the
lipid family to which the cannabinoids belong also
includes other members with opposite and peripheral effects on energy metabolism. Piomelli and
colleagues have accumulated evidence that the fatty
acid oleoylethanolamide (OEA), chemically but not
pharmacologically similar to the cannabinoids, is
produced in the duodenum and acts via the vagus
nerve to decrease body weight through activation of
the nTS [104]. OEA increases the inter-meal latency,
an effect distinct from that of, e.g. CCK, which
primarily decreases meal size [105]. However, changes in energy expenditure also underlie the OEAmediated weight reduction and are especially pronounced in models of obesity, involving in particular
increased fat utilization, whereas glucose homeostasis is relatively unaffected [106]. The catabolic
effects are most noticeable as a slowing of body
weight gain in growing rats, with OEA synthesis
reduced by food deprivation and stimulated in
response to increased demands on energy availability
such as cold exposure [104]. The metabolic actions
of OEA depend selectively and critically on genomic
as well as nongenomic actions of the ubiquitous
nuclear peroxisome proliferator-activated receptoralpha (PPAR-a) [107]. These results add obesity to
the growing list of potential therapeutic applications
for nuclear receptor pharmaceuticals. Notably, drugs
that target PPAR-a, e.g. gemfibrozil, are already in
clinical use to treat hypercholesterolaemia [108].
Integration of peripheral signals in the Arc
The peripheral signals described above thus act upon
the Arc (and nTS, see below) to influence the central
pathways regulating energy balance. In the Arc,
receptors for leptin and insulin found on NPY and
POMC neurones serve to inhibit transcription of NPY
[109, 55] and increase POMC mRNA levels [110–
112] via differential second messenger systems [113].
It is becoming evident that insulin, leptin and other
metabolically relevant hormones eventually converge not only on a common set of neurones, but
indeed also on the same molecules. Recent reports
highlight the role of the ATP-dependent potassium
current, IK(ATP), as a molecular target mediating
rapid, electrophysiological effects, of peripheral
hormones. This K+ conductance is a priori sensitive
to the availability of metabolic fuel as a fall in
intracellular levels of the energy donor ATP causes
the channel to open, leading to K+ influx and
hyperpolarization; this mechanism enables neurones
expressing IK(ATP) to vary their excitability in response
to changes in glucose concentration [114]. Leptin and
insulin both hyperpolarize Arc neurones by enhancing IK(ATP) [115, 116], by activating a common
enzyme, phosphoinositide 3 (PI3) kinase [116, 117].
It should be emphasized that the transmitter phenotype of Arc neurones expressing IK(ATP) is a controversial issue which remains to be conclusively
resolved [118–120]. Additional signals likely weigh
in on IK(ATP); this current is augmented when the
concentration of fatty acid derivatives is increased
locally within the Arc by inhibition of lipid oxidation,
a message of energy surplus that also decreases food
intake [66, 121]. This convergence of nutrient
information makes the PI3-kinase/IK(ATP) a key
integration node within the metabolic signalling
chain, attractive as a therapeutic target.
Modulation of the membrane potential of Arc
neurones has recently been demonstrated to control
glucose homeostasis. Opening of Arc K(ATP) channels via either hyperinsulinaemia or central inhibition of lipid oxidation inhibits vagal efferent (i.e.
parasympathetic) gluconeogenic signals to the liver,
promoting the use of fat as metabolic fuel [66, 122].
The Arc is also the site of central leptin regulation of
glucose homeostasis as selective restoration of Arc
leptin receptor expression in otherwise leptin receptor-deficient mice is sufficient to correct their
hyperglycaemia [123]. These results show that
insulin modulates glucose homeostasis by independent peripheral and central mechanisms and emphasize that interconnectivity within brain metabolic
regions serve to switch the body between different
fuel sources, in parallel to controlling food intake.
Interestingly, in obese rats, hypothalamic IK(ATP)
channels fail to respond to leptin and insulin [115,
116]. Whether similar defects underlie insulin and/
or leptin resistance in human diabetes and obesity is
an interesting possibility, which remains to be
investigated.
Output from the Arc
NPY neurones. Neuropeptide Y is one of the most
potent stimulators of feeding known [124], an
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REVIEW: BRAIN CONTROL OF FOOD INTAKE
307
suggests that NPY primarily stimulates appetitive
rather than consummatory behaviour [130].
Fig. 3 Expression of NPY and melanocortin receptors in the
mouse brain. In situ hybridization histochemistry (a) shows the
distribution of NPY Y1 receptor mRNA detected as silver grains in
a coronal section, revealing dense expression in the cerebral
cortex and nuclei in the amygdala, thalamus and hypothalamus.
In panel b, green fluorescent protein (GFP) is expressed in a
neurone under control of the melanocortin (MC) 4 receptor promoter; note strong immunoreactivity throughout cell soma and
dendrites. A Nissl-stained coronal section (c) shows neurones
clustered to form the paraventricular hypothalamic nucleus
(PVH) alongside the third ventricle. The PVH constitutes a central
integrative ‘hub’ within the metabolic circuitry. (d) Immunohistochemical for GFP (indicating the presence of the MC4 receptor)
and in situ hybridization for NPY Y1 receptor mRNA have been
combined in a section from the amygdala, revealing the coexistence of these receptors in neurones downstream of the Arc. Figure
produced by Drs Toshiro Kishi and Joel K. Elmquist. Reprinted
with permission from Macmillan Publishers Ltd.; Molecular Psychiatry 2005;10:132–146.
effect that has been confirmed by various approaches [40]. While there is conflicting data on whether deletion of the NPY gene produces hypophagia
(cf. [125] and [126]), the obesity of ob/ob mice is
attenuated when combined with an NPY)/) genotype [127], suggesting that NPY is an important
mediator of central leptin signalling. Stimulation of
feeding appears to be transduced predominantly via
postsynaptic NPY Y1 receptors, as determined from
pharmacological and genetic engineering studies
(reviewed in [128], Fig. 3a). However, the synergistic actions of multiple NPY receptor subtypes
participate to produce orexigenic effects in vivo
[129]. Detailed behavioural analysis of those effects
POMC neurones. Pro-opiomelanocortin is a large
precursor protein which gives rise to several bioactive peptides. Among these, the melanocortin peptides, in particular a- and c-melanocyte-stimulating
hormone, have been shown to exert potent anorexigenic effects when administered i.c.v. [131,
132]. Central melanocortin effects are mediated by
the melanocortin 3 and 4 receptors (MC3R and
MC4R, respectively; Fig. 3b). Deletion of the genes
for either POMC, MC3R or MC4R result in obesity in
mice, suggesting that the melanocortin system is
crucial in maintaining body weight [133–135] – as
supported by similar findings in humans (see below).
MC4R)/) mice also increase their feeding in
response to a high fat diet, in contrast to wild-type
littermates where a reduction is seen and ob/ob mice,
which maintain the same intake as with regular
chow [136], underlining the importance of the
melanocortin system for adjusting food intake in
response to caloric variations. In addition, the hallmark hypophagia seen in disease models as diverse
as renal failure, immunological challenge with
lipopolysaccharide (LPS) and tumour implants is
ablated. The obesity in MC4R-deficient animals is
partly due to changes in energy expenditure, such as
deficient diet-induced thermogenesis [136]. The
anatomical substrate for this effect may be a direct
projection from the POMC neurones in the Arc to
the preganglionic sympathetic neurones in the spinal cord [137–139] constituting a link between the
metabolic integrator and the autonomic effector
system. Interestingly, the spinal projection sets the
POMC neurones apart from the neighbouring NPY
neurones which otherwise exhibit very parallel
innervation patterns. However, it should be pointed
out, that in humans, the melanocortin system
appears to be more geared towards regulating feeding behaviour, with a proportionately smaller role in
peripheral metabolism [140].
NPY–POMC interactions. Interactions between the
Arc populations allow the NPY neurones to control
the activity of the POMC cells via two mechanisms.
First, NPY neurones coexpress agouti gene-related
peptide (AGRP), an endogenous melanocortin antagonist [141–143]. Thus, at the axon terminal,
melanocortin action can be blocked by simultaneous
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release of AGRP, and in agreement with such an
arrangement, a single i.c.v. administration of AGRP
causes an impressively long-lasting (one week)
suppression of food intake [144]. Secondly, at the
cell body level, POMC neurones are innervated by
NPY-ergic terminals [145] and express the Y1
receptor [146], through which NPY causes a
powerful membrane potential hyperpolarization (i.e.
inhibition) [147]. Surprisingly, no reciprocal innervation has yet been described and Roseberry et al.
[147] did not detect any changes in the electrical
properties of NPY neurones using a melanocortin
analogue. Thus, there may exist an asymmetrical
interaction in the Arc favouring the orexigenic
NPY/AGRP message over anorexigenic melanocortin signalling. However, an inhibitory influence over
the NPY neurones may be provided by PYY (3-36),
which is a selective agonist of the inhibitory Y2
autoreceptors [148] expressed by these cells [146].
Such gastrointestinal negative feedback has been
proposed as the mechanism whereby PYY(3-36)
inhibits feeding as no such effect is observed in mice
genetically deficient for the Y2 receptor and application of the peptide inhibits the electrical activity of
Arc NPY terminals [73]. This effect is relatively
selective as disruption of other relevant metabolic
pathways does not affect the satiety effect; the
PYY(3-36) effect persists both after vagotomy and in
MC4)/) mice [76], suggesting that neither the nTS
nor the Arc POMC neurones are directly involved.
Classical transmitters: glutamate and GABA. While
much of the current research on the central regulation of energy balance focuses on the role of peptides,
it should be emphasized that in the hypothalamus, as
in the rest of the brain, the key chemical mode of
communication between neurones is via amino acid
transmitters, i.e. excitatory glutamate and inhibitory
c-amino butyric acid (GABA). Indeed, in the absence
of glutamate and GABA-mediated transmission, little
remains of hypothalamic synaptic activity [149,
150]. The major function of peptides, in addition to
their genomic effects, is likely to modulate the synaptic transmission of ‘classical’ transmitters [151]
with which they coexist [152]. Interestingly, glutamate N-methyl-d-aspartate (NMDA) receptors
have been found to stimulate feeding with remarkable anatomical specificity within the lateral hypothalamic area (LHA), in comparison with other
hypothalamic regions tested and the amygdala
[153]. Infusion of NMDA antagonists locally within
the LHA blocks both agonist-induced and deprivation-induced food intake, indicating the involvement
of endogenous glutamatergic tone in natural feeding
[154]. Histochemical studies suggest that within the
Arc, NPY neurones largely contain GABA, whereas
POMC neurones signal via glutamate [155, 156].
Downstream targets of the Arc. The downstream
cellular effects of NPY are still mysterious. It was
initially assumed that ‘feeding-promoting neurones’
in loci sensitive to NPY orexigenesis were excited by
NPY. However, all known members of the NPY
receptor family couple to inhibitory second messenger systems [128]. Electrical excitation has been
proposed to come about in the form of disinhibition
via NPY-mediated suppression of GABA-dependent
inhibitory postsynaptic currents [157, 158], with
melanocortin stimulation producing the opposite
result, i.e. inhibition via stimulation of GABA release
[157]. However, that does not explain the role of
postsynaptic Y1 receptors, which exist throughout
the hypothalamus [146, 159, 160] (Fig. 3a). The
most potent orexigenic effects of NPY are seen
within the perifornical region/LHA [124], where
NPY/AGRP-ergic terminals appear to target two
separate populations of neurones expressing the
neuropeptides hypocretin (Hcrt; also known as
orexin) and melanin-concentrating hormone (MCH;
Fig. 4, [142, 161, 162]). This pathway is of interest
as Hcrt and MCH potently modulate wakefulness
[163–167], providing a means for metabolic signals
to control arousal state. Surprisingly, in a recent
investigation of the electrophysiology of the LHA
neurones, melanocortin stimulation did not affect
the electrical properties of MCH-expressing cells,
whereas both these and Hcrt-expressing cells were
inhibited by NPY [168, 169]. Furthermore, microinjection of NPY into the LHA appears to activate a
group of neurones distinct from those expressing
Hcrt or MCH [170]. As with all neural interactions,
it is important to bear in mind that the activity of
neurones can be influenced via several independent
mechanisms, including (but not exclusively) electrical and transcriptional effects, and that different
changes proceed along different temporal scales.
Thus, a functional Arc-LHA pathway cannot be
excluded. Nevertheless, these data invite a re-evaluation of the role of Hcrt and MCH as downstream
mediators of the NPY and POMC neurones.
