Download Galanin-like peptide: a key player in the homeostatic regulation of

International Journal of Obesity (2011) 35, 619–628
& 2011 Macmillan Publishers Limited All rights reserved 0307-0565/11
www.nature.com/ijo
REVIEW
Galanin-like peptide: a key player in the homeostatic
regulation of feeding and energy metabolism?
S Shioda1, H Kageyama1, F Takenoya1,2and K Shiba1
1
Department of Anatomy, Showa University School of Medicine, Tokyo, Japan and 2Department of Physical Education,
Hoshi University School of Pharmacy and Pharmaceutical Science, Tokyo, Japan
The hypothalamus has a critical role in the regulation of feeding behavior, energy metabolism and reproduction. Galanin-like
peptide (GALP), a novel 60 amino-acid peptide with a nonamidated C-terminus, was first discovered in porcine hypothalamus.
GALP is mainly produced in the hypothalamic arcuate nucleus and is involved in the regulation of feeding behavior and energy
metabolism, with GALP-containing neurons forming networks with several feeding-regulating peptide-containing neurons. The
effects of GALP on food intake and body weight are complex. In rats, the central effect of GALP is to first stimulate and then
reduce food intake, whereas in mice, GALP has an anorectic function. Furthermore, GALP regulates plasma luteinizing hormone
levels through activation of gonadotropin-releasing hormone-producing neurons, suggesting that it is also involved in the
reproductive system. This review summarizes the research on these topics and discusses current evidence regarding the function
of GALP, particularly in relation to feeding and energy metabolism. We also discuss the effects of GALP activity on food intake,
body weight and locomotor activity after intranasal infusion, a clinically viable mode of delivery.
International Journal of Obesity (2011) 35, 619–628; doi:10.1038/ijo.2010.202; published online 12 October 2010
Keywords: galanin-like peptide; feeding; energy metabolism; reproduction; clinical implication
Introduction
Galanin, which was originally isolated from porcine upper
small intestine, is a 29 amino-acid orexigenic peptide (30 in
humans).1 Galanin has a widespread distribution in various
brain regions such as the bed nucleus of the stria terminalis,
amygdala, hippocampus, locus coeruleus, hypothalamus
containing the preoptic suprachiasmatic nuclei, the supraoptic, the hypothalamic periventricular, the paraventricular
(PVH) and the arcuate nucleus (ARC).2 In addition, galanin is
also present in the sensory dorsal root ganglion cells,
interneurons in the spinal cord and sympathetic neurons
innervating the islet of Langerhans in the pancreas.3,4 The
galanin receptors are a member of the G-protein-coupled
receptor family and have three known subtypes, GALR1,
GALR2 and GALR3. On the basis of studies using pharmacological reagents, and the GALR1 and GALR2 knockout and
galanin-overexpressing transgenic animals, galanin has been
implicated in stimulating feeding behavior, cognitive performance and mood through the central mechanisms.5,6
Correspondence: Dr S Shioda, Department of Anatomy, Showa University
School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
E-mail: [email protected]
Received 24 September 2009; revised 2 May 2010; accepted 30 July 2010;
published online 12 October 2010
In 1999, galanin-like peptide (GALP) was isolated from
the porcine hypothalamus by Ohtaki et al.7 on the basis
of its ability to bind and activate galanin receptors in vitro.
GALP is a novel 60 amino-acid peptide, the amino-acid
residues (9th-21st) of which are identical with the biologically active N-terminal (1st-13th) portion of galanin,7
and its cDNA has been cloned from pig,7 rat,7,8 mouse,9,10
monkey11 and human.7 GALP can be detected in the general
circulation, with a high concentration being found in the
blood. Fasting for 48 h, but not for 24 h decreases both
plasma GALP levels and GALP influx into the brain.12 To
date, GALP has been shown to act as an agonist at all three
galanin receptor subtypes in vitro, although it shows
preference for GALR2 and GALR3, as compared with
GALR1.7,13
There is a considerable body of evidence linking GALP to
the regulation of food intake, energy metabolism and
reproduction,13–19 as well as fluid intake.20,21 Furthermore,
recent reports have suggested that GALP has a role in
conditions such as epilepsy, Alzheimer’s disease22 and
diabetes,22–24 in addition to serving a vasoactive function.25
Here, we review a number of lines of investigation that have
advanced our understanding of GALP systems in the
hypothalamic nuclei, including localization and regulatory
studies, and suggest possible future research that may help to
clarify the precise functional significance of GALP.
