Download Body weight is regulated by the brain: a link between feeding and

Molecular Psychiatry (2005) 10, 132–146
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FEATURE REVIEW
Body weight is regulated by the brain: a link between
feeding and emotion
T Kishi1 and JK Elmquist2,3
1
Department of Anatomy and Morphological Neuroscience, Shimane University School of Medicine, Izumo, Japan;
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, and Program in Neuroscience, Harvard Medical
School, Boston, MA, USA; 3Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, MA, USA
2
Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical
process is affected in a high number of mentally ill patients. Eating disorders such as anorexia
nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in
patients with depression. In addition, the use of neuroleptics frequently produces obesity and
diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these
behavioral and metabolic conditions are largely unknown. In this review, we first concentrate
on the established brain machinery of food intake and body weight, especially on the
melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical
role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It
is also notable that both systems modulate emotion and motivated behavior as well. Secondly,
we discuss the significance and potential promise of multidisciplinary molecular and
neuroanatomic techniques that will likely increase the understanding of brain circuitries
coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence
suggesting a link between the melanocortin/NPY systems and several neurotransmitter
systems on which many of the psychotropic agents exert their influence.
Molecular Psychiatry (2005) 10, 132–146. doi:10.1038/sj.mp.4001638
Published online 4 January 2005
Keywords: energy homeostasis; hypothalamus; leptin; melanocortin; neuropeptide Y; reward;
emotion; amines; amino-acid transmitters
Maintaining energy homeostasis is fundamental for
survival. However, obesity due to over-nutrition is an
increasing worldwide public health problem.1 In
psychiatric practice, on the other hand, impaired
appetite is one of the crucial issues. Anorexia and
weight loss are common, for example, in patients
suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the
so-called ‘atypical’ antipsychotic agents, currently
and widely used to treat psychoses, often induce
hyperphagia, obesity, and diabetes mellitus.2–4
In the past decade, fortunately, there has been
remarkable progress in understanding the molecular
mechanisms of food intake and body weight. This is
due in large part to increased research activity
towards combating the rising incidences of obesity
and associated metabolic disorders. As a result, it is
Correspondence: Dr T Kishi, MD, PhD, Department of Anatomy
and Morphological Neuroscience, Shimane University School of
Medicine, Izumo 693-8501, Japan.
E-mail: [email protected]
Received 28 September 2004; revised 30 November 2004;
accepted 30 November 2004
now established that the central nervous system
(CNS) senses and processes peripheral metabolic cues
including leptin5 and ghrelin,6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake
and expenditure in psychiatric disorders remains
largely unknown. Nevertheless, evidence suggests
that several CNS systems regulating energy balance
may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug
addiction.8–14
In the current review, we will illustrate the
neuroanatomic and molecular genetic aspects of the
melanocortin and neuropeptide Y (NPY) systems
residing in the CNS downstream of leptin and ghrelin,
to discuss the neural bases of feeding, metabolism,
and emotion. Additionally, we point the reader to
recent reviews for other critical CNS systems regulating food intake and body weight, including those by
Barsh and Schwartz,15 Elmquist et al,16 Friedman and
Halaas,17 Friedman,1 Grill and Kaplan,18 O’Rahilly
et al,19 Saper et al,20 Sawchenko,21 Schwartz et al,22
Spiegelman and Flier,23 van den Pol,24 Woods et al,25
Zigman and Elmquist.26
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
Anatomic and molecular bases for
metabolic/autonomic control of body weight
plicated other hypothalamic and extra-hypothalamic
sites in regulating energy homeostasis.
The classic ‘dual-center’ model has been modified
A primary CNS site controlling food intake and body
weight is the hypothalamus. The underpinnings of
this view are largely due to classic descriptions that
date back to Bramwell27 and Fröhlich.28 These are
based on clinical observations in many patients with
pituitary tumors who developed excessive fat mass
and hypogonadism (see Elmquist et al16 for discussion). Whether this syndrome resulted from the tumor
per se or its intrusion into the hypothalamus was
controversial at that time. Subsequently, the resection
of the dog pituitary gland without hypothalamic
damage was demonstrated not to produce obesity by
Aschner.29
In 1940, Hetherington and Ranson30 performed a
seminal study to further investigate the role of the
hypothalamus in maintaining body weight homeostasis, in which bilateral and extensive hypothalamic lesions were made. Subsequent studies including
those by Anand and Brobeck placed smaller lesions in
the lateral hypothalamus.31 Such a sequence of
attempts led to the ‘dual-center’ model that defines
the lateral hypothalamus as a ‘feeding’ center, and the
ventromedial hypothalamic nucleus as a ‘satiety’
center (Figure 1). Moreover, data developed over
ensuing years challenged components of this model.32
However, the anatomic substrate underlying coordinated food intake control still remained obscure, as
scientists in the field lacked key tools to unravel this
complex hypothalamic puzzle. Nevertheless, several
molecular discoveries in 1990s, especially identification of leptin5 and melanocortin receptors33–35 im-
a
b
Adipocyte
CeA
LHA
Arc
ME
VMH
leptin
Figure 1 Schematic illustration showing the arcuate
nucleus of the hypothalamus (Arc), a primary site of leptin
action, which is located bilaterally at the median and
ventralmost region of the hypothalamus. (a) Lateral view of
the rat brain. (b) Coronal section of the rat brain at a rostralto-caudal level shown by a vertical line in (a). The Arc is
gray-colored. CeA, central nucleus of the amygdala; LHA,
lateral hypothalamic area; ME, medial eminence; VMH,
ventromedial nucleus of the hypothalamus.
133
Leptin as an antiobesity hormone
A fundamental hormone was discovered in 1994 and
named ‘leptin’ for a Greek root ‘leptos’ meaning thin.5
Leptin is produced mainly by adipose tissue, circulates, and reaches the CNS.5,17 Leptin inhibits ingestive behavior and stimulates energy expenditure
by normalizing reduced sympathetic activity, thermogenesis, oxygen consumption, and locomotor activity.
Accordingly, mutations in the ob gene encoding
leptin produce hyperphagia and morbid obesity in
mice (ob/ob mice)5,17 and humans.36–40 Similar to
states of starvation, leptin deficiency also leads to
deficits in the reproductive, thyroid, and adrenal
axes.41–44 Moreover, exogenous leptin corrects these
manifestations in leptin-deficient mice45–48 and humans.38,40 Finally, the significance of leptin in
adaptive endocrine and metabolic responses to fasting was demonstrated in healthy subjects.49 In this
study, a replacement dose of recombinant human
leptin administered during fasting prevented the
starvation-induced changes of endocrine axes.