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
309
Cerebral Cor tex
PFCx
FOOD
INTAKE
MCH
AcbSh
Hcrt
LHA
Other
subcortical nuclei,
incl. BST,
MPO, PVT,
DMH,Amgdl,
Raphe, PAG
and PBN
INGESTIVE
(Motivated)
BEHAVIOUR
PVH
NPY
POMC
DMX
Arc
ENERGY
EXPENDITURE
IML
Pituitary
Endocrine
regulation
incl. thyroid and
adrenocortical axes
Sympathetic
ANS
Parasympathetic
Fig. 4 Integration in higher brain regions determines the central response to changes in peripheral metabolic state. Schematic illustration
of connections between brain regions responsible for coordinating the behavioural somatomotor (i.e. food intake), autonomic and endocrine
(the latter two regulating energy expenditure) responses that together constitute the motivated ingestive behaviour used by the nervous
system to meet nutritional challenges. The antagonistic orexigenic NPY and anorexigenic POMC neurones in the Arc project in parallel
paths to numerous subcortical nuclei [including the bed nucleus of the stria terminals (BST), the medial preoptic area (MPO), the
paraventricular nucleus of the thalamus (PVT), several hypothalamic nuclei, e.g. the dorsomedial nucleus (DMH), the amygdala (Amgdl),
the serotonin-containing system in the raphe nuclei, the periacqueductal grey area (PAG) and the parabrachial nucleus (PBN)] distributed
throughout the brain. A projection to neurones expressing melanin-concentrating hormone (MCH) or hypocretin (Hcrt) in the lateral
hypothalamic area (LHA) provides an indirect pathway to the cerebral cortex for metabolic signals relayed via the Arc. The cortex in turn
projects back heavily to both the LHA and other feeding-regulatory regions. In addition, the LHA also receives an inhibitory input from the
shell of the nucleus accumbens (AcbSh), which in turn is modulated via prominent excitatory inputs from the prefrontal cortex (PFCx).
Thus, the LHA is positioned to integrate both homeostatic and reward-related signals in the gating of food intake. Energy expenditure is
modulated via outputs from the Arc to neuroendocrine neurones in the paraventricular hypothalamic nucleus (PVH), which control
release of, e.g. thyrotropin-releasing hormone and adrenocorticotropic hormone from the pituitary gland. Energy expenditure is also
regulated by projections from POMC neurones in the Arc and descending pathways from the PVH to autonomic preganglionic neurones in,
e.g. the dorsal motor nucleus of the vagus (DMX; parasympathetic) and spinal cord intermediolateral cell column (IML; sympathetic).
Note that ascending projections from the brainstem, which provide parallel important metabolic inputs to the brain, have not been included
in the figure. See text for details.
Circadian regulation of metabolic processes. In addition
to the various controls summarized above, metabolic
processes also follow strict circadian variations – as
recently underscored by the demonstration that
inactivation of key genes maintaining circadian
rhythmicity results in manifest metabolic syndrome
in mice [171]. Thus, for example, in rats the active
period of the day is immediately preceded by
coordinated peaks in hepatic glucose output (via the
sympathetic nervous system) and glucose uptake in
striated muscle (a parasympathetic effect; see [172]).
Buijs et al. [173] have investigated which brain regions are responsible for this synchronization. Using
anatomical tracing they find that the chains of
neurones innervating liver and muscle are separated
all the way through brainstem and hypothalamus to
distinct populations of preautonomic master neurones in the suprachiasmatic nucleus [173], the
brain region maintaining circadian rhythmicity and
entrained by direct retinal input [174, 175]. The
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310
C. BROBERGER
distinct pathways originating in the suprachiasmatic nucleus are particularly interesting in conjunction with the discovery that the autonomic
inputs to intra-abdominal and subcutaneous fat
stores are also separate [176]. In humans, shift work
[177] and sleep deprivation [178] are associated
with increased adiposity, findings that have been
linked to the sleep-associated peak in leptin secretion
[179]. However, this anatomically separate innervation indicates that loss of periodicity in the circadian input to adipose tissue may disrupt the balance
between different fat compartments leading, in turn,
to manifestations of the metabolic syndrome, which
is correlated to abdominal but not subcutaneous fat
accumulation [180].
Contributions of hind- and forebrain to
feeding regulation
As mentioned above, the brainstem provides a port
for vagal and other neural sensory signals into the
brain. Classical accounts of brain regulation of
feeding described two systems balancing each other:
the hypothalamus, monitoring the periphery for
signals alerting central circuits to diminishing
energy stores, and the brainstem, receiving oral
and gastrointestinal information as an online signal
of the amounts and qualities of the food that was
being ingested. This arrangement would allow the
hypothalamus to function as a long-term control
orchestrating meal initiation and the brainstem
served as a short-term control for meal termination.
Much of our knowledge on the different contributions of the fore- and hindbrain in meal regulation
comes from a lesion model developed by Grill and
Norgren [33]. Disconnecting the forebrain (which
includes the hypothalamus) produces a rat incapable of the motor activation necessary for normal
feeding. However, if this animal – whose brainstem
remains intact – is provided sucrose solution via an
intraoral cannula, intake can be measured as the
solution consumed until the meal is terminated as
the animal lets solution drip out of the mouth. These
decerebrated rats maintain the ability to terminate
their meal in response to changes in gastrointestinal
feedback, but are unable to compensate for variations in the caloric value of the fed solution,
resulting in anorexia if the sucrose concentration
is reduced. Similarly, removal of the post-oral
feedback (by e.g. vagus nerve transection or gastric
drainage) leads to increases in meal size as well as
duration [181, 182], although there is a compensatory delay in the latency to meal initiation,
possibly mediated by the hypothalamus. These
results underscore the role of the Arc as a metabolic
sensor. It should be pointed out that an intact Arc is
not necessary for meal initiation – humans and
animals with selective lesion of this region not only
eat, they eat copiously [29, 183–185].
It is now becoming evident that the brainstem can
integrate much the same signals as have been
shown to modulate hypothalamic activity. Leptin
receptors are expressed at several strategically
located brainstem sites, and selective stimulation of
these receptors suppresses food intake at doses
comparable with those used in forebrain injections
[186, 187]. Here, leptin activates the same medial
region of the nTS that is stimulated by gastric
distension [188], suggesting an anatomical site of
integration of long- and short-term feeding controls.
Likewise, melanocortin agonists can reduce feeding
and body weight by brainstem mechanisms [189].
Interestingly, the neurones in the nTS mediating the
viscerosensory signal may also be POMC-encoded
[43, 190], a finding that puts our understanding of
melanocortin-mediated meal suppression in a new
light. Orexigenic effects of ghrelin are also seen with
selective local administration both in the hypothalamus [84] and in the brainstem [191] (Fig. 5a,b).
Finally, glucosensitive neurones have been recorded
in the nTS [192]. Thus, the nTS is in no way a
Fig. 5 Ghrelin increases food intake following brainstem administration. Unilateral injection of 10 pmol (but not 5) of ghrelin
(black bars) into the dorsal vagal complex, including the nucleus
tractus solitarii, results in a significant increase of food intake both
1.5 and 3 h after drug administration compared with vehicle
(white bars), in an experiment by Faulconbridge et al. [191].
Reprinted with permission from the American Diabetes Association; Diabetes 2003;52:2260–2265.
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REVIEW: BRAIN CONTROL OF FOOD INTAKE
passive transducer of viscerosensory signals, but
serves to integrate numerous indices of the animal’s
metabolic state. This conclusion is supported by the
observation that the hyperphagia of rats that lack
leptin receptors is caused by larger meal size (i.e.
meal termination delay) rather than an increased
number of feeding bouts [193], suggesting an action
localized in the hindbrain. However, the response to
CCK (i.e. brainstem satiety signalling) as well as
normal meal size is restored in these animals
following selective re-establishment of leptin receptor expression in the Arc. Weighed together, these
data emphasize that actions of metabolically relevant hormone take place at a few, but distributed,
sites in the brain contributing to a coordinated
feeding response.
Beyond the primary sensors: CNS
integration of hunger and satiety signals
As in all matters involving the brain, behaviour begs
the question: What are the pathways? For the
metabolic signals to produce behaviour they need to
proceed further into the brain beyond the primary
sensors in the Arc and nTS and ultimately engage
regions that initiate and organize behavioural,
autonomic and endocrine response patterns. Histochemical studies have revealed that (i) the Arc
projections diverge widely throughout the brain
[194–197] including, via indirect pathways, a
massive cortical innervation [198] (Fig. 4), (ii) the
NPY and POMC populations project in remarkably
parallel paths [196] and may converge on the same
cells as supported by the widespread coexistence of
Y1 and MC4 receptors [199] (Fig. 3d), and (iii) the
nTS innervates largely the same nuclei as the
ascending projections from the Arc [196, 200–
202]. This circuitry indicates that integration
between the primary metabolic sensors in the Arc
and nTS is a distributed phenomenon, and it has
been suggested that this arrangement allows for
motivational state to be weighed into the network
before reconvergence and the final decision for a
proper metabolic response is made [40]. In addition
to this scheme, extensive reciprocal projections
connect the Arc with its target regions [203]. The
functional implications of this arrangement are not
clear at present. There may exist a sequential
arrangement hidden within the network that has
so far eluded the techniques used to investigate the
311
system. Another alternative is that the reciprocity
may produce a reverberating signal, such as the
large-scale oscillations described in, e.g. thalamocortical systems [204]. Possibly, such persistent
activity may be important in the triggering and
maintenance of an anabolic response. The hierarchical organization of the metabolic circuits and its
relationship to behaviour presents a major future
scientific challenge. (For further discussion of the
systems organization of energy balance regulation,
the reader is referred to recent exhaustive reviews
[37, 38].)
Coordinating the metabolic output
It also remains to explain how the divergence–
convergence organization of the Arc/nTS projections interdigitates with the efferent networks
underlying the final metabolic response. As
already mentioned, motivated behaviours (classically divided into ingestive, reproductive and defensive) involve three distinct outlets: components of
the autonomic and neuroendocrine systems as
well as coordinating the overall behaviour of the
animal [44]. Activity within these three effector
systems is hypothesized to be organized by a
collection of cell groups within the medial hypothalamus area, collectively termed the hypothalamic visceromotor pattern generator network
[205], which subsequently recruits elements within a ‘behavioural control column’, spanning the
mes- and diencephalic midline [206]. Separate
groups of control column nuclei produce ingestive,
reproductive and defensive behaviours, but connections between these networks allow them to
interact for purposes of mutual exclusion so that
only one behaviour is expressed at once [207].
The paraventricular nucleus (PVH; Fig. 3c) is a
crucial control column module for ingestive behaviour. The PVH collects metabolic information
from oropharyngeo- and viscerosensory receptors
and humoral signals (both directly and via the
Arc), and is regulated by biological rhythms via
the suprachiasmatic nucleus and by the overall
state of the animal as reported from the cerebral
hemispheres via relays in the septum [206].
Output from the PVH, in turn, employs all
three outlets described above: endocrine via neuroendocrine neurones controlling pituitary hormone
release, autonomic via direct projections to
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C. BROBERGER
preganglionic neurones in the spinal cord intermediolateral cell column (sympathetic) and the
dorsal motor nucleus of the vagus (parasympathetic), and behavioural (i.e. somatomotor) via several
pathways innervating the brainstem [137, 208–
210] (Figs 1 and 4). The hierarchical arrangement
upstream of these motor nuclei bears some similarity to the basal ganglia organization for the
control of conscious movement [206]. The details
of the underlying anatomy remain mysterious, but
it is clear that, rather than a simple sequential
organization where information flows neatly from
one collection of neurones to another, we are
faced with an interconnected series of ‘hubs’ that
collect, integrate and disseminate information.
Food intake in lower organisms: models for
the organization of behaviour
Intriguingly, an improved understanding of the
organization of feeding behaviour is now coming
from studies of lower organisms. Animals such as
the nematode Caenorhabditis elegans and the sea slug
Aplysia present several technical advantages: behaviour is easily divided into discrete sequences, the
nervous system consists of a limited number of
neurones whose electrical properties and interconnectivity has been characterized in detail, and, in the
case of C. elegans, the genome is highly accessible for
molecular manipulation. This knowledge makes it
possible to understand how nature organizes physical networks to efficiently initiate, organize and
terminate behaviour.
Caenorhabditis elegans
Feeding in C. elegans is polymorphic; depending on
genetic background animals will feed either alone or
in aggregates [211–213]. Naturally occurring variations in a single amino acid position of the
neuropeptide receptor NPR-1 (for neuropeptide
receptor resemblance-1) translate into either a
solitary or a social feeding phenotype [212]. Activation of NPR-1, by shifting network properties,
leads to activation of social feeding behaviour, and
the amino acid substitution in NPR-1 determines the
response to stimulation with the neuropeptide
ligands flp 18 or )21 [214]. Conversely, null
mutations in the npr-1 locus alter the balance in
favour of solitary feeding [214]. Thus, a single gene
is sufficient to redirect behaviour. Intriguingly, the
predicted transmembrane domains of NPR-1 display
considerable homology to mammalian NPY receptors [212], suggesting that similar molecular components underlie related behaviours throughout
evolution. Recent data demonstrate that within this
network an important upstream regulator of NPR-1mediated feeding is oxygen concentration, showing
how external cues reset behaviour [215, 216].