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S Shioda et al
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GALP and its receptors
GALP was originally discovered as an endogenous ligand for
galanin receptors in the porcine hypothalamus.7,11,26 The
GALP gene comprises six exons with a structural organization similar to that of galanin (Figure 1).7,11 GALP is encoded
by a distinct gene located on chromosome 19 in humans,
chromosome 7 in mice and chromosome 1 in rat. GALP
(1st-60th) is cleaved from the precursor peptide preproGALP,
which consists of 115–120 amino acids depending on the
species, with GALP residues 9–21 being homologous to
residues 1–13 of galanin (Figure 2). The second region of
GALP (14th-60th) is dissimilar to any other known peptides
and may represent the binding portion for a GALP-specific
receptor.
Although the existence of a putative receptor for endogenous GALP has been suggested,27 the molecular identity of
this receptor remains unknown. The members of the galanin
peptide family were initially described as high-affinity
agonists for both GALR1 and GALR2, with GALP binding
preferentially to GALR2.7 In a later study, binding of GALP
was observed at all three human galanin receptor subtypes
expressed in human neuroblastoma cells, with the highest
affinity being observed for GALR3, followed by GALR2; the
putative fragment GALP (3rd-32nd) was also more effective
than mature GALP (1st-60th) at displacing 125I-galanin.13
In situ hybridization mapping studies have shown that all
three galanin receptor (GALR1–3) transcripts are present
throughout the hypothalamus, including the PVH, dorsomedial nucleus (DMH), lateral hypothalamus (LHA) and
periventricular nucleus, although each subtype exhibits a
unique profile in terms of its abundance and distribution. In
addition, GALR1 is expressed in the supraoptic nucleus and
nucleus tractus solitarius.28,29 When GALP is injected
centrally, GALR2-expressing neurons in the PVH do not
show c-Fos expression, whereas GALR1-expressing neurons
in the supraoptic nucleus display strong c-Fos expression.
Thus, there are differences in the distribution of neurons
activated by GALP and those expressing its receptor. These
results imply the existence of an unidentified galanin
receptor that may be specific for GALP.
The receptor responsible for the anorectic function
of GALP is currently unknown. GALP reduces food intake
and body weight to the same degree in GALR1- and
GALR2-deficient mice when compared with wild-type
mice,30 and GALR2-deficient mice do not show abnormal
Figure 1 Gene structure of GALP in mouse. GALP is located on the chromosome 7. GALP gene consists of six exons. Amino acid is represented by one letter code.
EX, exon; bp, base pair; aa, amino acid.
Figure 2 The primary structure of galanin and GALP. The gray area indicates a common amino acid sequence in both galanin and GALP among different
organisms.
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Feeding and energy metabolism by GALP
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feeding behavior.15 Furthermore, the GALR2/3 agonist
(AR-M1896) has no effect on feeding or body weight in
either the rat or the mouse.19 Therefore, more studies are
required to determine the receptor mediating the anorectic
actions of GALP but, as this peptide can act differently in
rodents when compared with galanin, a new/unidentified
GALP-specific receptor is likely to be involved.