The leptin receptor (Ob-R) belongs to the class-1
cytokine receptor superfamily.50,51 The Ob-R has a
single transmembrane spanning domain and functions via the JAK-STAT pathway.51,52 Thus far, splice
variants of Ob-R mRNA encoding six isoforms have
been identified, and only the long form (Ob-Rb) has
intracellular signaling motifs of leptin.51 Consequently, the db/db mice lacking Ob-Rbs and ob/ob
mice exhibit an almost identical obesity phenotype.53–55
Moreover, the phenotype in db/db mice is not
corrected by exogenous leptin.53–55 Mutations in the
human Ob-Rb also produce morbid obesity.56 Importantly, the gene expression of the Ob-Rb is evident in
the mediobasal hypothalamic sites including the
arcuate nucleus.57–60 The leptin receptor has also
been identified in the human brain.61
The arcuate nucleus: a site of leptin action
Evidence indicates that leptin directly acts on the
arcuate nucleus of the hypothalamus (Arc; Figure 1):
(i) Radiolabeled leptin binds highly to the mediobasal
hypothalamic region involving the Arc;62 (ii) cells
expressing Ob-Rb mRNA populate in the Arc and
several other brain sites;57–61 (iii) leptin induces the
expression of an immediate early gene, c-fos (a marker
of neuronal activation)63–66 and suppressor of cytokine signaling-3 (SOCS-3, a cellular marker of direct
leptin action)65–67 in the Arc; (iv) Arc cells are directly
hyperpolarized and depolarized by leptin.68,69
The central melanocortin system mediates leptin
action
The term ‘melanocortin’ indicates a series of peptides that are cleaved from pro-opiomelanocortin
(POMC).70 One of the POMC products, adrenocorticotropic hormone, is secreted by the anterior pituitary
and stimulates adrenocortical cells. In the CNS,
Molecular Psychiatry
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
134
Figure 2 A series of photomicrographs showing a-MSHimmunoreactive (a-MSH-IR) neurons in the human hypothalamus (modified from Elias et al72 with permission).
(a) a-MSH-IR neurons are localized in the arcuate nucleus of
the hypothalamus, especially in the lateral region of this
nucleus. (b) a-MSH-IR fibers are densely distributed in the
perifornical region of the LHA. (c) Higher magnification of a
boxed area in (a). (d) Higher power view of a boxed area in
(b). fx, fornix; 3v, third ventricle. Scale bars ¼ 200 mm in (a)
(also applied to (b)), 100 mm in (c); 50 mm in (d).
POMC neurons are localized in two sites in rodents
and humans, the Arc (Figure 2a, c)71,72 and the
nucleus of the solitary tract (NTS).70 Currently,
considerable attention has focused on another POMC
product, a-melanocyte-stimulating hormone (a-MSH).
Accumulating evidence strongly suggests that a-MSH
is a critical regulator of food intake, body weight, and
glucose homeostasis, and that a-MSH mediates
several of the biological effects of leptin. For example,
most of POMC-expressing Arc neurons coexpress
Ob-Rb mRNA.73 Leptin increases POMC mRNA in
the Arc74 and induces the expression of c-fos and
SOCS-3 mRNA in Arc POMC neurons.65,66 In addition, POMC mRNA in the Arc is markedly reduced in
leptin-deficient ob/ob mice as well as in fasted
rodents (when leptin levels rapidly fall).75,76 The
decrease in POMC expression is prevented by leptin
administration.74–76 Finally, leptin directly depolarizes POMC neurons.69
Of importance, a-MSH acts as an agonist for the
melanocortin-4 receptor (MC4-R),70,77,78 a Gs-proteincoupled receptor distributed in the CNS.35,79,80 The
MC4-R is an established regulator of food intake and
body weight, and blockade of this receptor causes
obesity.77,78 An overeating/obesity syndrome is produced, for example, by targeted deletion of the MC4R81 and by mutations in the human MC4-R.82–88 The
importance of MC4-Rs in humans is highlighted by an
estimate that 3–5% of the population suffering from
morbid obesity may result from MC4-R mutations.89
Another important piece of data supporting this
model is that POMC-deficient mice and humans
display similar obesity phenotypes.90,91
A unique component of the melanocortin regulatory system is an endogenous MC4-R antagonist,
Molecular Psychiatry
Figure 3 A series of photomicrographs showing AgRPimmunoreactive (AgRP-IR) axons and neurons in the
human hypothalamus (modified from Elias et al72 with
permission. (a, b) Low-power photomicrographs demonstrating AgRP-IR neurons localized in the rostral (a) and
caudal (b) regions of the arcuate nucleus. In (b), AgRP-IR
fibers are observed to stream dorsally out of this nucleus. A
boxed area in (b) is magnified in (c), and a boxed area in (c)
is further magnified in (e). Arrows indicate AgRP-IR cells.
(d, f) AgRP-IR axons in the perifornical region of the LHA. A
boxed area in (d) is magnified in (f). Scale bars ¼ 2 mm in (b)
(also applied to (a)), 200 mm in (d) (also applied to (c)),
100 mm in (f) (also applied to (e)). ARC, arcuate nucleus; fx,
fornix; ot, optic tract; 3v, third ventricle.
agouti-related protein (AgRP).92–94 Interestingly, AgRP
is produced exclusively in the Arc in rodents,
monkeys, and humans.71,72,93–97 Alpha-MSH-producing (Figure 2a, c) and AgRP-producing (Figure 3c, e)
neurons are distributed and segregated in the medial
and lateral regions of the Arc, respectively.71,72 In line
with the results from the aforementioned molecular
genetic studies on the MC4-R, transgenic overexpression of AgRP produces obesity.93,94 In contrast to
POMC mRNA, AgRP mRNA is increased in leptindeficient ob/ob mice and leptin-resistant db/db mice,
and during periods of fasting when leptin levels
rapidly fall.97,98 Finally, it is important to note that
AgRP is coexpressed with NPY in the Arc (see the
section ‘the NPY/Y1-receptor system’).71,98
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
A popular current model suggests that leptin
stimulates melanocortin signaling, resulting in decreased energy intake and increased energy expenditure, whereas opposite effects by AgRP are inhibited
by leptin (Figure 4). Such an interrelation between
leptin and melanocortins is supported by pharmacological evidence demonstrating that leptin-induced
anorexia can be attenuated by coadministration of
MC4-R antagonists,99 as can the effects of leptin on
heat production.100,101 Brown adipose tissue (BAT),
located at the interscapular region, regulates body
temperature and diet-induced thermogenesis, and is
therefore critical in energy expenditure.100,101 Leptin
increases uncoupling protein-1 (UCP-1) via the
sympathetic nervous system, which is produced by
BAT in the process of thermogenesis. MC4-R antagonism suppresses the expression of UCP-1 mRNA by
leptin.102
Recently, our laboratory provided evidence concerning the functional importance of leptin action on
POMC neurons by deleting leptin receptors specifically from this cellular population in mice.103
Notably, mice lacking leptin signaling in POMC
neurons display mild obesity, hyperleptinemia, and
altered expression levels of hypothalamic peptides.