Aplysia
In Aplysia, a meticulously dissected network has
been highly informative in characterizing the neural
mechanisms underlying various behavioural components. Aplysia feeding can be initiated by sensory
stimulation of the lip and is consolidated by arousal
caused by the exposure to food. In parallel with the
feeding central pattern generator (CPG) circuit, a
network controlling arousal is triggered, which then
feeds back into the CPG [217]. Termination of food
intake is achieved by switching ingestion to the
opposite behaviour of egestion [218]. Separate
motor neurones within the CPG effectuate ingestion
and egestion. Switching the balance between these
neurones is elegantly accomplished by recruiting a
single additional interneurone into the circuitry via
an electrical synapse [219]. Feeding patterns in this
social mollusc also differ substantially in the absence
or presence of other animals; company is an
important incentive for feeding. Pheromones secreted from other Aplysia stimulate a neurone directly
driving the appetitive phase of feeding, which also
excites a control neurone for the consummatory
phase so that these behaviours are properly organized, leading to larger and more frequent eating
bouts [220]. These studies provide information on
how organization within a neural system translates
into behaviour, with potentially broad implications
considering the surprisingly large overlaps between
human and mollusc feeding behaviour. Importantly,
they may shed light on the process of selection
within the behavioural repertoire and why we eat in
apparent violation of homeostatic mechanisms
when our fat stores are filled to the brim.
Food reward: role of the nucleus accumbens
However, to elucidate the neural organization of
feeding in complex vertebrates, it is necessary to
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REVIEW: BRAIN CONTROL OF FOOD INTAKE
consider that our choice of food is not simply a
function of energy supply and demand, but also very
much linked to reward value. Homeostatic systems
active within the brain operate at the mercy of
motivational states. The motivational state is a
product of, inter alia, limbic influences relayed in
part via the amygdala, and reward factors. Obviously, adding reward experience to food is a means
of, e.g. avoiding consumption of foods whose taste
indicate the presence of invasive microorganisms,
but also promoting those whose taste signals
particular nutritional value. As a result, pairing
feeding with pleasure may override normal satiety
mechanisms, resulting in hyperphagia and obesity.
The concept of reward is intimately linked to that of
addiction, and it has been suggested that obesity is a
consequence of an addiction to food [221]. Drugs of
abuse converge upon the mesolimbocortical system
to produce reward, specifically by enhancing dopamine release in the nucleus accumbens (Acb) of the
forebrain as a final common pathway [222]. There
is little doubt that changes in dopaminergic transmission affects food intake. Indeed, animals unable
to produce brain dopamine die of starvation unless
fed by gavage [223], and a common side-effect of
neuroleptics affecting dopamine signalling is obesity
[224]. However, novel data suggest that dopamine
primarily acts to reinforce behaviours at the initial
encounter with a novel reward, but the release of
dopamine decreases once the behaviour has been
established within the behavioural repertoire [225].
Thus, whilst dopamine modulates learning and
locomotion associated with motivational behaviour,
it appears not to modulate feeding behaviour per se;
blocking Acb dopamine signalling does not alter
total food consumption in starved rats, although it
suppresses ambulation associated with feeding
[226].
However, transmitter systems other than the
dopaminergic system connect Acb to components
of the metabolic circuitry [227]. Notably, chronic
access to a preferred flavour (chocolate-fat solution)
produces the same transmitter changes in the Acb
as chronic morphine or ethanol, suggesting a
common reward mechanism for palatable food
and conventional drugs of abuse [228]. These
changes include increased transcription of opioid
peptides such as enkephalin. In turn, stimulating lopioid receptors in the Acb increases intake of fatenriched foods with high palatability value [229],
313
which may be interpreted as positive reinforcement.
This effect is not seen following inhibition of neural
transmission in the basolateral amygdala (BLA) or
the LHA [230]. The connection between the BLA
and forebrain cortical regions has been implicated
in gauging food palatability, and an intact BLA is
required for determining the reward value embedded in sensory input [231]. In contrast, the central
amygdala (CeA) serves more like a general gatekeeper of feeding as inactivation of this subnucleus
blocks consumption of all foods [230]. This dichotomy may be explained by the different projections
of the BLA (innervating higher forebrain regions
such as the prefrontal cortex) and the CeA (aimed
towards the postulated hypothalamic and brainstem feeding pattern generators). The connection
between the Acb and the LHA has also been shown
to modulate food intake (Fig. 4). Kelley and
colleagues have shown that blocking excitation of
the GABA-encoded Acb results in hyperphagia, an
effect contingent upon intact transmission in the
LHA [232]. Glutamatergic excitation in the Acb is
predominantly supplied by the cortex, so that this
cortex-Acb-LHA pathway could offer the prefrontal
cortex in particular a channel for inhibiting feeding
behaviour in favour of other behaviours [227].
These data indicate that in the regulation of
ingestive behaviour, the Acb is indeed at the
interface between ‘motivation and action’ as originally postulated for this structure [233].
Studies on the food intake experience in
humans and monkeys: relevance for
understanding obesity
Defining the cortical involvement in feeding behaviour is likely vital for understanding human
eating disorders. Crosstalk between the cerebral
cortex and primary sensors is extensive; impressively, the hypothalamus provides the largest
external cortical input with the exception of the
thalamus [198], and reciprocal connections are
plenteous [234]. Investigations of monkeys and
humans by Rolls and collaborators have revealed
that the sensory properties of food are processed in
two steps in the cortex [see 235]. The insular
cortex, functionally and neuroanatomically implicated as viscerosensory cortex [236], acts as a
primary taste cortex where these individual features, i.e. taste, appearance, smell and texture, are
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C. BROBERGER
represented to determine which food is being
ingested. Individual neurones are sensitive to
single stimuli, and do not adapt their firing even
when the stimulus (e.g. glucose) has been present
for a long time [237]. The orbitofrontal cortex
(which receives direct input from the insular
cortex), however, acts as a higher-order taste
cortex, which determines how pleasant a particular
food is. Orbitofrontal neurones are broadly tuned
to react to multiple sensory features, so that the
firing of these cells result from the combined
inputs from several sensory modalities [238],
although different cells respond to different quantitative combinations of stimuli. The subjective
pleasantness rating is proportional to orbitofrontal
activation and this activation drops accordingly
when a particular food is eaten to satiety [239]
(Fig. 6). Thus, computations within the orbitofrontal cortex confer hedonic qualities upon the
feeding circuitry, a role whose importance in
human appetite may be underestimated when
extrapolating from rodent studies. The orbitofrontal cortex feeds directly into the LHA, which may
thus constitute an important nexus for linking the
subjective experience of food with homeostatic
signals.
The relationship of the hedonic/pleasure experience to human obesity has begun to be addressed in
neuroimaging studies, further emphasizing the cortical parcellation of different feeding-related processing. Whereas during hunger, activation is observed
predominantly in regions associated with the regulation of emotions (limbic and paralimbic cortex),
satiety is followed by activation in the prefrontal
cortex, postulated to play a role in the inhibition of
inappropriate behaviours [240]. The presentation of
a palatable sweet solution after a day and a half
of fast resulted in increased signal from the insular
cortex [241]. Moreover, almost all observed changes
are accentuated in obese compared with lean
subjects, i.e. both increases and decreases in activity
are of greater amplitude [241] (Fig. 7). These
differences are not exclusively accounted for by the
hyperglycaemia and hyperinsulinaemia manifest in
obese subjects. The functional implication of the
intensified patterns of activation and inactivation in
obese subjects is not clear at present, but may be of
pathophysiological importance. Indeed, these responses persist also after weight loss in postobese
subjects [242] suggesting that they are not a
consequence of the overweight as such, although
it is not known if such accentuated responses are
seen also prior to the development of obesity.
Elucidating these mechanisms may be significant
also for understanding the human response to food
advertisements.
40
banana odour
Firing rate
30
Blackcurrant odour
(spikes s–1)
mango odour
pe
ct
on
20
Spontaneous
10
Behavioural
response to
satiating
food
+2
+1
0
-1
-2
0
50
80
mL
Volume of 20% blackcurrant juice
Fig. 6 Neurones in the orbitofrontal cortex decrease their firing in
response to a particular food as that
food is consumed to satiety. Extracellular recording from an odourresponsive neurone in the orbitofrontal cortex of a male macaque.
The firing rate of one neurone in
response to different odours was
recorded whilst the animal consumed a blackcurrant juice. As
satiety increases (lower panel), the
electrophysiological response to
blackcurrant odour diminishes,
whereas the response to unrelated
odours [banana, mango, phenyl
ethanal (pe), citral (ct), onion (on)]
is unaffected or elevated. Figure
produced by H.D. Critchley and
E.T. Rolls and is used with permission from the American Physiological Society; J Neurophysiol
1996;75:1673–1686.
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REVIEW: BRAIN CONTROL OF FOOD INTAKE
315
Fig. 7 Lean and obese subjects show differences in brain activation during different states of hunger. Statistical parametric maps of
significant brain responses (P £ 0.005, not corrected for multiple comparisons) to hunger and early satiety in obese (top row) and lean
(bottom row) subjects, respectively, at 4 mm above (left images), 4 mm below (middle images), and 16 mm below (right images) a
horizontal plane passing through the anterior and posterior commissures (coordinates from the Montreal Neurological Institute). The right
hemisphere in each section is on the reader’s right. The T-value colour-coded areas were regions of the brain in which significant
changes in blood flow (a marker of neural activity) were detected in response to hunger (from yellow to white, in increasing order of
T-value), as stimulated by a 36-h fast, or in response to early satiety (from blue to green, in increasing order of T-value), as stimulated by
consumption of a satiating liquid meal [304]. The figure is intended for visual inspection only of several brain regions, where significantly
greater responses in obese compared with lean individuals were detected, including the middle temporal gyrus (TEMP) insula (INS),
dorsolateral prefrontal cortex (DLPFC), hippocampus (HIPP), temporal pole (T.POLE), orbitofrontal cortex (OFC), and ventrolateral
prefrontal cortex (VLPFC). Figure generously provided by Dr Angelo DelParigi.
Development of the feeding circuitry
A series of recent studies have shed light both on the
normal ontogenetic development of hypothalamic
circuits as well as how these processes are influenced
by the nutritional state of the young animal, with
important implications for the aetiology of obesity. At
birth, the hypothalamus is rather sparsely innervated by Arc NPYergic fibres, and in, e.g. the PVH a
substantial NPY/AGRP innervation is seen first at
postnatal day (P) 15 [197, 243, 244]. Similarly,
whilst Arc NPY and AGRP mRNAs are detectable
from birth, levels peak at P15, and drop to adult
levels by P30 [244] (Fig. 8). This development
parallels the maturation of the ability to regulate
suckling in response to caloric demands [245],
linking changes within the Arc metabolic sensor
and adult control of feeding. Notably, failure in the
development of the Arc is associated with fatal
anorexia in a genetic model [246, 247]. It should be
mentioned, that during the early postnatal period,
and under certain physiological circumstances, transient expression of NPY in other hypothalamic nuclei
can be seen [243, 248]. The role of these transitory
NPY projections remains to be determined.
As the Arc provides a main conduit for leptin, it is
perhaps not surprising, given these data, that pups
are unable to respond to leptin by changing their
food intake [249], nor to ghrelin [250]. Yet, there is
a pronounced peak in serum leptin prior to weaning
[251]. Recent data from Bouret et al. [252] suggest
that a postnatal leptin surge is essential for the
development of Arc projections. In adult ob/ob mice,
there is a distinct paucity of Arc-derived terminals.
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C. BROBERGER
Fig. 8 Arc NPY/AGRP projections to the PVH develop during the postnatal period in the rat. Figure displays confocal micrographs of
double-label immunofluorescence for NPY (red) and AGRP (green) in the PVH. Double-labelled fibres are shown in yellow. These images
demonstrate that at postnatal day 5 (P5) that there are minimal Arc NPY/AGRP projections to the PVH, whilst there is an abundance
of NPY fibres that originate from other sources. By P10 there is a significant concentration of Arc NPY/AGRP projection in the PVH, but
they do not reach the adult levels until around P15. Images represent a 10-lm thick collection of optical sections collected at 0.5-lm
intervals. Images were captured with a 25· oil objective (0.75 NA) and represent an area of 400 · 400 lm. Figure generously provided
by Dr Kevin Grove.