Distribution and localization of GALP-containing
neurons
Galanin is widely distributed in the brain, but GALP is found
only in neurons in the hypothalamic ARC, the median
eminence and the posterior pituitary gland. Using in situ
hybridization, GALP mRNA has been shown to be distributed
within the periventricular regions of the ARC,26,31,32 as well
as in the median eminence26,31 and posterior pituitary gland
of the rat.21 Larm et al.32 have reported that GALP mRNA
is highly expressed in the periventricular region of the
ARC, gradually increasing between postnatal days 8 and 14,
before markedly increasing between days 14 and 40,
which represent the weaning and pubertal period in rats.33
The expression of GALP may therefore be associated
with developmental changes linked to weaning, feeding
and maturation of reproductive function.33
Subsequently, based on immunohistochemical analysis
using an anti-GALP monoclonal antibody, GALP-positive
neuronal cell bodies have been demonstrated in the ARC,
being particularly dense in its medial posterior section and
in the posterior pituitary.34–36 In addition, GALP-positive
cell bodies are distributed in the median eminence and in
infundibular stalk, but are absent from other hypothalamic
nuclei and brain loci.9,35 GALP-containing neurons in
the ARC are reported to be different from the leptin
receptor-expressing neurons that express neuropeptide Y
(NPY)/agouti-related protein and galanin.32,36–38 GALP has
been shown to be coexpressed with a-melanocyte-stimulating
hormone, which is derived from pro-opiomelanocortin
in neurons in the ARC,36 with orexin-1 receptor immunoreactivity also being observed in a few GALP-positive neurons.38
We have previously reported that 3–12% of GALP-positive
cells contain a-melanocyte-stimulating hormone-like immunoreactivity.36 In spite of these findings, there are no other
neuropeptides or transmitters that are colocalized with GALP
in the ARC, suggesting that it is a unique peptide.
GALP-positive fibers in the rat ARC project to several
hypothalamic nuclei. There are at least two major proposed
GALP neural pathways, one in which GALP-containing
neurons project from the ARC to the PVH and the other in
which they project to the medial preoptic area, the bed
nucleus of the stria terminalis and the lateral septal nucleus
(Figure 3). GALP-positive cell bodies are present from the
rostral to the caudal part of the ARC, with fibers projecting to
PVH, bed nucleus of the stria terminalis, medial preoptic area
and lateral septal nucleus.35,39 In addition, GALP-positive
fibers are found in the LHA near the fornix.39
With regard to the target for GALP-containing neurons,
morphological studies have shown that GALP-positive fibers
appear to have direct contact with orexin- and melaninconcentrating hormone (MCH)-containing neurons in the
LHA.39 In addition, we have found that GALP-positive nerve
fibers appear to make direct contact with tyrosine hydroxylase-containing neurons in the ARC,40 suggesting that
GALP may interact with dopaminergic neurons in this
region. At the ultrastructural level, GALP-containing neurons in the ARC receive synapses from immunonegative
axon terminals that are symmetrical in the case of synapses
on the perikarya, and both asymmetric and symmetric
for dendritic processes.41 The axon terminals of these
Figure 3 Distribution of GALP-producing neurons in the brain. GALP-positive cell bodies are located in the ARC and posterior pituitary gland. GALP-positive fibers
project from the ARC to other part of the hypothalamus.
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GALP-positive neurons also often make synapses, all of
which are symmetric, on immunonegative dendrites.41
Synapses are also found between axon terminals and
perikarya, as well as dendrites, of GALP-positive neurons.41
GALP-positive axon terminals have been found to make
synapses on orexin-positive cell bodies and dendrites, but
not on MCH-positive neurons in the LHA.42 Further, in vitro
studies have suggested additional targets for GALP in the
hypothalamus, with activation of growth hormone-releasing
hormone-containing neurons isolated from the ARC, this
being reflected by increased cytosolic Ca2 þ levels.43 In
electrophysiological studies of ARC neurons in hypothalamic slices, GALP was shown to inhibit excitatory and
inhibitory postsynaptic currents in a similar way to galanin,
whereas the two peptides differentially affected the intrinsic
membrane properties, with galanin inducing hyperpolarization of the resting membrane potential and GALP having no
effect.44 Galanin also suppressed spontaneous firing in the
ARC, whereas GALP produced a mixture of suppression and
enhancement of firing, and appeared to antagonize the
galanin effects.44
Regulation of GALP neurons
Morphological studies have shown that GALP-containing
neurons in the ARC may be a target for the orexigenic
neuropeptides, NPY and orexin. Orexin-containing neurons
have been reported to make contact with GALP-positive
neurons in the ARC, with 9% of these neurons expressing
orexin-1 receptor protein.38 Furthermore, NPY-positive fibers
project to GALP-containing neurons in the ARC and PVH.36
These morphological studies suggest a potential role for
GALP in feeding and energy metabolism. GALP may exert
this effect through the galanin receptors GALR1–3, and is a
potential target for NPY and/or orexin.