The significance of this study will be discussed in a
later section.
Moreover, Cowley et al69 substantiated that NPY/
AgRP neurons inhibited POMC neurons in the Arc.
By using a strain of transgenic mice expressing green
fluorescent protein (GFP) under the control of the
POMC promoter, the authors demonstrated that leptin
increased the frequency of action potentials in POMC
neurons by two mechanisms: depolarization through
a cation channel; and disinhibition by inhibiting
NPY/AgRP neurons that contain g-amino butyric acid
(GABA) and tonically inhibit POMC neurons.
Hyperphagia /Obesity
Hypothalamus
3v
PVH
+
–
+
Arc
Y1-R
MC4-R
CeA
Increased Energy
Expenditure
NPY/
AgRP
ghrelin
+ –
α-MSH
Emotion and Motivated Behavior
+
leptin
Figure 4 Summary diagram showing the central melanocortin system that counterpoises the NPY/Y1-R system to
contribute to coordinated emotion and motivated behavior.
These systems mediate peripheral metabolic cues such as
leptin and ghrelin. Arc, arcuate nucleus of the hypothalamus; CeA, central nucleus of the amygdala; PVH, paraventricular nucleus of the hypothalamus, 3v, third ventricle.
Apparently, MC4-R-mediated melanocortin signaling is one of the targets of leptin action. Clearly,
however, several other CNS systems are also involved
in leptin-signaling brain systems. Indeed, it is now
clear that leptin-independent melanocortinergic CNS
pathways exist.103–105 Nonetheless, it is clearly established that a-MSH acting through MC4-Rs is a
fundamental regulator of coordinated energy homeostasis. Key questions that remain include what
metabolic and neural cues, beside leptin, drive the
melanocortinergic neural circuits. The MC4-R-positive sites that function to suppress excessive weight
gain are also to be identified.
135
Melanocortin neurons project to MC4-R-positive CNS
sites involved in regulating food intake and body
weight
Despite the very limited distribution of POMC and
AgRP cells bodies,71,72,106 their axonal projections are
widespread across the CNS. Several immunohistochemical studies have demonstrated CNS distributions of a-MSH-positive and AgRP-positive axons in
rodents, monkeys, and humans.71,72,96,106,107 The CNS
localization of MC4-R has also been examined in the
rat and mouse.35,79,80 For this purpose, radioisotopic
in situ hybridization histochemistry has been applied,
as high-affinity antibodies against MC4-R protein are
unavailable. Notably, nearly all the CNS sites thought
to be critical for energy balance regulation display
overlapping distributions of melanocortinergic axons
and MC4-R mRNA in rodents.35,79,80 Some of these
representative sites are discussed below.
1. Paraventricular nucleus of the hypothalamus
(PVH): Lesions of the PVH cause hyperphagia in the
rat, indicating that a regulator of food intake resides in
this nucleus.32 Several lines of evidence nominate
subsets of MC4-R-positive PVH neurons as candidates
for the regulator (Figure 5). For example, microinjections of a synthetic MC4-R agonist MT-II into the rat
PVH inhibit food intake, whereas PVH administration
of a synthetic MC4-R antagonist SHU9119 exerts
opposite effects.108,109 In addition, levels of POMC
mRNA in the Arc and a-MSH in the PVH are lower in
genetically obese Zucker rats that have a mutant ObRb isoforms, than are those in lean rats, suggesting a
role of the melanocortinergic Arc-PVH projection in
energy homeostasis regulation.110
In the rat, the PVH is composed of parvicellular and
magnocellular divisions, and the former is further
divided into several subdivisions (Figure 5).111–113
These divisions and subdivisions can be readily and
cytoarchitectonically distinguished by Nissl staining.
In the rat, neurons innervating parasympathetic and
sympathetic preganglionic neurons are located in the
dorsal, ventral, and lateral parvicellular subdivisions,
while hypophysiotropic neurons are characteristically distributed in the medial parvicellular subdivision.111–113 Relevant to current discussions, these
subdivisions display overlapping distributions of
MC4-R mRNA and axon terminals containing aMSH or AgRP. First, a population of MC4-R-positive
Molecular Psychiatry
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
136
Figure 5 (a) Radioisotopic in situ hybridization demonstrates MC4-R mRNA expression (white silver grains) in the
PVH in the rat (modified from Kishi et al,79 with permission). The expression is evident especially in the medial
parvicellular division (mp) that contains hypophysiotropic
neurons, as well as in the dorsal parvicellular (dp) and
ventral parvicellular (vp) divisions that contain neurons
projecting to autonomic preganglionic neurons in the
medulla and spinal cord. (b) Lateral view of the rat brain.
(c) Coronal section of the rat brain at a rostral-to-caudal level
shown by a vertical line in b. A boxed area in (c) indicates
the location of the PVH in the coronal section. pm, posterior
magnocellular division; 3v, third ventricle.
PVH neurons may relay inputs from leptin-responsive
a-MSH neurons in the Arc to autonomic preganglionic neurons, supporting the implication of melanocortins and MC4-Rs in autonomic regulation.35,79,80
Secondly, Lu and colleagues provided evidence
that melanocortins regulate the hypothalamic–
pituitary–adrenal axis via MC4-R-positive PVH
neurons.114 The authors demonstrated a subset of
PVH cells that coexpresses MC4-R and corticotropinreleasing hormone (CRH) mRNAs. Centrally administered MT-II (a melanocortin receptor agonist)
rapidly induced CRH gene transcription, and MT-IIinduced increase in plasma corticosterone levels
was suppressed by a selective MC4-R antagonist
HS014.