However, administration of leptin to ob/ob mice
during early development, but not in adulthood,
results in innervation patterns similar to what is
seen in lean littermates, in parallel with a normalization of body weight. These data provide a novel
mechanism for how nutritional signals in the early
postnatal stage exerts long-lasting effects on the
metabolic wiring in the adult. It will be of interest to
determine if similar mechanisms are at play in the
development of the brainstem-vagal system. In this
context, the importance of the prenatal metabolic
environment should also be remembered. Gestational diabetes and obesity is associated with obesity
in the offspring of both rats [253] and humans
[254]. An extensive long-term study is currently in
progress to investigate what changes can be seen in
central metabolic circuits in nonhuman primates
following intrauterine exposure to diabetes [255].
Conversely, changes in hypothalamic circuitry during senescence may contribute to the loss of appetite
that often accompanies ageing [17]. Such changes
are observed in older rats, who display significantly
lower levels of expression of NPY [256] and POMC,
as well as POMC-positive neurones [257] and
diminished dendritic arbours [258] in the arcuate
nucleus compared with younger animals.
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REVIEW: BRAIN CONTROL OF FOOD INTAKE
Mechanisms of anorexia in infection and
cancer
The central systems mediate not only obesity but also
anorexia of various aetiologies. Infection-based anorexia is a well-established and clinically highly relevant model [259], which has been instrumental in
uncovering the pathways through which microorganisms cause reduced food intake. Bacterial components such as LPS from Gram-negative bacteria and
muramyl dipeptide from Gram-positive bacteria activate CD14- and Toll-like receptors on host T-cells to
induce production of cytokines such as interferon-c;
these results are corroborated by experiments
employing genetic removal of strategic components
along the pathway [260]. Cytokines are produced
peripherally, but activate vagal afferents [261]. In
addition, cytokines stimulate prostaglandin production via the enzyme cyclooxygenase 2 (COX-2) in
cerebral endothelial and perivascular cells [262]. This
latter pathway is important for the induction of LPSinduced anorexia, and can be blocked with indomethacin and other, more selective, COX-2 inhibitors
[263]. Further downstream, the prostaglandins activate neurones producing serotonin (5-HT; [264]), a
known anorexigenic transmitter [265, 266], which
in turn has recently been shown, via 5-HT2C receptors, to stimulate melanocortin signalling [267].
Thus, the signalling cascade set off by pathogenic
bacteria ultimately results in activation of the central
anorexigenic system. These results may shed light
also on the anorexia accompanying noninfectious
inflammatory conditions. In this context it is interesting to note that, based on structure and signalling
pathways, leptin itself belongs to the cytokine family
[268, 269].
While anorexia is an important component also of
wasting in cancer patients, nutritional supplements
only alleviate part of the cachectic syndrome [270],
which accounts for a fifth of cancer deaths [271].
Cachexia differs from starvation in that both adipose
and lean mass is lost, whereas starvation primarily
decreases fat stores [272]. A main explanation for
this relationship is that many cancer tumours
secrete proteins, e.g. proteolysis-inducing factor
[273], which suppress protein synthesis in skeletal
muscle, via activation of an ubiquitin proteolytic
pathway [274]. Parenteral nutrition may thus be of
very limited value to the patient if such catabolic
mechanisms are not interrupted. However, it turns
317
out that a polyunsaturated fatty acid found in fish,
eicosapentaenoic acid (EPA), suppresses the activity
of the proteolytic complex whilst simultaneously
inhibiting tumour growth [275]. This finding has
promising bedside implications; adding EPA to the
diet of cancer patients attenuates muscle degradation and stabilizes body weight [276].
From rodent to human: genetic dissection
In few fields of medicine is the question of nature
versus nurture more immediate than in the regulation of body weight. While it is evident that the
incidence of obesity has accelerated far more rapidly
than can be explained by population shifts within the
genome, it is also true that individual differences
determine how we react in an energy-dense environment. Aptly summed up by Olden and Wilson [277]:
genes load the gun, environment pulls the trigger.
Studies of monozygotic twins show that the heritable
component of obesity equals that of height and
surpasses virtually every other major disease studied,
e.g. breast cancer, schizophrenia, cardiovascular
disease [278–280]; some 40% of obesity can be
attributed to genetic causes [281]. In a series of
elegant studies, in particular by O’Rahilly, Farooqi
and their colleagues, it has been shown that mutations in several components of the anorexigenic signal
chain, including leptin [282] (Fig. 9), the leptin
receptor [283], POMC [284] and neuropeptide processing enzymes [285] result in severe early-onset
obesity in humans. While these monogenic disorders
incontrovertibly demonstrate that genetic abnormalities can cause obesity, it cannot automatically be
concluded that mutations and sequence variants are
common causes of the metabolic syndrome.
However, it is now becoming apparent that
mutation of a particular key signalling protein, the
MC4R [286], accounts for as many as 5% of cases
of severe obesity [140, 287–289]. There is a
remarkably solid relationship between the severity
of the mutation, as revealed in in vitro assays, and
the size of a test meal consumed by the patient
[140]. Indeed, the heritable component is almost
exclusively represented by increased intake of
energy, with only a small component accounted
for by changes in resting metabolic rate [140]. (In
contrast, in the mouse MC4R)/) counterpart,
deficient energy expenditure is an important factor
underlying overweight [136].) The sometimes
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
318
C. BROBERGER
Fig. 9 Leptin deficiency in humans responds to leptin treatment.
A 3-year-old boy with congenital leptin deficiency with severe
obesity (body weight 38 kg; BMI SD ¼ 7.2) (left). On the right,
the same patient, after four years of daily subcutaneous administration of recombinant leptin. Leptin treatment results in a
dramatic decrease in adiposity (body weight 29 kg; BMI SD ¼
0.9) and normalization of all metabolic abnormalities including
hyperinsulinaemia. Figure generously provided by Drs Sadaf
Farooqi and Stephen O’Rahilly.
modest phenotypes observed in rodent gene knockout experiments (e.g. NPY gene deletion [125])
have been interpreted as evidence for a high
degree of redundancy within the system underlying metabolic regulation. However, genetic studies such as these (as well as, notably, observed in
nematodes [212]), suggest that there are weak
points distributed throughout the system where
minute changes in nucleotide sequence can have
profound effects on the expression of behaviour.
These vulnerable links along the metabolic signalling chain offer promising targets for therapeutic
intervention.
Therapeutic prospects
As pointed out in the Introduction, effective treatments for eating disorders are short in supply and
urgently needed. While much can be gained simply
by increased efforts to educate patients in the
benefits of weight loss and exercise [290, 291], it
is also clear that such therapies in many cases fail in
the absence of adequate pharmacological buttress.
The anti-obesity drugs presently used in clinical
practice have relatively modest effects, and others
still have been withdrawn due to intolerable cardiovascular adverse effects [22]. These drugs have often
targeted broadly distributed systems, e.g. serotonin
pharmacology, and it is perhaps not surprising that
alterations ensue within multiple body functions.
Another issue to consider is the timing of administration of feeding-regulatory drugs, which may be
more crucial than in any other therapeutic application (T. Bartfai, personal communication). However,
based largely on the research summarized above,
several novel compounds are now being tested in
clinical trials, phases II and III [22, 292]. Many of
these compounds target neuropeptide systems. The
selective neuroanatomical distribution of many
neuropeptides may provide an advantage in
attempting to minimize side-effects, and whilst the
field of peptide-based pharmaceuticals has not lived
up to initial hopes, the clinical experience from
opioid drugs such as morphine and naloxone [293]
suggest that interfering with peptide signalling can
produce powerful neuropsychiatric effects in
humans [294]. In particular, drug development
initiatives have centred on the melanocortin system
[295], encouraged by the human genetic
data reviewed above, and several nonpeptide compounds are now being tested in a clinical setting
[22].
The cannabinoid system also provides an attractive target, with promising early results with the
inverse CB1 receptor agonist, rimonabant [296],
currently in phase III clinical trial. Initial evaluations suggest that rimonabant decreases body
weight by ca 5–10%, with beneficial effects also on
insulin resistance and dyslipidaemia [292]. Interestingly, this drug has the added benefit of facilitating
smoke cessation. However, the full safety profile of
rimonabant has not yet been released. Conversely,
the active component of marijuana, D9-tetrahydrocannabinol, is also being evaluated for treatment of
AIDS-associated anorexia [297].
Early hopes for a leptin-based obesity regimen
were quelled by clinical trials showing only very
limited weight loss following leptin administration to
obese subjects [298], and there are also indications
that such treatment may in itself produce the leptin
resistance hypothesized to be a part of obesity [299].
It should be pointed out, however, that in the rare
cases of genetic leptin-deficiency, treatment with
recombinant leptin has virtually normalized body
weight in near-fatally obese children, whilst simultaneously inducing age-appropriate puberty [300]
(Fig. 9). The same treatment has also been used to
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
successfully rectify several of the metabolic abnormalities associated with lipodystrophy [301, 302].
Furthermore, pertaining to a not uncommon diagnosis, leptin treatment has recently been demonstrated as a highly promising therapy for functional
amenorrhoea [303].
Conclusion
In summary, significant advances in our understanding of feeding behaviour have been achieved
using a combination of clinical, behavioural, electrophysiological, anatomical, genetic and imaging
techniques. This investigation has defined an underlying circuitry and neuropharmacology, which can
now be probed for therapeutic targets. Thus, whilst
many questions remain to be answered, in particular regarding the causal mechanisms of obesity and
anorexia as well as the central circuitry bridging
metabolic input and output, there is reason for hope
in offering effective treatments for these exceptionally common and debilitating disorders.
Conflict of interest statement
No conflict of interest was declared.
Acknowledgements
The author gratefully acknowledges generous financial support from Wenner-Gren Stiftelserna, Vetenskapsrådet, Jeanssons Stiftelser, Hagbergs Stiftelse,
Rut och Arvid Wolffs Stiftelse, Thurings Stiftelse,
Svenska Läkaresällskapet, Åke Wibergs Stiftelse, Kgl.
Vetenskapsakademien, Hedlunds Stiftelse, Magnus
Bergvalls Stiftelse, Lars Hiertas Minne, Axel Linders
Stiftelse, Längmanska Kulturfonden, Teodor Neranders Fond and internal funds of Karolinska Institutet.
References
1 Galbraith JK. The New Industrial State. Boston, MA: Houghton Mifflin, 1967.
2 World Health Organization. Obesity: Preventing and Managing
the Global Epidemic. Geneva: World Health Organization,
2000.
3 National Task Force on the Prevention and Treatment of
Obesity. Overweight, obesity, and health risk. Arch Intern
Med 2000; 160: 898–904.
4 World Health Organization. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser
2003; 916: i–viii, 1–149, backcover.
319
5 Maclure KM, Hayes KC, Colditz GA, Stampfer MJ, Speizer FE,
Willett WC. Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N Engl J Med 1989; 321:
563–9.
6 Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan
RF. Obesity and knee osteoarthritis. The Framingham Study.
Ann Intern Med 1988; 109: 18–24.
7 Grodstein F, Goldman MB, Cramer DW. Body mass index
and ovulatory infertility. Epidemiology 1994; 5: 247–50.
8 Rexrode KM, Hennekens CH, Willett WC et al. A prospective
study of body mass index, weight change, and risk of stroke
in women. JAMA 1997; 277: 1539–45.
9 Scheinfeld NS. Obesity and dermatology. Clin Dermatol
2004; 22: 303–9.
10 Gottschlich MM, Mayes T, Khoury JC, Warden GD. Significance of obesity on nutritional, immunologic, hormonal,
and clinical outcome parameters in burns. J Am Diet Assoc
1993; 93: 1261–8.
11 Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr.
Body-mass index and mortality in a prospective cohort of
U.S. adults. N Engl J Med 1999; 341: 1097–105.
12 Puhl R, Brownell KD. Bias, discrimination, and obesity. Obes
Res 2001; 9: 788–805.
13 Pontiroli AE. Type 2 diabetes mellitus is becoming the most
common type of diabetes in school children. Acta Diabetol
2004; 41: 85–90.
14 Hoek HW, van Hoeken D. Review of the prevalence and
incidence of eating disorders. Int J Eat Disord 2003; 34: 383–
96.
15 Plata-Salaman CR. Cytokines and feeding. News Physiol Sci
1998; 13: 298–304.
16 Strasser F, Bruera ED. Update on anorexia and cachexia.
Hematol Oncol Clin North Am 2002; 16: 589–617.
17 Briefel RR, McDowell MA, Alaimo K et al. Total energy intake of the US population: the third National Health and
Nutrition Examination Survey, 1988–1991. Am J Clin Nutr
1995; 62: 1072S–80S.
18 Johnson D, Drenick EJ. Therapeutic fasting in morbid obesity. Arch Intern Med 1977; 137: 1381–2.
19 Mitchel JS, Keesey RE. Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: evidence from a restriction-refeeding regimen. Physiol Behav
1977; 18: 1121–5.
20 Sims EA, Danforth E Jr, Horton ES, Bray GA, Glennon JA,
Salans LB. Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 1973; 29:
457–96.