It has previously been shown that 485% of GALPcontaining neurons express the leptin receptor.35 Fasting
decreases both the number of GALP-expressing neurons26
and the expression of GALP mRNA.45 Leptin administration
restores GALP-expressing cells in fasted rats26 and ob/ob
mice.9 It also induces a significant increase in GALP mRNA
levels in the hypothalamus, and GALP mRNA levels are
reduced in the hypothalamus of Zucker obese rats and db/db
and ob/ob obese mice,10 with GALP mRNA expression in
ob/ob mice being reversed by leptin replacement.10 These
findings clearly show that leptin positively regulates GALPrelated neuronal activity in the hypothalamus. Fraley et al.23
have also demonstrated that GALP-containing neurons are
responsive to changes in circulating concentrations of
insulin using streptozotocin-induced diabetic rats and
central injection of insulin into the fasted rat.
On the basis of studies using castrated, ovariectomized,
adrenalectomized and growth hormone-deficient rats,
neither gonadal or adrenal steroids nor growth hormone
appear to be involved in the expression of GALP mRNA in
International Journal of Obesity
the pituicytes of the posterior pituitary.46 Thyroidectomy in
rats leads to a reduction in GALP mRNA expression, as
compared with the intact control, with thyroxine replacement normalizing this expression.46 The expression of GALP
mRNA is increased in the posterior pituitary of lactating rats,
whereas GALP mRNA expression in the hypothalamic ARC is
not affected by lactation.46 These findings suggest that GALP
mRNA in the pituicytes is controlled by thyroid hormone,
and that GALP mRNA is physiologically associated with the
activation of oxytocin- and vasopressin-secreting neurons
during lactation.46 Catecholaminergic neurons in the A1/C1
region in the medulla oblongata are glucose responsive and
project to the ARC,47 and A1/C1 efferents to the hypothalamus are involved in the glucostatic regulation of GALP
mRNA, feeding behavior and LH secretion.47
Neuronal network of GALP neurons
Central administration of GALP activates neurons in various
regions of the rat brain (Figure 4). However, different doses
of GALP lead to different patterns of GALP-induced c-Fos
expression. Injection of GALP into the lateral ventricle
activates several brain regions, including the hypothalamic
ARC, medial preoptic area, supraoptic nucleus, DMH,
periventricular nucleus and LHA, as well as the nucleus
tractus solitarius of the medulla.48 Furthermore, the same
paradigm activates astrocytes but not microglia.48 In contrast, infusion of GALP into the third ventricle induces
c-Fos expression in the caudal preoptic area, ARC, median
eminence and horizontal limb of the diagonal band of
Broca.49 However, it has not yet been determined what kind
of neurons are activated by GALP, and further studies are
required to reveal the physiological significance of the effect
of GALP on both neurons and astrocytes.