Thirdly, evidence supporting the role of leptin and
melanocortin action on the thyroid axis is also
increasing. For example, the PVH contains a number
of cells coexpressing pro-thyrotropin-releasing hormone (proTRH) and MC4-R mRNAs.115 Transcriptional control of the TRH gene is regulated by leptin
and melanocortin signaling.115 An electron-microscopic study demonstrated a-MSH-positive terminals
that synapse on TRH-producing PVH neurons.116
Recently, the effect of AgRP on the thyroid axis was
examined in wild-type (WT) and MC4-R-deficient
mice.117 As a result, centrally administered AgRP
suppressed circulating levels of thyroxine and inhibited proTRH mRNA expression in the PVH of WT
mice, whereas these effects were not observed in mice
lacking MC4-Rs.
Taken together, once again, these observations
suggest that subsets of PVH neurons expressing
MC4-Rs may mediate leptin action to control the
autonomic and neuroendocrine systems responsible
for maintaining energy equilibrium.
Molecular Psychiatry
2. Lateral hypothalamic area (LHA): Alpha-MSHpositive and AgRP-positive fibers densely terminate
in LHA, especially in the perifornical region (Figures
2b, d and 3d, f).71,72 Notably, subsets of these neurons
providing these inputs are leptin-responsive.66 As
noted, the LHA has long been considered to play an
essential role in regulating food intake. Recently, two
orexigenic peptides produced by discrete populations
of LHA neurons in rodents and humans refocused
attention on the LHA: melanin-concentrating hormone (MCH)118–120 and the orexins (ORX, also called
hypocretins).121 One of the unique features of both
sets of neurons is that they provide monosynaptic
projections to a variety of CNS sites including the
cerebral cortex, amygdala, and the spinal cord.118–121
Similarly, a broad distribution of the receptors that
bind these peptides has also been reported.122–125
MCH stimulates feeding behavior when administered centrally.119 Levels of MCH mRNA are increased
during fasting when leptin levels rapidly fall. Importantly, mice lacking MCH are hypophagic and lean
despite lowered levels of POMC mRNA and leptin,120
whereas mice overexpressing MCH are obese and
hyperleptinemic.126 More importantly, mice lacking
both MCH and Ob-Rbs display a significant reduction
in fat mass, compared with ob/ob mice.127 Taken
together, it is persuasive that MCH signaling is
downstream of leptin.
ORX knockout mice exhibit deficits in sleep/wake
control and a narcolepsy-like phenotype.128 Dogs
lacking the ORX-2 receptor are also narcoleptic.129
Notably, a very high percentage of narcoleptic
patients are ORX-deficient.130,131 Like MCH, ORX
exerts a stimulatory effect on food intake, although
the effect on consolidating sleep/wake states is more
profound and clearly established.121,128–132 Therefore,
it is conceivable that ORX may maintain arousal and
locomotor activity, both of which are essential for
food-seeking behavior following periods of fasting.133
Finally, as noted, the distribution of MCH- and ORXpositive terminals is widespread not only in subcortical regions but also in cortical regions.118–121,133
This unique hypothalamo-cortical innervation pattern implicates both peptides in regulating complex
cognitive function. This concept is worth noting
when attempting to link sites regulating body weight
homeostasis and those involved in several psychiatric
disorders. Clearly, feeding represents a fundamental
goal-oriented behavior.
Based on the aforementioned neuroanatomic
data,71,72 one might expect that MCH and/or ORX
neurons coexpress MC4-Rs. However, the levels of
MC4-R mRNA expression in the rodent LHA are
relatively low, and only a few MC4-R-positive cells
are scattered in the perifornical region.79,80 In addition, an electrophysiological study reported no detectable effect of synthetic MC4-R/MC3-R ligands on
membrane potentials or firing rate in MCH cells.134
On the other hand, a presynaptic action of a-MSH
on PVH-projecting GABAergic neurons has been
demonstrated electrophysiologically.135 Thus, whether
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
endogenous melanocortins act presynaptically on
MC4-Rs expressed on axon terminals that synapse on
MCH and/or ORX neurons deserves future analysis.
3. Central nucleus of the amygdala (CeA): The
amygdala has received relatively little attention in the
field of obesity research; however, this limbic site is
potentially important in regulating food intake. For
example, amygdala lesions produce hyperphagia and
obesity in rodents.136 Bilateral microinjections of a
selective MC4-R antagonist HS014 into the CeA
increase food intake.137 Within the CeA (Figure 1b),
a subnucleus of the amygdala, a-MSH- or AgRPpositive axons are accumulated preferentially in the
medial region107 in which MC4-R-positive cells
populate.35,79,80 Thus, although relatively understudied, the CeA represents a potentially important site
of melanocortin action.
4. Intermediolateral nucleus of the spinal cord
(IML): Subsets of Arc POMC neurons project to the
IML in which sympathetic preganglionic cholinergic
neurons113 and cells expressing MC4-R mRNA reside.79 These MC4-R-positive cells are sympathetic
preganglionic neurons, as they coexpress choline
acetyltransferase mRNA.79 Notably, a population of
Arc POMC neurons projecting to the IML is leptinresponsive.65 Additionally, cholinergic cells in the
dorsal motor nucleus of the vagus (ie, parasympathetic preganglionic neurons) also express MC4-R
mRNA.79 These findings support a critical role of
MC4-Rs in autonomic regulation, as did the expression of MC4-R mRNA in the PVH. Put another way,
this model predicts that both the direct Arc-IML and
indirect Arc-PVH-IML pathways likely contribute to
the autonomic and metabolic effects of melanocortin
receptor agonists.138–141
Combinations of genetic and anatomic approaches
to characterize leptin–melanocortin signaling
CNS circuits
1. Deletion of leptin receptors specifically from POMC
neurons: As stressed above, a large body of evidence
indicates that POMC neurons in the Arc mediate
leptin action. However, Ob-Rbs are not localized
exclusively in the Arc. As noted, leptin-independent
melanocortinergic pathways also exist.103–105 Therefore, our laboratory has recently tested the extent to
which Arc POMC neurons contribute to CNS leptin
signaling by using the Cre/loxP system.103 First,
transgenic mice expressing Cre in POMC neurons
(POMC-Cre mice) were generated by using a POMC
bacterial artificial chromosome. Subsequently,
POMC-Cre mice were crossed with mice bearing the
lox-modified leptin receptor allele (POMC-Cre,
Leprflox/flox mice). This cross successfully deleted leptin
receptors specifically from POMC neurons, resulting
in increased fat mass, hyperleptinemia, and altered
hypothalamic peptide levels. However, the loss of
leptin receptors on POMC neurons did not significantly affect food intake and energy expenditure.