21 Neel JV. Diabetes mellitus: a ‘‘thrifty’’ genotype rendered
detrimental by ‘‘progress’’? Am J Hum Genet 1962; 14: 353–
62.
22 Farrigan C, Pang K. Obesity market overview. Nat Rev Drug
Discov 2002; 1: 257–8.
23 Sjöström L, Lindroos AK, Peltonen M et al. Lifestyle, diabetes,
and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 2683–93.
24 Bergh C, Brodin U, Lindberg G, Sodersten P. Randomized
controlled trial of a treatment for anorexia and bulimia
nervosa. Proc Natl Acad Sci U S A 2002; 99: 9486–91.
25 Mohr B. Hypertrophie der Hypophysis cerebri und adurch
bedingter Druck auf die Hirngrundfläche, ins besondere auf
die Sehnerven, das Chiasma derselben und den linkseitigen
Hirnschenkel. Wschr ges Heilk 1840; 6: 565–71.
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
320
C. BROBERGER
26 Babinski MJ. Tumeur du corps pituitaire sans acromégalie et
avec arrêt de développement des organes génitaux. Rev
Neurol 1900; 8: 531–3.
27 Fröhlich A. Ein Fall von Tumor der Hypophysis cerebri ohne
Akromegalie. Wien Klin Rundschau 1901; 15: 883–6, 906–
8.
28 Bray GA, Gallagher TF Jr. Manifestations of hypothalamic
obesity in man: a comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore)
1975; 54: 301–30.
29 Aschner B. Über die funktion der hypophyse. Arch f d ges
Physiol 1912; 146: 1–146.
30 Hetherington AW, Ranson SW. Hypothalamic lesions and
adiposity in the rat. Anat Rec 1940; 78: 149–72.
31 Anand BK, Brobeck JR. Hypothalamic control of food intake
in rats and cats. Yale J Biol Med 1951; 24: 123–40.
32 Anand BK, Brobeck JR. Localization of a ‘‘feeding center’’ in
the hypothalamus of the rat. Proc Soc Exp Biol Med 1951;
77: 323–4.
33 Grill HJ, Norgren R. Chronically decerebrate rats demonstrate
satiation but not bait shyness. Science 1978; 201: 267–9.
34 Kennedy GC. The role of depot fat in the hypothalamic
control of food intake in the rat. Proc R Soc Lond B Biol Sci
1953; 140: 578–96.
35 MacLagan NF. The role of appetite in the control of body
weight. J Physiol 1937; 90: 385–94.
36 Stellar E. The physiology of motivation. Psychol Rev 1954;
61: 5–22.
37 Berthoud HR. Multiple neural systems controlling food
intake and body weight. Neurosci Biobehav Rev 2002; 26:
393–428.
38 Grill HJ, Kaplan JM. The neuroanatomical axis for control of
energy balance. Front Neuroendocrinol 2002; 23: 2–40.
39 Khosla T, Billewicz WZ. Measurement of change in bodyweight. Br J Nutr 1964; 18: 227–39.
40 Broberger C, Hökfelt T. Hypothalamic and vagal neuropeptide circuitries regulating food intake. Physiol Behav 2001;
74: 669–82.
41 Ramón y Cajal S. Histologie du système nerveux de l’homme et
des vertébrés. Oxford: Oxford University Press (republ. 1995),
1909.
42 Harding R, Leek BF. Central projections of gastric afferent
vagal inputs. J Physiol 1973; 228: 73–90.
43 Appleyard SM, Bailey TW, Doyle MW et al. Proopiomelanocortin neurons in nucleus tractus solitarius are activated by
visceral afferents: regulation by cholecystokinin and opioids.
J Neurosci 2005; 25: 3578–85.
44 Swanson LW, Mogenson GJ. Neural mechanisms for the
functional coupling of autonomic, endocrine and somatomotor responses in adaptive behavior. Brain Res 1981; 228: 1–34.
45 Smith GP. The direct and indirect controls of meal size.
Neurosci Biobehav Rev 1996; 20: 41–6.
46 Sclafani A, Ackroff K, Schwartz GJ. Selective effects of vagal
deafferentation and celiac-superior mesenteric ganglionectomy on the reinforcing and satiating action of intestinal
nutrients. Physiol Behav 2003; 78: 285–94.
47 Gibbs J, Young RC, Smith GP. Cholecystokinin decreases
food intake in rats. J Comp Physiol Psychol 1973; 84: 488–
95.
48 Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ.
Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 1981; 213: 1036–7.
49 Schwartz GJ, McHugh PR, Moran TH. Integration of vagal
afferent responses to gastric loads and cholecystokinin in
rats. Am J Physiol Regul Integr Comp Physiol 1991; 261:
R64–9.
50 Schwartz GJ, McHugh PR, Moran TH. Gastric loads and
cholecystokinin synergistically stimulate rat gastric vagal
afferents. Am J Physiol Regul Integr Comp Physiol 1993; 265:
R872–6.
51 Sykes RM, Spyer KM, Izzo PN. Demonstration of glutamate immunoreactivity in vagal sensory afferents in the
nucleus tractus solitarius of the rat. Brain Res 1997; 762:
1–11.
52 Broberger C, Holmberg K, Kuhar MJ, Hökfelt T. Cocaine- and
amphetamine-regulated transcript in the rat vagus nerve: a
putative mediator of cholecystokinin-induced satiety. Proc
Natl Acad Sci U S A 1999; 96: 13506–11.
53 Aja S, Schwartz GJ, Kuhar MJ, Moran TH. Intracerebroventricular CART peptide reduces rat ingestive behavior and
alters licking microstructure. Am J Physiol Regul Integr Comp
Physiol 2001; 280: R1613–9.
54 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,
Friedman JM. Positional cloning of the mouse obese gene
and its human homologue. Nature 1994; 372: 425–32.
55 Ahima RS, Prabakaran D, Mantzoros C et al. Role of leptin in
the neuroendocrine response to fasting. Nature 1996; 382:
250–2.
56 Halaas JL, Gajiwala KS, Maffei M et al. Weight-reducing
effects of the plasma protein encoded by the obese gene.
Science 1995; 269: 543–6.
57 Maffei M, Halaas J, Ravussin E et al. Leptin levels in human
and rodent: measurement of plasma leptin and ob RNA in
obese and weight-reduced subjects. Nat Med 1995; 1: 1155–
61.
58 Flier JS. Obesity wars: molecular progress confronts an
expanding epidemic. Cell 2004; 116: 337–50.
59 Cohen P, Zhao C, Cai X et al. Selective deletion of leptin
receptor in neurons leads to obesity. J Clin Invest 2001; 108:
1113–21.
60 Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake
and body weight of baboons. Nature 1979; 282: 503–5.
61 Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L.
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 2002; 5:
566–72.
62 Nicolaı̈dis S, Rowland N. Metering of intravenous versus oral
nutrients and regulation of energy balance. Am J Physiol
1976; 231: 661–8.
63 Woods SC, Stein LJ, McKay LD, Porte D Jr. Suppression of
food intake by intravenous nutrients and insulin in the baboon. Am J Physiol 1984; 247: R393–401.
64 Parra-Covarrubias A, Rivera-Rodriguez I, Almaraz-Ugalde
A. Cephalic phase of insulin secretion in obese adolescents.
Diabetes 1971; 20: 800–2.
65 Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic
insulin signaling is required for inhibition of glucose production. Nat Med 2002; 8: 1376–82.
66 Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metab 2005; 1: 53–
61.
67 Strader AD, Woods SC. Gastrointestinal hormones and food
intake. Gastroenterology 2005; 128: 175–91.
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
68 Lundberg JM, Tatemoto K, Terenius L et al. Localization of
peptide YY (PYY) in gastrointestinal endocrine cells and
effects on intestinal blood flow and motility. Proc Natl Acad
Sci U S A 1982; 79: 4471–5.
69 Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak
JM, Bloom SR. Human distribution and release of a putative
new gut hormone, peptide YY. Gastroenterology 1985; 89:
1070–7.
70 Adrian TE, Bacarese-Hamilton AJ, Smith HA, Chohan P,
Manolas KJ, Bloom SR. Distribution and postprandial release
of porcine peptide YY. J Endocrinol 1987; 113: 11–14.
71 Greeley GH Jr, Hashimoto T, Izukura M et al. A comparison
of intraduodenally and intracolonically administered nutrients on the release of peptide-YY in the dog. Endocrinology
1989; 125: 1761–5.
72 Morley JE, Flood JF. An investigation of tolerance to the
actions of leptogenic and anorexigenic drugs in mice. Life Sci
1987; 41: 2157–65.
73 Batterham RL, Cowley MA, Small CJ et al. Gut hormone
PYY(3-36) physiologically inhibits food intake. Nature 2002;
418: 650–4.
74 Tschöp M, Castaneda TR, Joost HG et al. Physiology: does
gut hormone PYY3-36 decrease food intake in rodents?
Nature 2004, 430: 165.
75 Batterham RL, Cowley MA, Small CJ et al. Physiology: does
gut hormone PYY3-36 decrease food intake in rodents?
(reply). Nature 2004; 430: 165.
76 Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY3-36
inhibits food intake in mice through a melanocortin-4
receptor-independent mechanism. Endocrinology 2004; 145:
2585–90.
77 Pittner RA, Moore CX, Bhavsar SP et al. Effects of PYY[3-36]
in rodent models of diabetes and obesity. Int J Obes Relat
Metab Disord 2004; 28: 963–71.
78 Batterham RL, Bloom SR. The gut hormone peptide YY
regulates appetite. Ann N Y Acad Sci 2003; 994: 162–8.
79 Imamura M, Takahashi H, Mikami Y, Yamauchi H. Elevation of plasma peptide YY and pancreatic juice hypersecretion following massive small bowel resection in the rat.
Tohoku J Exp Med 1998; 184: 49–59.
80 Adrian TE, Savage AP, Fuessl HS, Wolfe K, Besterman HS,
Bloom SR. Release of peptide YY (PYY) after resection of
small bowel, colon, or pancreas in man. Surgery 1987; 101:
715–9.
81 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H,
Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656–60.
82 Kojima M, Kangawa K. Ghrelin: structure and function.
Physiol Rev 2005; 85: 495–522.
83 Wren AM, Small CJ, Ward HL et al. The novel hypothalamic
peptide ghrelin stimulates food intake and growth hormone
secretion. Endocrinology 2000; 141: 4325–8.
84 Wren AM, Small CJ, Abbott CR et al. Ghrelin causes
hyperphagia and obesity in rats. Diabetes 2001; 50: 2540–7.
85 Nakazato M, Murakami N, Date Y et al. A role for ghrelin
in the central regulation of feeding. Nature 2001; 409:
194–8.
86 Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased
in human obesity. Diabetes 2001; 50: 707–9.
87 Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse
BE, Weigle DS. A preprandial rise in plasma ghrelin levels
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
321
suggests a role in meal initiation in humans. Diabetes 2001;
50: 1714–9.
Masuda Y, Tanaka T, Inomata N et al. Ghrelin stimulates
gastric acid secretion and motility in rats. Biochem Biophys
Res Commun 2000; 276: 905–8.
Date Y, Murakami N, Toshinai K et al. The role of the gastric
afferent vagal nerve in ghrelin-induced feeding and growth
hormone secretion in rats. Gastroenterology 2002; 123:
1120–8.
Wang L, Saint-Pierre DH, Tache Y. Peripheral ghrelin
selectively increases Fos expression in neuropeptide Y-synthesizing neurons in mouse hypothalamic arcuate nucleus.
Neurosci Lett 2002; 325: 47–51.
Shintani M, Ogawa Y, Ebihara K et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic
peptide that antagonizes leptin action through the activation
of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 2001; 50: 227–32.
Lu S, Guan JL, Wang QP et al. Immunocytochemical
observation of ghrelin-containing neurons in the rat arcuate
nucleus. Neurosci Lett 2002; 321: 157–60.
Cowley MA, Smith RG, Diano S et al. The distribution and
mechanism of action of ghrelin in the CNS demonstrates a
novel hypothalamic circuit regulating energy homeostasis.
Neuron 2003; 37: 649–61.
Näslund E, Hellström PM, Kral JG. The gut and food
intake: an update for surgeons. J Gastrointest Surg 2001;
5: 556–67.
Mason EE, Ito C. Gastric bypass in obesity. Surg Clin North
Am 1967; 47: 1345–51.
Halmi KA, Mason E, Falk JR, Stunkard A. Appetitive behavior
after gastric bypass for obesity. Int J Obes 1981; 5: 457–64.
Cummings DE, Weigle DS, Frayo RS et al. Plasma ghrelin
levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346: 1623–30.
Cummings DE, Clement K, Purnell JQ et al. Elevated plasma
ghrelin levels in Prader Willi syndrome. Nat Med 2002; 8:
643–4.