NPY- and orexin-containing axon terminals lie in close
apposition with GALP-containing neurons in the ARC.36,38
Using a double-labeling in situ hybridization method,
Cunningham et al.50 have demonstrated that GALPcontaining neurons in the macaque express both NPY Y1
and serotonin 2C receptor. In an in vitro study of GALPtreated hypothalamic explants, GALP-induced hyperphagia
appeared to be mediated through an increase in NPY release
and a decrease in cocaine- and amphetamine-regulated
transcript (CART) release.26 However, GALP may not be the
target of neurons that contain NPY and/or pro-opiomelanocortin, as these neurons do not respond to GALP in vitro.43
Orexigenic effect of GALP on feeding behavior
and energy metabolism
The intracerebroventricular (i.c.v.) infusion of GALP into the
rat lateral ventricle increases cumulative food intake in the
first 1–2 h.48,49,51 The potency of GALP is 10 times higher
than that of galanin in terms of the stimulation of food
Feeding and energy metabolism by GALP
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Figure 4 Dual immunofluorescence photomicrographs of neural interaction between GALP and several neuropeptides. (a) NPY-immunoreactive fibers(green) are
in close apposition (arrow) with GALP-immunoreactive neurons (red) in the ARC. (b) Orexin-immunoreactive fibers (red) are in close apposed (arrow) to GALP-like
immunoreactive neurons (green) in the ARC. (c) GALP-immunoreactive fibers (red) are in direct contact (arrow) with orexin-immunoreactive neurons (green) in the
LH. (d) GALP-immunoreactive fibers (red) make direct contact (arrow) on MCH-immunoreactive neurons (green) in the LH. (e) aMelanocyte-stimulating hormoneimmunoreactive neurons (green) are colocalized with GALP (red) (arrow head). (f) GALP-immunoreactive neurons (green) in the ARC express orexin type-1 receptor
(orexin1-R) (red). Yellow color indicates the colocalized GALP and orexin1-R (arrow head). (g) GALP-immunoreactive fibers (red) are closely apposed (arrow) to
tyrosine hydroxylase (TH)-like immunoreactive neurons (green) in the ARC. (h) GALP-immunoreactive fibers (red) are closely apposed (arrow) to green fluorescent
protein (GFP)-positive immunoreactive neurons (green) in the medial preoptic area of the transgenic (Tg) rat that expresses GFP driven by a LHRH promoter (LHRHGFP Tg rat). (i) GALP-positive terminals (red) in direct contact (arrow) with GFP-positive dendritic processes (green) in the LHRH-GFP Tg rat. 3V, the third ventricle.
Scale bar is 20 mm.
intake,49,52 and thus it is considered that GALP is an
orexigenic peptide. Furthermore, the orexigenic effects of
GALP are intensified in high-fat-diet-induced obese rats,53
although these findings have yet to be confirmed in mice.
In an in vitro study of GALP-treated rat hypothalamic
explants, it was shown that GALP-induced hyperphagia
could be mediated by an increase in NPY release and
a decrease in CART release.51 In vivo, the number of
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pro-opiomelanocortin mRNA-expressing cells in the ARC of
the ob/ob mouse is reduced after chronic GALP injection.54
NPY release in the DMH has been proposed to have a role in
mediating the effects of GALP on feeding regulation,55
although another study reported no such effect.56 Furthermore, inhibition of endogenous NPY or NPY receptors
suppresses GALP-induced acute orexigenic effect in rats.55
These findings suggest that GALP promotes feeding behavior
through suppression of the anorexigenic pro-opiomelanocortin system and NPY release from the DMH.
Our recent experimental data suggest that the orexigenic
actions of GALP are mediated by orexin in the LHA, based
on the electromicroscopic observation that GALP-positive
axon terminal appears to have made synapse with orexinpositive perikaryon and dendritic process in the rat
LHA.39,42 Furthermore, i.c.v. injection of GALP in the rat
induces expression of c-Fos in orexin-positive neurons in
the LHA, and blocking the actions of orexin with an antiorexin antibody inhibits GALP-induced hyperphagia.42
However, injection of GALP into the LHA fails to stimulate
feeding.55,56 One possible explanation is that the distribution of orexin is different within the LHA, which is
long between rostral and caudal part.57 Therefore, it is not
yet known whether a position for infusions is suitable.
Further study is required to address the issue whether GALP
has a direct effect on orexin-containing neurons in the LHA.
GALP-containing fibers also make direct contact with
MCH-containing neurons in the LHA.39 However, in contrast to orexin, i.c.v. injection of GALP fails to induce c-Fos
expression in MCH neurons.42 Thus, the contribution of
MCH to the orexigenic actions of GALP remains unknown.
Our findings, together with those of others, suggest that
GALP stimulates feeding through the release of orexin in the
LHA and/or NPY in the DMH of rats. Nonetheless, the
relationship between the action of GALP on these two
neuropeptides needs to be clarified in further studies. Direct
microinjection of GALP into the medial preoptic area or PVH
also promotes food intake,56 suggesting the possibility that
other nuclei such as the medial preoptic area and PVH may
have roles in the regulation of feeding behavior.