These observations indicate that Ob-Rb expression
by POMC neurons is required for normal body weight
homeostasis and that leptin action on neurons other
than POMC neurons contributes to the varied effects
of this hormone. Deletion of leptin receptors in other
brain sites (alone and in combination with POMC
deletion) may help to unravel this complex web of
circuitries. This attempt will include the use of other
transgenic mice expressing Cre in selected neuronal
populations, as well as of stereotaxic injections of an
adenoassociated viral vector that drive the Cre
expression.142 Clearly, these combined approaches
will continue to evolve strategies to survey the
physiologically important CNS circuitries mediating
the effects of key metabolic signals including leptin,
glucose, and ghrelin.
2. Labeling of MC4-R-positive cells with GFP: The
melanocortinergic CNS network has hitherto been
difficult to trace, as sensitive and specific antibodies
against the MC4-R protein are unavailable. Therefore,
it remains unknown whether a-MSH- and/or AgRPpositive terminals synapse on MC4-R-positive cell
bodies, dendrites, or axon terminals. The brain sites
downstream of neurons expressing MC4-Rs are also to
be determined. Moreover, relevant research is behind
in identifying chemical profiles of MC4-R-positive
neurons (ie, potential neurotransmitters by which
melanocortinergic pathways are engaged), with only a
few notable exceptions such as TRH-producing or
CRH-producing PVH cells,114,115 and cholinergic
autonomic preganglionic cells in the DMV and
IML.79,80
To help address these issues, we recently validated
a transgenic mouse line expressing GFP under the
control of the MC4-R promoter, which had been
generated by Friedman and coworkers.80 For this
purpose, we confirmed that the brain distribution
patterns of GFP-immunoreactive cells are reconciled
with those of cells expressing MC4-R mRNA in WT
mice (Figure 6), that MC4-R mRNA is expressed on
nearly all the GFP-immunoreactive cells, and that
MT-II, a synthetic MC3-R/MC4-R agonist, depolarizes
GFP-positive cells. This animal model will facilitate
the demonstration of melanocortinergic axon terminals that make synaptic contacts with MC4-Rpositive cells using electron microscopy. Moreover,
the projection patterns of MC4-R-positive neurons
can be determined by using retrograde tract tracing,
an established neuroanatomic technique that is based
on the ability of axon terminals to take up substances
(eg, cholera toxin B subunit and fluorogold) from
extracellular space and transport them back to cell
bodies. This mouse model will also promote the
identification of the chemical phenotypes of cells
expressing MC4-Rs. In this model, for example, we
identified oxytocin-positive, GABAergic, and CRHpositive GFP cells, respectively, in the PVH, LHA, and
in the CeA by using a combination of immunohistochemistry for GFP and in situ hybridization histochemistry.80 Consistent with the electrophysiological
evidence introduced earlier,134 no GFP cells coexpressed MCH mRNA in the LHA. ORX cells were also
MC4-R-negative.
137
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T Kishi and JK Elmquist
138
Figure 6 (a–g) A series of line drawings arranged rostrocaudally showing the distribution of cells (red dots) showing
immunoreactivity for GFP in the transgenic mouse expressing GFP under the control of the MC4-R promoter (modified from
Liu et al (2003), with permission). h: GFP-producing cell labeling the MC4-R. Bar ¼ 10 mm. ac, anterior commissure; Acb,
nucleus accumbens; ACo, anterior cortical nucleus of the amygdala; AHP, anterior hypothalamic nucleus, posterior part;
AVPV, anteroventral periventricular nucleus; BLA, basolateral nucleus of the amygdala, anterior part; BLP, basolateral
nucleus of the amygdala, posterior part; BMA, basomedial nucleus of the amygdala; BST, bed nucleus of the stria terminalis;
CA1, hippocampal field of CA1; CA3, hippocampal field of CA3; CeA, central nucleus of the amygdala; Cg, cingulated cortex;
CPu, caudate-putamen; DG, dentate gyrus; DMH, dorsomedial nucleus of the hypothalamus; Ect, ectorhinal cortex; fx, fornix;
IL, infralimbic cortex; Ins, insular cortex; LA, lateral nucleus of the amygdala; LEnt, lateral entorhinal cortex; LHA, lateral
hypothalamic area; LHb, lateral habenular nucleus; LOT, nucleus of the lateral olfactory tract; LSN, lateral septal nucleus; lv,
lateral ventricle; MeA, medial nucleus of the amygdala; Mo, motor cortex; MPO, medial preoptic nucleus; PFA, perifornical
area; Pir, piriform cortex; PLCo, posterolateral cortical nucleus of the amygdala; PRh, perirhinal cortex; PVH, paraventricular
nucleus of the hypothalamus; Re, nucleus reuniens; SFO, subfornical organ; SS, somatosensory cortex; Tu, olfactory tubercle;
VMH, ventromedial nucleus of the hypothalamus; VMPO, ventromedial preoptic nucleus; ZI, zona incerta.
Clearly, this approach is useful for identifying
the MC4-R system in the CNS. A larger point is that
the use of several similar mouse models will drive the
field of ‘molecular neuroanatomy’. Moreover, these
tools provide more invaluable information concerning a multitude of neuropeptide and neurotransmitter
systems that have so far been difficult to study due to
the inherent lack of specific and sensitive regents.
The MC3-R underlying diverse melanocortin effects on
energy homeostasis
Another melanocortin receptor subtype, the MC3-R
coupled to Gs/Gq, is also expressed in the brain and
plays a role in regulating metabolism, albeit much
less studied.33,34,143 Notably, another POMC-derived
peptide g-MSH binds to MC3-Rs with a high affinity,
and AgRP antagonizes g-MSH action on MC3-Rs.33,143
The brain distribution of MC3-Rs also significantly
differs from that of MC4-Rs. The rat PVH, for example,
expresses MC4-R mRNA but apparently not MC3-R
mRNA.33,79 Conversely, the ventromedial nucleus of
the hypothalamus (VMH) is one of the sites that
express high levels of MC3-R mRNA, whereas MC4-RMolecular Psychiatry
positive VMH cells are relatively few.33,79 Another
noticeable difference is that POMC and AgRP neurons
in the Arc express MC3-Rs but not MC4-Rs, suggesting a potential role of MC3-Rs in regulating the
melanocortinergic local circuits within the Arc.107
Although MC3-R-deficient mice are not hyperphagic,
they do display an increased fat mass.144,145 Clearly,
more studies are needed to identify the MC3-Rpositive sites responsible for energy balance regulation. Nevertheless, these observations indicate the
existence of anatomically and functionally divergent
melanocortinergic CNS pathways.