Hollister LE. Hunger and appetite after single doses of marihuana, alcohol, and dextroamphetamine. Clin Pharmacol
Ther 1971; 12: 44–49.
American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 4th edn. Washington, DC:
American Psychiatric Association, 1994.
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 2003; 4: 873–84.
Williams CM, Kirkham TC. Anandamide induces overeating:
mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 1999; 143: 315–7.
Berry EM, Mechoulam R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol Ther 2002;
95: 185–90.
Rodriguez de Fonseca F, Navarro M, Gomez R et al. An
anorexic lipid mediator regulated by feeding. Nature 2001;
414: 209–12.
Gaetani S, Cuomo V, Piomelli D. Anandamide hydrolysis: a
new target for anti-anxiety drugs? Trends Mol Med 2003; 9:
474–8.
Guzman M, Lo Verme J, Fu J, Oveisi F, Blazquez C, Piomelli
D. Oleoylethanolamide stimulates lipolysis by activating the
nuclear receptor peroxisome proliferator-activated receptor
alpha (PPAR-alpha). J Biol Chem 2004; 279: 27849–54.
322
C. BROBERGER
107 Fu J, Gaetani S, Oveisi F et al. Oleylethanolamide regulates
feeding and body weight through activation of the nuclear
receptor PPAR-alpha. Nature 2003; 425: 90–3.
108 Issemann I, Green S. Activation of a member of the steroid
hormone receptor superfamily by peroxisome proliferators.
Nature 1990; 347: 645–50.
109 Schwartz MW, Marks JL, Sipols AJ et al. Central insulin
administration reduces neuropeptide Y mRNA expression in
the arcuate nucleus of food-deprived lean (Fa/Fa) but
not obese (fa/fa) Zucker rats. Endocrinology 1991; 128:
2645–7.
110 Schwartz MW, Seeley RJ, Woods SC et al. Leptin increases
hypothalamic pro-opiomelanocortin mRNA expression in
the rostral arcuate nucleus. Diabetes 1997; 46: 2119–23.
111 Thornton JE, Cheung CC, Clifton DK, Steiner RA. Regulation
of hypothalamic proopiomelanocortin mRNA by leptin in
ob/ob mice. Endocrinology 1997; 138: 5063–6.
112 Kim EM, Grace MK, Welch CC, Billington CJ, Levine AS. STZinduced diabetes decreases and insulin normalizes POMC
mRNA in arcuate nucleus and pituitary in rats. Am J Physiol
1999; 276: R1320–6.
113 Elias CF, Aschkenasi C, Lee C et al. Leptin differentially
regulates NPY and POMC neurons projecting to the lateral
hypothalamic area. Neuron 1999; 23: 775–86.
114 Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell
AA. Neuronal glucosensing: what do we know after
50 years? Diabetes 2004; 53: 2521–8.
115 Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML.
Leptin inhibits hypothalamic neurons by activation of ATPsensitive potassium channels. Nature 1997; 390: 521–5.
116 Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford
ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci
2000; 3: 757–8.
117 Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers
MG Jr, Schwartz MW. Intracellular signalling. Key enzyme
in leptin-induced anorexia. Nature 2001; 413: 794–5.
118 Dunn-Meynell AA, Rawson NE, Levin BE. Distribution and
phenotype of neurons containing the ATP-sensitive K+
channel in rat brain. Brain Res 1998; 814: 41–54.
119 Ibrahim N, Bosch MA, Smart JL et al. Hypothalamic
proopiomelanocortin neurons are glucose responsive and
express K(ATP) channels. Endocrinology 2003; 144: 1331–
40.
120 Wang R, Liu X, Hentges ST et al. The regulation of glucoseexcited neurons in the hypothalamic arcuate nucleus by
glucose and feeding-relevant peptides. Diabetes 2004; 53:
1959–65.
121 Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of
hypothalamic carnitine palmitoyltransferase-1 decreases food
intake and glucose production. Nat Med 2003; 9: 756–61.
122 Pocai A, Lam TK, Gutierrez-Juarez R et al. Hypothalamic
K(ATP) channels control hepatic glucose production. Nature
2005; 434: 1026–31.
123 Coppari R, Ichinose M, Lee CE et al. The hypothalamic
arcuate nucleus: a key site for mediating leptin’s effects on
glucose homeostasis and locomotor activity. Cell Metab
2005; 1: 63–72.
124 Stanley BG, Magdalin W, Seirafi A, Thomas WJ, Leibowitz
SF. The perifornical area: the major focus of (a) patchily
distributed hypothalamic neuropeptide Y-sensitive feeding
system(s). Brain Res 1993; 604: 304–17.
125 Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and
susceptibility to seizures of mice lacking neuropeptide Y.
Nature 1996; 381: 415–21.
126 Bannon AW, Seda J, Carmouche M et al. Behavioral characterization of neuropeptide Y knockout mice. Brain Res
2000; 868: 79–87.
127 Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the
obesity syndrome of ob/ob mice by the loss of neuropeptide
Y. Science 1996; 274: 1704–7.
128 Lin S, Boey D, Herzog H. NPY and Y receptors: lessons from
transgenic and knockout models. Neuropeptides 2004; 38:
189–200.
129 McCrea K, Wisialowski T, Cabrele C et al. 2–36[K4, RYYSA(19–23)]PP a novel Y5-receptor preferring ligand with
strong stimulatory effect on food intake. Regul Pept 2000;
87: 47–58.
130 Ammar AA, Sederholm F, Saito TR, Scheurink AJ, Johnson
AE, Sodersten P. NPY-leptin: opposing effects on appetitive
and consummatory ingestive behavior and sexual behavior.
Am J Physiol Regul Integr Comp Physiol 2000; 278: R1627–
33.
131 Poggioli R, Vergoni AV, Bertolini A. ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa
opiate agonists. Peptides 1986; 7: 843–8.
132 Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role
of melanocortinergic neurons in feeding and the agouti
obesity syndrome. Nature 1997; 385: 165–8.
133 Huszar D, Lynch CA, Fairchild-Huntress V et al. Targeted
disruption of the melanocortin-4 receptor results in obesity
in mice. Cell 1997; 88: 131–41.
134 Yaswen L, Diehl N, Brennan MB, Hochgeschwender U.
Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 1999; 5:
1066–70.
135 Butler AA, Kesterson RA, Khong K et al. A unique metabolic
syndrome causes obesity in the melanocortin-3 receptordeficient mouse. Endocrinology 2000; 141: 3518–21.
136 Butler AA, Marks DL, Fan W, Kuhn CM, Bartolome M, Cone
RD. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 2001;
4: 605–11.
137 Swanson LW, Kuypers HG. The paraventricular nucleus of
the hypothalamus: cytoarchitectonic subdivisions and
organization of projections to the pituitary, dorsal vagal
complex, and spinal cord as demonstrated by retrograde
fluorescence double-labeling methods. J Comp Neurol 1980;
194: 555–70.
138 Cechetto DF, Saper CB. Neurochemical organization of the
hypothalamic projection to the spinal cord in the rat. J Comp
Neurol 1988; 272: 579–604.
139 Elias CF, Lee C, Kelly J et al. Leptin activates hypothalamic
CART neurons projecting to the spinal cord. Neuron 1998;
21: 1375–85.
140 Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T,
O’Rahilly S. Clinical spectrum of obesity and mutations in
the melanocortin 4 receptor gene. N Engl J Med 2003; 348:
1085–95.
141 Ollmann MM, Wilson BD, Yang YK et al. Antagonism of
central melanocortin receptors in vitro and in vivo by
agouti-related protein. Science 1997; 278: 135–8.
142 Broberger C, De Lecea L, Sutcliffe JG, Hökfelt T. Hypocretin/
orexin- and melanin-concentrating hormone-expressing
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti
gene-related protein systems. J Comp Neurol 1998; 402:
460–74.
Hahn TM, Breininger JF, Baskin DG, Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic
neurons. Nat Neurosci 1998; 1: 271–2.
Hagan MM, Rushing PA, Pritchard LM et al. Long-term
orexigenic effects of AgRP-(83-132) involve mechanisms
other than melanocortin receptor blockade. Am J Physiol
Regul Integr Comp Physiol 2000; 279: R47–52.
Csiffáry A, Görcs TJ, Palkovits M. Neuropeptide Y innervation
of ACTH-immunoreactive neurons in the arcuate nucleus of
rats: a correlated light and electron microscopic double immunolabeling study. Brain Res 1990; 506: 215–22.
Broberger C, Landry M, Wong H, Walsh JN, Hökfelt T.
Subtypes Y1 and Y2 of the neuropeptide Y receptor are
respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic
arcuate nucleus. Neuroendocrinology 1997; 66: 393–408.
Roseberry AG, Liu H, Jackson AC, Cai X, Friedman JM.
Neuropeptide Y-mediated inhibition of proopiomelanocortin
neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice. Neuron 2004; 41: 711–22.
Dumont Y, Fournier A, St-Pierre S, Quirion R. Characterization of neuropeptide Y binding sites in rat brain membrane
preparations using [125I][Leu31, Pro34]peptide YY and
[125I]peptide YY3-36 as selective Y1 and Y2 radioligands.
J Pharmacol Exp Ther 1995; 272: 673–80.
Decavel C, Van den Pol AN. GABA: a dominant neurotransmitter in the hypothalamus. J Comp Neurol 1990; 302:
1019–37.
van den Pol AN, Wuarin JP, Dudek FE. Glutamate, the
dominant excitatory transmitter in neuroendocrine regulation. Science 1990; 250: 1276–8.
van den Pol AN. Weighing the role of hypothalamic feeding
neurotransmitters. Neuron 2003; 40: 1059–61.
Hökfelt T, Johansson O, Ljungdahl Å, Lundberg JM,
Schultzberg M. Peptidergic neurones. Nature 1980; 284:
515–21.
Stanley BG, Willett VL, III, Donias HW, Ha LH, Spears LC.
The lateral hypothalamus: a primary site mediating excitatory amino acid-elicited eating. Brain Res 1993; 630: 41–9.
Stanley BG, Willett VL, III, Donias HW, Dee MG, II, Duva
MA. Lateral hypothalamic NMDA receptors and glutamate
as physiological mediators of eating and weight control. Am
J Physiol 1996; 270: R443–9.
Horvath TL, Bechmann I, Naftolin F, Kalra SP, Leranth C.
Heterogeneity in the neuropeptide Y-containing neurons of
the rat arcuate nucleus: GABAergic and non-GABAergic
subpopulations. Brain Res 1997; 756: 283–6.
Collin M, Backberg M, Ovesjo ML et al. Plasma membrane
and vesicular glutamate transporter mRNAs/proteins in
hypothalamic neurons that regulate body weight. Eur J
Neurosci 2003; 18: 1265–78.
Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers
WF, Cone RD. Integration of NPY, AGRP, and melanocortin
signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 1999; 24:
155–63.
Pronchuk N, Beck-Sickinger AG, Colmers WF. Multiple NPY
receptors inhibit GABA(A) synaptic responses of rat medial
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
323
parvocellular effector neurons in the hypothalamic paraventricular nucleus. Endocrinology 2002; 143: 535–43.
Wahlestedt C, Yanaihara N, Hakanson R. Evidence for different pre- and post-junctional receptors for neuropeptide Y
and related peptides. Regul Pept 1986; 13: 307–18.
Kopp J, Xu ZQ, Zhang X et al. Expression of the neuropeptide
Y Y1 receptor in the CNS of rat and of wild-type and Y1
receptor knock-out mice. Focus on immunohistochemical
localization. Neuroscience 2002; 111: 443–532.
Elias CF, Saper CB, Maratos-Flier E et al. Chemically defined
projections linking the mediobasal hypothalamus and the
lateral hypothalamic area. J Comp Neurol 1998; 402: 442–
59.
Peyron C, Tighe DK, van den Pol AN et al. Neurons containing hypocretin (orexin) project to multiple neuronal
systems. J Neurosci 1998; 18: 9996–10015.
Chemelli RM, Willie JT, Sinton CM et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
Cell 1999; 98: 437–51.
Lin L, Faraco J, Li R et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin)
receptor 2 gene. Cell 1999; 98: 365–76.
Peyron C, Faraco J, Rogers W et al. A mutation in a case of
early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;
6: 991–7.
Thannickal TC, Moore RY, Nienhuis R et al. Reduced
number of hypocretin neurons in human narcolepsy. Neuron
2000; 27: 469–74.
Verret L, Goutagny R, Fort P et al. A role of melanin-concentrating hormone producing neurons in the central
regulation of paradoxical sleep. BMC Neurosci 2003; 4: 19.
Fu LY, Acuna-Goycolea C, van den Pol AN. Neuropeptide Y
inhibits hypocretin/orexin neurons by multiple presynaptic
and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J Neurosci 2004; 24: 8741–51.
van den Pol AN, Acuna-Goycolea C, Clark KR, Ghosh PK.