The NPY/Y1-receptor system: another feeding
regulator counterpoised to the melanocortin system
NPY is an established potent stimulator of food
intake.146–148 NPY also affects endocrine/autonomic
responses, seizures, and anxiety.146–148 NPY neurons
are distributed in many CNS sites, including the
Arc.149,150 Importantly, NPY-producing Arc neurons
coexpress AgRP and are inhibited by leptin.66,68,69,97,98
Of NPY receptor subtypes, the Y1-, (Y1-R), Y2-, and
Y5-receptors have been implicated in the regulation
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
of feeding.146–148,151–155 NPY neurons in the Arc may
contribute to ORX’s effects on food intake, as ORX
neurons innervate this NPY neuronal population
and stimulate it.156 Presently, we will focus on the
Y1-R, as accumulating evidence suggests that this
Y-receptor subtype contributes to NPY action not only
on consummatory behavior but also on emotional
responses.
Here, it should also be noted that several genetic
studies do not generally support a role of NPY/Y1-R
system in food intake. For example, NPY/ and Y1R/ mice are not hypophagic,157–160 although this
may be dependent on the background strain of the
mouse studied. Nevertheless, other lines of evidence
indicate that such discrepancies do not diminish the
potential therapeutic efficacy of NPYergic agents.
When ob/ob mice are crossed with NPY/ mice, the
obesity phenotype is partially corrected.161 Moreover,
Y1-R/ mice display a markedly blunted feeding
response to fasting.159 Finally, the stomach-derived
hormone, ghrelin, increases food intake and can
directly act on Arc NPY neurons,6,7,26,162–164 supporting an important role of Arc NPY/AgRP neurons in
feeding regulation. Ghrelin is the endogenous ligand
for the growth hormone secretagogue receptor.6,7,26,162–164
Ghrelin administration not only increases food
intake but also causes hypothermia and decreased
oxygen consumption. Deletion of ghrelin also affects
metabolic responses to high-fat diet feeding in
mice.165
Like MC4-R mRNA, Y1-R mRNA is expressed in
several brain sites critical for energy balance regulation in rodents, including the PVH and CeA.166–168
Moreover, by using the MC4-R/GFP mice line, we
identified MC4-R-positive cells coexpressing Y1-R
mRNA in these forebrain sites that receive both
NPY and melanocortinergic inputs.80,107,149,150 Consequently, relevant to current discussions,15,23 we
hypothesize that the convergence of leptin/melanocortin and NPY signaling pathways likely contributes
to their counterpoised relationship in energy balance
regulation (Figure 4).
The intersection of body weight homeostasis, classic
neurotransmitters, and psychiatry
Ideally, when discussing body weight homeostasis,
one could distinguish ‘appetite’ from other metabolic
processes such as the regulation of energy storage and
expenditure, insulin secretion, and gastrointestinal
mobility. However, this is inherently difficult as
various homeostatic control systems are intrinsically
linked and interconnected. Nonetheless, in this
section, we will discuss the melanocortin and NPY
systems once again from this point of view, and
classic neurotransmitters, as well on which many of
psychotropic agents exert their influence. We will
also discuss a link between feeding and emotion, and
relevant several psychiatric issues.
The brain reward mechanism is a key to trace
the neural mechanism of appetite. The reader is
referred to reviews by Saper et al,20 and by Figlewicz
and Woods169 that outline the hedonic aspect of
feeding.
The dopaminergic projection to the nucleus accumbens (Acb) from the ventral tegmental area (VTA)
is clearly important in reward processes.170 The VTA–
Acb pathway has also been implicated in motivating
and rewarding aspects of food intake, for example, by
electrochemically monitoring dopamine transmission
in the Acb of rats lever-pressing to feed.171 Here, it is
interesting to note that high levels of MC3-R mRNA
are expressed in the VTA, where g-MSH-positive axon
terminals are distributed.33,107 As opioid receptor
antagonists block the feeding-stimulatory effect of
AgRP, the melanocortin system may regulate appetite.172 Thus, whether dopaminergic VTA neurons
projecting to the Acb coexpress MC3-Rs is worth
exploring.
Cancer-induced cachexia (ie, anorexia and weight
loss) is another example that implicates the melanocortin system in the control of appetite. Notably, in
anorectic tumor-bearing rats, food intake can be
markedly increased by treatment with a synthetic
MC4-R antagonist SHU9119.173 MC4-R/ mice and
mice treated with AgRP also resist tumor-induced
weight loss.174
It has also been speculated that melanocortins may
counteract addiction. Chronic morphine administration reduces levels of MC4-R mRNA in the olfactory
tubercle, striatum, Acb, and the periaqueductal gray
(PAG) in the rat.12–14 Interestingly, the m-opioid
receptor (m-R) is enriched in these sites.175 Melanocortins can antagonize the addictive properties of
opiates and can provoke signs analogous to those by
opiate withdrawal in drug-naive animals.13,176 In
addition, b-endorphin, like a-MSH and g-MSH, is
cleaved from POMC,13,70,177 suggesting that the endogenous opioid peptide and melanocortins may be
coreleased.13,77 Moreover, mice lacking b-endorphin
display a deficit in the ability of food reward to
increase bar-pressing behavior.178 As hypothesized by
Alvaro et al,13 melanocortin and opioid signaling may
converge on neurons coexpressing the MC4-R and
m-R, in which functional antagonism could occur
intracellularly at the second messenger level. Interestingly, the PAG receives melanocortin inputs and
expresses MC4-R mRNA and m-R mRNAs.77,79,80,107,175
In addition, the PAG is more deeply implicated in
morphine dependence than is the VTA.179 Collectively, it is attractive to speculate that melanocortinergic agents may be effective in treating addiction.