Physiological properties of hypothalamic MCH neurons
identified with selective expression of reporter gene after
recombinant virus infection. Neuron 2004; 42: 635–52.
Campbell RE, Smith MS, Allen SE, Grayson BE, FfrenchMullen JM, Grove KL. Orexin neurons express a functional
pancreatic polypeptide Y4 receptor. J Neurosci 2003; 23:
1487–97.
Turek FW, Joshu C, Kohsaka A et al. Obesity and metabolic
syndrome in circadian Clock mutant mice. Science 2005;
308: 1043–5.
Kreier F, Yilmaz A, Kalsbeek A et al. Hypothesis: shifting the
equilibrium from activity to food leads to autonomic
unbalance and the metabolic syndrome. Diabetes 2003; 52:
2652–6.
Buijs RM, la Fleur SE, Wortel J et al. The suprachiasmatic
nucleus balances sympathetic and parasympathetic output
to peripheral organs through separate preautonomic neurons. J Comp Neurol 2003; 464: 36–48.
Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat.
Brain Res 1972; 42: 201–6.
Stephan FK, Zucker I. Circadian rhythms in drinking
behavior and locomotor activity of rats are eliminated by
hypothalamic lesions. Proc Natl Acad Sci U S A 1972; 69:
1583–6.
324
C. BROBERGER
176 Kreier F, Fliers E, Voshol PJ et al. Selective parasympathetic
innervation of subcutaneous and intra-abdominal fat –
functional implications. J Clin Invest 2002; 110: 1243–50.
177 Karlsson B, Knutsson A, Lindahl B. Is there an association
between shift work and having a metabolic syndrome?
Results from a population based study of 27,485 people.
Occup Environ Med 2001; 58: 747–52.
178 Sekine M, Yamagami T, Handa K et al. A dose-response
relationship between short sleeping hours and childhood
obesity: results of the Toyama Birth Cohort Study. Child Care
Health Dev 2002; 28: 163–70.
179 Sinha MK, Ohannesian JP, Heiman ML et al. Nocturnal rise
of leptin in lean, obese, and non-insulin-dependent diabetes
mellitus subjects. J Clin Invest 1996; 97: 1344–7.
180 Vague J. The degree of masculine differentiation of obesities:
a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;
4: 20–34.
181 Davis JD, Smith GP. Learning to sham feed: behavioral
adjustments to loss of physiological postingestional stimuli.
Am J Physiol 1990; 259: R1228–35.
182 Schwartz GJ, Salorio CF, Skoglund C, Moran TH. Gut vagal
afferent lesions increase meal size but do not block gastric
preload-induced feeding suppression. Am J Physiol 1999;
276: R1623–9.
183 Erdheim J. Über Hypophysengangsgeschwülste und Hirncholesteatome. Sitzungsb d k Akad d Wissensch Math-naturw
Cl Wien 1904; 113: 537–726.
184 Olney JW. Brain lesions, obesity, and other disturbances in
mice treated with monosodium glutamate. Science 1969;
164: 719–21.
185 Bugarith K, Dinh TT, Li AJ, Speth RC, Ritter S. Basomedial
hypothalamic injections of neuropeptide Y conjugated to
saporin selectively disrupt hypothalamic controls of food
intake. Endocrinology 2005; 146: 1179–91.
186 Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J,
Baskin DG. Evidence that the caudal brainstem is a target for
the inhibitory effect of leptin on food intake. Endocrinology
2002; 143: 239–46.
187 Hosoi T, Kawagishi T, Okuma Y, Tanaka J, Nomura Y. Brain
stem is a direct target for leptin’s action in the central nervous system. Endocrinology 2002; 143: 3498–504.
188 Huo L, Grill HJ, Bjorbaek C. Leptin-dependent activation of
STAT3 phosphorylation in the medial sub-nucleus of the
nucleus of the solitary tract (NTS) and regulation of proopiomelanocortin (POMC), pro-glucagon and galanin-likepeptide (GALP) mRNA. In Endocrine Society Proceedings, San
Francisco, CA, USA, 2005.
189 Grill HJ, Ginsberg AB, Seeley RJ, Kaplan JM. Brainstem
application of melanocortin receptor ligands produces longlasting effects on feeding and body weight. J Neurosci 1998;
18: 10128–35.
190 Fan W, Ellacott KL, Halatchev IG, Takahashi K, Yu P, Cone
RD. Cholecystokinin-mediated suppression of feeding
involves the brainstem melanocortin system. Nat Neurosci
2004; 7: 335–6.
191 Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ.
Hyperphagic effects of brainstem ghrelin administration.
Diabetes 2003; 52: 2260–5.
192 Mizuno Y, Oomura Y. Glucose responding neurons in the
nucleus tractus solitarius of the rat: in vitro study. Brain Res
1984; 307: 109–16.
193 Morton GJ, Blevins JE, Williams DL et al. Leptin action in the
forebrain regulates the hindbrain response to satiety signals.
J Clin Invest 2005; 115: 703–10.
194 Eskay RL, Giraud P, Oliver C, Brown-Stein MJ. Distribution of
alpha-melanocyte-stimulating hormone in the rat brain:
evidence that alpha-MSH-containing cells in the arcuate
region send projections to extrahypothalamic areas. Brain
Res 1979; 178: 55–67.
195 Sim LJ, Joseph SA. Arcuate nucleus projections to brainstem
regions which modulate nociception. J Chem Neuroanat
1991; 4: 97–109.
196 Broberger C, Johansen J, Johansson C, Schalling M, Hökfelt
T. The neuropeptide Y/agouti gene-related protein (AGRP)
brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc Natl Acad Sci U S A 1998; 95:
15043–8.
197 Bouret SG, Draper SJ, Simerly RB. Formation of projection
pathways from the arcuate nucleus of the hypothalamus
to hypothalamic regions implicated in the neural control
of feeding behavior in mice. J Neurosci 2004; 24: 2797–
805.
198 Saper CB. Organization of cerebral cortical afferent systems
in the rat. II. Hypothalamocortical projections. J Comp Neurol
1985; 237: 21–46.
199 Kishi T, Aschkenasi CJ, Choi BJ et al. Neuropeptide Y Y1
receptor mRNA in rodent brain: distribution and colocalization with melanocortin-4 receptor. J Comp Neurol 2005;
482: 217–43.
200 Norgren R. Projections from the nucleus of the solitary tract
in the rat. Neuroscience 1978; 3: 207–18.
201 Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat.
Brain Res 1978; 153: 1–26.
202 ter Horst GJ, de Boer P, Luiten PG, van Willigen JD.
Ascending projections from the solitary tract nucleus to the
hypothalamus. A Phaseolus vulgaris lectin tracing study in
the rat. Neuroscience 1989; 31: 785–97.
203 DeFalco J, Tomishima M, Liu H et al. Virus-assisted mapping
of neural inputs to a feeding center in the hypothalamus.
Science 2001; 291: 2608–13.
204 McCormick DA. Cortical and subcortical generators of normal and abnormal rhythmicity. Int Rev Neurobiol 2002; 49:
99–114.
205 Thompson RH, Swanson LW. Structural characterization of
a hypothalamic visceromotor pattern generator network.
Brain Res Brain Res Rev 2003; 41: 153–202.
206 Swanson LW. Cerebral hemisphere regulation of motivated
behavior. Brain Res 2000; 886: 113–64.
207 Choi GB, Dong HW, Murphy AJ et al. Lhx6 delineates a
pathway mediating innate reproductive behaviors from the
amygdala to the hypothalamus. Neuron 2005; 46: 647–
60.
208 Bargmann W. Über die neurosekretorische verknüpfung von
hypothalamus und neurohypophyse. Z Zellforsch Mikr 1949;
34: 610–34.
209 Saper CB, Loewy AD, Swanson LW, Cowan WM. Direct
hypothalamo-autonomic connections. Brain Res 1976; 117:
305–12.
210 Swanson LW, Sawchenko PE. Hypothalamic integration:
organization of the paraventricular and supraoptic nuclei.
Annu Rev Neurosci 1983; 6: 269–324.
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
211 Hodgkin J, Doniach T. Natural variation and copulatory
plug formation in Caenorhabditis elegans. Genetics 1997; 146:
149–64.
212 de Bono M, Bargmann CI. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and
food response in C. elegans. Cell 1998; 94: 679–89.
213 de Bono M. Molecular approaches to aggregation behavior
and social attachment. J Neurobiol 2003; 54: 78–92.
214 Rogers C, Reale V, Kim K et al. Inhibition of Caenorhabditis
elegans social feeding by FMRFamide-related peptide activation of NPR-1. Nat Neurosci 2003; 6: 1178–85.
215 Cheung BH, Arellano-Carbajal F, Rybicki I, de Bono M.
Soluble guanylate cyclases act in neurons exposed to the
body fluid to promote C. elegans aggregation behavior. Curr
Biol 2004; 14: 1105–11.
216 Gray JM, Karow DS, Lu H et al. Oxygen sensation and social
feeding mediated by a C. elegans guanylate cyclase homologue. Nature 2004; 430: 317–22.
217 Teyke T, Weiss KR, Kupfermann I. An identified neuron
(CPR) evokes neuronal responses reflecting food arousal in
Aplysia. Science 1990; 247: 85–7.
218 Kupfermann I. Feeding behavior in Aplysia: a simple system
for the study of motivation. Behav Biol 1974; 10: 1–26.
219 Hurwitz I, Kupfermann I, Susswein AJ. Different roles of
neurons B63 and B34 that are active during the protraction
phase of buccal motor programs in Aplysia californica.
J Neurophysiol 1997; 78: 1305–19.
220 Blumberg S, Susswein AJ. Consummatory feeding movements in Aplysia fasciata are facilitated by conspecifics with
access to mates, by reproductive tract homogenates and
by bag cell peptides. J Comp Physiol 1998; 182: 175–
82.
221 Del Parigi A, Chen K, Salbe AD, Reiman EM, Tataranni PA.
Are we addicted to food? Obes Res 2003; 11: 493–5.
222 Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the
mesolimbic system of freely moving rats. Proc Natl Acad Sci U
S A 1988; 85: 5274–8.
223 Zhou QY, Palmiter RD. Dopamine-deficient mice are severely
hypoactive, adipsic, and aphagic. Cell 1995; 83: 1197–209.
224 Wirshing DA. Schizophrenia and obesity: impact of antipsychotic medications. J Clin Psychiatry 2004; 65 (Suppl.
18): 13–26.
225 Saper CB, Chou TC, Elmquist JK. The need to feed: homeostatic and hedonic control of eating. Neuron 2002; 36: 199–
211.
226 Baldo BA, Sadeghian K, Basso AM, Kelley AE. Effects of
selective dopamine D1 or D2 receptor blockade within
nucleus accumbens subregions on ingestive behavior and
associated motor activity. Behav Brain Res 2002; 137: 165–
77.
227 Kelley AE. Ventral striatal control of appetitive motivation:
role in ingestive behavior and reward-related learning.
Neurosci Biobehav Rev 2004; 27: 765–76.
228 Kelley AE, Will MJ, Steininger TL, Zhang M, Haber SN.
Restricted daily consumption of a highly palatable food
(chocolate Ensure(R)) alters striatal enkephalin gene
expression. Eur J Neurosci 2003; 18: 2592–8.
229 Zhang M, Gosnell BA, Kelley AE. Intake of high-fat food is
selectively enhanced by mu opioid receptor stimulation
within the nucleus accumbens. J Pharmacol Exp Ther 1998;
285: 908–14.
325
230 Will MJ, Franzblau EB, Kelley AE. The amygdala is critical
for opioid-mediated binge eating of fat. Neuroreport 2004;
15: 1857–60.
231 Balleine BW, Killcross AS, Dickinson A. The effect of lesions
of the basolateral amygdala on instrumental conditioning.
J Neurosci 2003; 23: 666–75.
232 Maldonado-Irizarry CS, Swanson CJ, Kelley AE. Glutamate
receptors in the nucleus accumbens shell control feeding
behavior via the lateral hypothalamus. J Neurosci 1995; 15:
6779–88.
233 Mogenson GJ, Jones DL, Yim CY. From motivation to action:
functional interface between the limbic system and the
motor system. Prog Neurobiol 1980; 14: 69–97.
234 Risold PY, Thompson RH, Swanson LW. The structural
organization of connections between hypothalamus and
cerebral cortex. Brain Res Brain Res Rev 1997; 24: 197–
254.
235 Rolls ET. Smell, taste, texture, and temperature multimodal
representations in the brain, and their relevance to the
control of appetite. Nutr Rev 2004; 62: S193–204; discussion: S224–141.
236 Cechetto DF, Saper CB. Evidence for a viscerotopic sensory
representation in the cortex and thalamus in the rat. J Comp
Neurol 1987; 262: 27–45.