Alcohol can also be regarded as a reward. Evidence
suggests that the NPY/Y1-R system regulates ethanol
consumption and resistance. NPY-deficient mice
consume significantly more ethanol than do WT
mice, and are less sensitive to the sedative effect.180
In contrast, transgenic overexpression of the NPY
gene in neurons results in a lower preference for
ethanol in mice.180 Moreover, Y1-R/ mice exhibit
significantly increased voluntary consumption of
ethanol solutions, compared to WT control mice.181
Evidence that implicates the dopaminergic reward
139
Molecular Psychiatry
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
140
system in alcoholism is also growing.182 Clearly,
however, more studies are required to better understand the relation between the NPY/Y1-R and reward
systems, and that between these systems and alcoholism. Nonetheless, it has been demonstrated that
the Acb receives NPY inputs149,150 and expresses Y1-R
mRNA in rodents.166–168 Additionally, Y1-R mRNA is
faintly expressed in the mouse VTA but not at all in
the rat VTA.166–168
Historically, serotonin 5-hydroxytryptamine (5-HT)
remains one of the amines most intensively studied in
psychopharmacology.183 Currently, serotonin-selective reuptake inhibitors (SSRIs) are widely used for
the treatment of depression and bulimia nervosa.
Melanocortins including a-MSH also influence several classes of emotion and motivated behavior.70 In
addition, the significance of MC4-Rs in regulating
emotion has been re-evaluated pharmacologically.
When administered centrally, for example, a MC4R-selective antagonist HS014 attenuates anorexia
induced by restraint stress.184 A novel MC4-R-selective antagonist MCL0020 also prevents stress-induced
behavioral changes in rodents.185
As noted above, the melanocortin system is involved in regulating the hypothalamo–pituitary–
adrenal (HPA) axis.114 The dysregulation of this axis
is likely associated with mood disorders including
depression, although it remains unclear whether
deficits in the HPA axis cause depression or are
secondary to it.186,187 In either case, excessive activation of the HPA axis is common in patients with
depressive mood and is corrected by treatment with
antidepressants.186 Interestingly, an electrophysiological study demonstrated that MT-II, a synthetic
agonist for MC3-R/MC4-R, increased the firing rate of
5-HTergic dorsal raphe (DR) neurons that may play a
role in regulating emotion and behavior.188 Consistent
with this finding, the DR contains cells expressing
MC4-R mRNA in rodents.35,79,80 Collectively, PVH and
DR neurons expressing MC4-Rs may be involved in
the pathophysiology of anxiety and mood disorders.
Serotonergic drugs significantly reduce appetite,
whereas 5-TH2cR-deficient mice are hyperphagic and
obese.189 Notably, the Arc receives inputs from 5-HTpositive raphe nucleus neurons.190 Recently, Heisler
et al191 reported that a subset of Arc POMC cells
coexpressed 5-TH2c receptors (5-HT2cRs) and was
activated by anorectic doses of d-fenfluramine (dFen), a drug that blocks the reuptake of 5-HT and
stimulates its release. In the mid-1990s, d-Fen was
prescribed to millions of patients suffering from
morbid obesity in the United States, frequently in
combination with phentermine.192 This treatment
regimen proved to be very effective in decreasing
food intake and body weight. However, after reports
of adverse cardiopulmonary events, the Food and
Drug Administration withdrew d-Fen from clinical
use in 1997.193 Nevertheless, the existence of 5-HTresponsive POMC cells strongly suggests that the
central melanocortin system contributes to the anorectic effects of 5-HT. It is also interesting to speculate
Molecular Psychiatry
based on the observation that auto-antibodies are
raised against a-MSH and adrenocorticotropic hormone in patients with anorexia and bulimia nervosa.9
Taken together, it is conceivable that 5-HT action on
Arc melanocortinergic neurons may contribute to the
pathophysiology of morbid ingestive behavior. The
Arc provides reciprocal innervation to the DR
nucleus,194,195 supporting an interaction between
these two brain sites. In mood disorders, however,
the relationship between 5-HT and prevalent anorexia
is paradoxical. Serotonergic agents apparently suppress appetite, whereas 5-HT levels in anorectic
depressed patients are presumably low. Many of the
commonly used antidepressants inhibit the uptake of
serotonin. As serotonergic innervation is widespread
across the brain, 5-HT neural circuits underlying
feeding and emotion have been inherently difficult to
discern. However, the serotonergic pathway to the
Arc from raphe nuclei merits further investigation.
Antipsychotic agents, especially ‘atypical’ antipsychotics, often produce obesity and diabetes mellitus,
and infrequently diabetic ketoacidosis or coma.2–4 On
one hand, there is a possibility that antipsychotics
directly influence peripheral organs per se, including
pancreatic b-cells, liver, adipose tissue, and skeletal
muscle, resulting in impaired glucose tolerance.196,197
On the other hand, antipsychotics may affect CNS
systems regulating glucose metabolism. The 5-HT/5HT2cR system is one of the candidates, as several
antipsychotic agents bind to 5-HT2cRs with high
affinities.198 As noted, a population of Arc a-MSH
neurons expresses 5-HT2cRs and is leptin-responsive.
In addition, the MC4-R likely regulates pancreatic
b-cell function, as MC4-R/ mice exhibit hyperglycemia and impaired insulin tolerance before the onset
of obesity.138 The MC4-R is also involved in sensitizing peripheral tissue to insulin action.139–141 Centrally
administered a-MSH markedly enhances insulin
action on glucose uptake as well as on hepatic
glucose production, whereas MC4-R antagonism exerts opposite effects.139 Finally, patients with MC4-R
mutations are very insulin-resistant.84 Collectively,
these findings suggest that dysregulation of the 5-HTdriven melanocortin system may be involved in
obesity and diabetes as adverse effects of antipsychotic agents.
Additionally, the use of antipsychotics often produces hyperleptinemia.2–4 It is unknown, though,
whether this condition is due to the use of antipsychotics itself or obesity resulting from it. Nonetheless, rapid increases in leptin levels may be a
marker to predict long-term weight gain in patients on
medication with clozapine.199
Acetylcholine has also been indicated to influence
MCH signaling; for example, a cholinergic agonist
carbachol increases MCH mRNA expression in hypothalamic slices.200 MCH is, as stressed, an established
regulator of energy balance118–120,126,127 and is produced at the LHA that receives leptin and melanocortinergic signals.66,71,72 Notably, a subset of MCH
neurons coexpresses the M3 muscarinic acetylcholine
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
receptor (M3Ach-R), and M3Ach-R/ mice are
hypophagic despite extremely low levels of serum
leptin.201 MCH accelerates feeding in M3Ach-R/
mice when administered centrally, whereas an AgRP
analogue does not. This study indicates that M3AchR-mediated acetylcholine signaling at a site downstream of the leptin/melanocortin system and upstream of the MCH system is critical in facilitating
food intake.201 Anticholinergic agents are occasionally used to alleviate extrapyramidal adverse effects
by neuroleptics. It is significant to examine if and
how anticholinergic medication in psychiatric practice influences body weight homeostasis.