237 Yaxley S, Rolls ET, Sienkiewicz ZJ. The responsiveness of
neurons in the insular gustatory cortex of the macaque
monkey is independent of hunger. Physiol Behav 1988; 42:
223–9.
238 Rolls ET, Baylis LL. Gustatory, olfactory, and visual convergence within the primate orbitofrontal cortex. J Neurosci
1994; 14: 5437–52.
239 Kringelbach ML, O’Doherty J, Rolls ET, Andrews C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb
Cortex 2003; 13: 1064–71.
240 Tataranni PA, Gautier JF, Chen K et al. Neuroanatomical
correlates of hunger and satiation in humans using positron
emission tomography. Proc Natl Acad Sci U S A 1999; 96:
4569–74.
241 DelParigi A, Chen K, Salbe AD, Reiman EM, Tataranni PA.
Sensory experience of food and obesity: a positron emission
tomography study of the brain regions affected by tasting a
liquid meal after a prolonged fast. Neuroimage 2005; 24:
436–43.
242 DelParigi A, Chen K, Salbe AD et al. Persistence of abnormal
neural responses to a meal in postobese individuals. Int J
Obes Relat Metab Disord 2004; 28: 370–7.
243 Kagotani Y, Hashimoto T, Tsuruo Y, Kawano H, Daikoku S,
Chihara K. Development of the neuronal system containing
neuropeptide Y in the rat hypothalamus. Int J Dev Neurosci
1989; 7: 359–74.
244 Grove KL, Smith MS. Ontogeny of the hypothalamic neuropeptide Y system. Physiol Behav 2003; 79: 47–63.
245 Cramer CP, Blass EM. Nutritive and nonnutritive determinants of milk intake of suckling rats. Behav Neurosci 1985;
99: 578–82.
246 Broberger C, Johansen J, Schalling M, Hökfelt T. Hypothalamic neurohistochemistry of the murine anorexia (anx/
anx) mutation: altered processing of neuropeptide Y in the
arcuate nucleus. J Comp Neurol 1997; 387: 124–35.
247 Broberger C, Johansen J, Brismar H, Johansson C, Schalling
M, Hökfelt T. Changes in neuropeptide Y receptors and
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
326
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
C. BROBERGER
pro-opiomelanocortin in the anorexia (anx/anx) mouse
hypothalamus. J Neurosci 1999; 19: 7130–9.
Singer LK, Kuper J, Brogan RS, Smith MS, Grove KL. Novel
expression of hypothalamic neuropeptide Y during postnatal
development in the rat. Neuroreport 2000; 11: 1075–80.
Mistry AM, Swick A, Romsos DR. Leptin alters metabolic
rates before acquisition of its anorectic effect in developing
neonatal mice. Am J Physiol 1999; 277: R742–7.
Hayashida T, Nakahara K, Mondal MS et al. Ghrelin in
neonatal rats: distribution in stomach and its possible role.
J Endocrinol 2002; 173: 239–45.
Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge
and regulation of circadian rhythm of leptin by feeding.
Implications for energy homeostasis and neuroendocrine
function. J Clin Invest 1998; 101: 1020–7.
Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on
hypothalamic neurons that regulate feeding. Science 2004;
304: 108–10.
Levin BE, Govek E. Gestational obesity accentuates obesity
in obesity-prone progeny. Am J Physiol 1998; 275:
R1374–9.
Dabelea D, Hanson RL, Lindsay RS et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity:
a study of discordant sibships. Diabetes 2000; 49: 2208–11.
Grove KL, Williams SM, Xiao XQ, Smith MS. Fetal metabolic
adaptations in nonhuman primates (NHP): effects of dietinduced gestational hyperinsulinemia and hyperleptinemia.
In Endocrine Society Proceedings, San Francisco, CA, USA,
2005.
Gruenewald DA, Naai MA, Marck BT, Matsumoto AM. Agerelated decrease in neuropeptide-Y gene expression in the
arcuate nucleus of the male rat brain is independent of
testicular feedback. Endocrinology 1994; 134: 2383–9.
Gruenewald DA, Matsumoto AM. Age-related decrease in
proopiomelanocortin gene expression in the arcuate
nucleus of the male rat brain. Neurobiol Aging 1991; 12:
113–21.
Leal S, Andrade JP, Paula-Barbosa MM, Madeira MD.
Arcuate nucleus of the hypothalamus: effects of age and sex.
J Comp Neurol 1998; 401: 65–88.
Langhans W. Anorexia of infection: current prospects.
Nutrition 2000; 16: 996–1005.
von Meyenburg C, Hrupka BH, Arsenijevic D, Schwartz GJ,
Landmann R, Langhans W. Role for CD14, TLR2, and TLR4
in bacterial product-induced anorexia. Am J Physiol Regul
Integr Comp Physiol 2004; 287: R298–305.
Bret-Dibat JL, Bluthe RM, Kent S, Kelley KW, Dantzer R.
Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain
Behav Immun 1995; 9: 242–6.
Cao C, Matsumura K, Yamagata K, Watanabe Y. Induction
by lipopolysaccharide of cyclooxygenase-2 mRNA in rat
brain; its possible role in the febrile response. Brain Res
1995; 697: 187–96.
Lugarini F, Hrupka BJ, Schwartz GJ, Plata-Salaman CR,
Langhans W. A role for cyclooxygenase-2 in lipopolysaccharide-induced anorexia in rats. Am J Physiol Regul Integr
Comp Physiol 2002; 283: R862–8.
von Meyenburg C, Langhans W, Hrupka BJ. Evidence for a
role of the 5-HT2C receptor in central lipopolysaccharide-,
interleukin-1 beta-, and leptin-induced anorexia. Pharmacol
Biochem Behav 2003; 74: 1025–31.
265 Waldbillig RJ, Bartness TJ, Stanley BG. Increased food
intake, body weight, and adiposity in rats after regional
neurochemical depletion of serotonin. J Comp Physiol Psychol
1981; 95: 391–405.
266 Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptinindependent hyperphagia and type 2 diabetes in mice with a
mutated serotonin 5-HT2C receptor gene. Nat Med 1998; 4:
1152–6.
267 Heisler LK, Cowley MA, Tecott LH et al. Activation of central
melanocortin pathways by fenfluramine. Science 2002; 297:
609–11.
268 Madej T, Boguski MS, Bryant SH. Threading analysis suggests that the obese gene product may be a helical cytokine.
FEBS Lett 1995; 373: 13–8.
269 Baumann H, Morella KK, White DW et al. The full-length
leptin receptor has signaling capabilities of interleukin 6type cytokine receptors. Proc Natl Acad Sci U S A 1996; 93:
8374–8.
270 Evans WK, Makuch R, Clamon GH et al. Limited impact of
total parenteral nutrition on nutritional status during
treatment for small cell lung cancer. Cancer Res 1985; 45:
3347–53.
271 Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of
death in cancer patients. Cancer 1974; 33: 568–73.
272 Tisdale MJ. Tumor-host interactions. J Cell Biochem 2004;
93: 871–7.
273 Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, Tisdale
M. Characterization of a cancer cachectic factor. Nature
1996; 379: 739–42.
274 Lorite MJ, Smith HJ, Arnold JA, Morris A, Thompson MG,
Tisdale MJ. Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro
by a proteolysis-inducing factor (PIF). Br J Cancer 2001; 85:
297–302.
275 Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism
of attenuation of skeletal muscle protein catabolism in
cancer cachexia by eicosapentaenoic acid. Cancer Res 2001;
61: 3604–9.
276 Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC. The
effect of an oral nutritional supplement enriched with fish oil
on weight-loss in patients with pancreatic cancer. Br J
Cancer 1999; 81: 80–6.
277 Olden K, Wilson S. Environmental health and genomics:
visions and implications. Nat Rev Genet 2000; 1: 149–53.
278 Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC,
Hayakawa K. The heritability of body mass index among an
international sample of monozygotic twins reared apart. Int J
Obes Relat Metab Disord 1996; 20: 501–6.
279 Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The
body-mass index of twins who have been reared apart.
N Engl J Med 1990; 322: 1483–7.
280 Friedman JM. A war on obesity, not the obese. Science 2003;
299: 856–8.
281 Ravussin E, Bogardus C. Energy balance and weight regulation: genetics versus environment. Br J Nutr 2000; 83
(Suppl. 1): S17–20.
282 Montague CT, Farooqi IS, Whitehead JP et al. Congenital
leptin deficiency is associated with severe early-onset obesity
in humans. Nature 1997; 387: 903–8.
283 Clement K, Vaisse C, Lahlou N et al. A mutation in the
human leptin receptor gene causes obesity and pituitary
dysfunction. Nature 1998; 392: 398–401.
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE
284 Krude H, Biebermann H, Luck W, Horn R, Brabant G,
Gruters A. Severe early-onset obesity, adrenal insufficiency
and red hair pigmentation caused by POMC mutations in
humans. Nat Genet 1998; 19: 155–7.
285 Jackson RS, Creemers JW, Ohagi S et al. Obesity and
impaired prohormone processing associated with mutations
in the human prohormone convertase 1 gene. Nat Genet
1997; 16: 303–6.
286 Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG,
O’Rahilly S. A frameshift mutation in MC4R associated with
dominantly inherited human obesity. Nat Genet 1998; 20:
111–2.
287 Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B,
Froguel P. Melanocortin-4 receptor mutations are a frequent
and heterogeneous cause of morbid obesity. J Clin Invest
2000; 106: 253–62.
288 Hinney A, Hohmann S, Geller F et al. Melanocortin-4
receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are
compatible with a major gene effect for extreme obesity.
J Clin Endocrinol Metab 2003; 88: 4258–67.
289 Jacobson P, Ukkola O, Rankinen T et al. Melanocortin 4
receptor sequence variations are seldom a cause of human
obesity: the Swedish Obese Subjects, the HERITAGE Family
Study, and a Memphis cohort. J Clin Endocrinol Metab 2002;
87: 4442–6.
290 Galuska DA, Will JC, Serdula MK, Ford ES. Are health care
professionals advising obese patients to lose weight? JAMA
1999; 282: 1576–8.
291 Wee CC, McCarthy EP, Davis RB, Phillips RS. Physician
counseling about exercise. JAMA 1999; 282: 1583–8.
292 Fong TM. Advances in anti-obesity therapeutics. Expert Opin
Investig Drugs 2005; 14: 243–50.
293 Raisch DW, Fye CL, Boardman KD, Sather MR. Opioid
dependence treatment, including buprenorphine/naloxone.
Ann Pharmacother 2002; 36: 312–21.
294 Jones RM, Boatman PD, Semple G, Shin YJ, Tamura SY.
Clinically validated peptides as templates for de novo peptidomimetic drug design at G-protein-coupled receptors. Curr
Opin Pharmacol 2003; 3: 530–43.
327
295 MacNeil DJ, Howard AD, Guan X et al. The role of melanocortins in body weight regulation: opportunities for the
treatment of obesity. Eur J Pharmacol 2002; 450: 93–109.
296 Chen RZ, Huang RR, Shen CP, MacNeil DJ, Fong TM.
Synergistic effects of cannabinoid inverse agonist AM251
and opioid antagonist nalmefene on food intake in mice.
Brain Res 2004; 999: 227–30.
297 Beal JE, Olson R, Laubenstein L et al. Dronabinol as a
treatment for anorexia associated with weight loss in
patients with AIDS. J Pain Symptom Manage 1995; 10:
89–97.
298 Heymsfield SB, Greenberg AS, Fujioka K et al. Recombinant
leptin for weight loss in obese and lean adults: a randomized,
controlled, dose-escalation trial. JAMA 1999; 282: 1568–
75.
299 Montez JM, Soukas A, Asilmaz E, Fayzikhodjaeva G, Fantuzzi
G, Friedman JM. Acute leptin deficiency, leptin resistance,
and the physiologic response to leptin withdrawal. Proc Natl
Acad Sci U S A 2005; 102: 2537–42.
300 Farooqi IS, Matarese G, Lord GM et al. Beneficial effects of
leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin
deficiency. J Clin Invest 2002; 110: 1093–103.
301 Oral EA, Simha V, Ruiz E et al. Leptin-replacement therapy
for lipodystrophy. N Engl J Med 2002; 346: 570–8.
302 Javor ED, Ghany MG, Cochran EK et al. Leptin reverses
nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005; 41: 753–60.
303 Welt CK, Chan JL, Bullen J et al. Recombinant human leptin
in women with hypothalamic amenorrhea. N Engl J Med
2004; 351: 987–97.
304 Del Parigi A, Gautier JF, Chen K et al. Neuroimaging and
obesity: mapping the brain responses to hunger and satiation in humans using positron emission tomography. Ann
N Y Acad Sci 2002; 967: 389–97.
Correspondence: Christian Broberger MD, PhD, Department of
Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
(fax: +468 33 16 92; e-mail: [email protected]).
2005 Blackwell Publishing Ltd Journal of Internal Medicine 258: 301–327