The ascending cholinergic projections to the lateral
hypothalamus originate in the laterodorsal tegmental
and pedunculopontine tegmental nuclei in the
brainstem.200,202 These nuclei are responsible for
regulating sleep and wakefulness, especially for
rapid-eye-movement (REM) sleep.132 Thus, it is
plausible that subsets of MCH neurons may integrate
sleep and metabolic cues into coordinated behavioral
responses.
Cognitive function, regulated by cortical circuits,
should also be mentioned to discuss feeding, a class
of goal-oriented behavior. The hippocampus is noteworthy in this respect, as this limbic structure is
thought to integrate neocortical information, resulting
in coordinated emotional and behavioral responses to
external stimuli.203 The efferent pathways from the
hippocampus are glutamatergic.203 Importantly, the
medial and perifornical hypothalamic regions receive
dense hippocampal inputs204 and are enriched with
ionotropic glutamate receptors.205 A recent electrophysiological study demonstrated that glutamate
release excited MCH cells, in which a viral approach
was used to label MCH cells with GFP expression.134
In contrast, NPY was found to be inhibitory by preand postsynaptic mechanisms in this study.
NPY-positive fibers densely terminate in the perifornical area of the lateral hypothalamus (PFA), many
of which originate in the Arc.71,72 Whereas levels of
Y1-R mRNA expression are relatively low in the
PFA, the subiculum (a major output source of the
hippocampus203,204) expresses high levels of Y1-R
mRNA in rodents.166–168 The expression of Y1-R
mRNA in the hippocampus has also been demonstrated in humans.206 Collectively, these findings
imply that multi-modal cortical information may
influence the activity of MCH neurons via the
hippocampus–hypothalamus pathway to regulate
ingestive behavior. In addition, Arc-derived NPY
may act presynaptically on Y1-Rs expressed on
hippocampal axon terminals that synapse on a subset
of MCH neurons, in order to modulate the cortical
information by mediating peripheral metabolic cues.
Consistent with this hypothesis, Y1-R-immunoreactive axons are densely distributed in the lateral
hypothalamus.167
When administered centrally, an antisense oligodeoxynucleotide for the Y1-R produces behavioral
signs of anxiety measured with plus maze testing.207
Transgenic overexpression of NPY in the rat markedly
attenuated behavioral sensitivity to restraint stress
and decreased NPY-Y1-R binding in the hippocampus.208 Thus, Y1-R-mediated hippocampal NPY
signaling may be involved in anxiety and related
disorders.
As mentioned earlier, the hypothalamus innervates
a wide extent of cortical areas via neurons producing
MCH or ORX.118,121,133 Thus, metabolic, emotional,
and cognitive information may be assimilated at the
hypothalamus, and in turn forwarded to the neocortex, resulting in the ultimate decision to eat or not to
eat. An interrelation between cortical glutamatergic
and ascending dopaminergic systems has also been
discussed to re-evaluate the classic dopamine hypothesis of schizophrenia,209 which may also be relevant
to the CNS mechanisms of feeding as a motivated
behavior. Needless to say, GABA is also important not
only in cortico-subcortical circuits but also in subcortical circuits.24 It is notable that GABA plays a role
in regulating key hypothalamic circuits, as illustrated
by Cowley et al,69 and van den Pol et al.134 Clearly,
neuropeptides have received much attention in the
field of obesity research. However, the regulation of
hypothalamic synaptic activity critical for coordinated food intake and body weight likely relies on the
action of amino-acid transmitters including glutamate
and GABA.
141
Conclusion and perspectives
A series of classic lesion studies established that
certain hypothalamic cell groups regulate food intake
and body weight. The discovery of leptin in 1994
catalyzed a remarkable increase in understanding of
hypothalamic mechanisms of energy homeostasis
regulation.5 Since then, an enormous amount of work
traced the CNS machinery downstream of leptin
signaling, including the central melanocortin and
NPY systems. These systems are critical to explore the
mechanism of the disequilibrium between energy
intake and expenditure by mental disorders and/or by
psychotropic agents. In addition to a variety of
molecules involved in feeding regulation, neuromedin U (NMU) has recently been established as a novel
anorexigenic hypothalamic peptide independent of
leptin signaling.210 Like the MC4-R and Y1-R, a
subtype of NMU receptors is expressed in the rat
hypothalamus.211,212 If and how NMU affects CNS
systems regulating emotion and behavior remain open
to future analysis. Moreover, there are undoubtedly
other molecules that will be discovered and may
serve as links between obesity and psychiatry research.
Apparently, focusing on such functionally and
anatomically defined brain systems should promote
a new line of psychiatric research. These types of
studies have long been very difficult to undertake
despite a large body of evidence that several CNS
neurotransmitter systems mediate psychotropic action. This was due in large part to the lack of CNS
Molecular Psychiatry
Brain systems regulating energy homeostasis and emotion
T Kishi and JK Elmquist
142
molecules that define respective psychiatric disorders, and therefore the target brain sites have been
unspecified. Nevertheless, food intake and body
weight are psychiatric parameters that are readily
quantified, and thus, relevant genetically modified
animals are useful in psychiatry research. Moreover,
as discussed, several CNS systems responsible for
energy balance are also involved in regulating emotion and several classes of behavior. We believe that
the use of multidisciplinary molecular and neuroanatomic techniques illustrated in this article will
elucidate the brain circuits underlying energy homeostasis and emotion, and will contribute to establishing new therapeutic strategies for psychiatric
illnesses.
Acknowledgements
This work was supported by the National Institute of
Health; Grant number DK56116; Grant number
DK53301; Grant number MH61583; Grant number
DK 567658; Grant number 2 R01 DK041096-14A1, as
well as by the Yamada Science Foundation and Kato
Memorial Bioscience Foundation.
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