The receptor responsible for the orexigenic effect of GALP in
rats is likely to be GALR1, as it has been shown to be expressed
in the LHA and DMH,28 and in vivo studies using agonists of
GALR1–3 have demonstrated that activation of GALR1
stimulates feeding behavior.29 There is no evidence to support
a role for GALR2 or GALR3 in orexigenic function in
rats.19,29,51 It is possible that the GALR1 mediates the transient
orexigenic effects of GALP through actions on orexinand NPY-containing neurons in the LHA and DMH,
respectively.
Recently, it was reported that high-fat diet-fed GALPdeficient mice gain less body weight compared with wildtype animals.58 Moreover, GALP-deficient mice do not change
the balance of energy intake and expenditure under normal
nutritional conditions,58 suggesting that GALP may regulate
energy balance to imposed nutritional circumstances.58
International Journal of Obesity
Anorexigenic effect of GALP on feeding behavior
and energy metabolism
In experiments with rat and mouse, both body weight gain
and food intake were reduced at 24 h after injection of
GALP.52,59 In genetically obese rodents, such as the ob/ob,
db/db mice and Zucker rats (fa/fa), both gene and/or peptide
expression of GALP is undetectable in the ARC9,10,60,61 as
well as in hypoleptinemic diabetic animals, and in rats that
are acutely or chronically deprived of food.23,61 Although
some studies using rat, but not mouse, have indicated a
transient increase in food intake after i.c.v. injection of
GALP, it is possible that decrease in GALP level in the ARC
causes obesity. Thus, it is possible that GALP has a
physiologically important role in anorexigenic action.18,47
Interestingly, GALP can be detected in the general circulation, and fasting decreases both plasma levels and GALP
influx into the brain.12 These findings suggest that GALP
conveys a satiety signal from peripheral organs to brain,
although there are few studies mentioning the presence of
GALP-producing cells in the peripheral organs. Central and/
or peripheral infusion of leptin restores to normal level of
the expression of GALP mRNA in the ARC of fasted rats and
leptin-deficient obese ob/ob mice.9,10,26 Leptin directly upregulates GALP neuronal activity in the hypothalamus, as
more than 85% of GALP neurons express leptin receptors in
the ARC of rats and macaques.23,35 However, the effect of
elevated endogenous leptin on GALP expression in the
normal animals is less clear. Although rats fed a diet high in
either saturated or polyunsaturated fats become hyperleptinemic, GALP mRNA is only increased in the ARC of the
obese rat fed a high polyunsaturated fat diet 62. This result
indicated that apart from leptin, GALP mRNA expression
level might be affected by various forms of dietary fat.
Although the injection of GALP into the lateral ventricle
results in a decrease in food intake in the first hour after
infusion in mice, this is not the case for rats.59 Krasnow
et al.59 speculate that the observed recovery of food intake
and body weight are attributable to the activation of a
compensatory neural feeding pathway, driving the animals
to eat in an attempt to restore body weight back to normal.
Although the i.c.v. injection of GALP into ob/ob mice
initially decreases both food intake and body weight gain,54
chronic GALP injection, results in a sustained decrease in
body weight and an increase in core body temperature,
despite the recovery of food intake.54 In a pair-fed study,
chronic GALP administration produced a greater decrease in
body weight than that which occurred in the control.54
Taken together, these findings lead us to theorized that
GALP-positive neurons in the ARC are a target for leptin, and
that GALP could be used as a replacement for leptin.
Core body temperature increased in a dose-dependent
manner, and this increase was maintained for 6–8 h after
injection of GALP.52 Cytokines such as interleukin-1 (IL-1)
and IL-6 are important mediators of inflammation that
induce fever by the release of prostaglandins in the
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hypothalamus. Central administration of GALP induced
c-Fos expression in astrocytes or neurons in the peri-third
ventricle. Astrocytes express cyclooxygenase, which is a ratelimiting enzyme for the biosynthesis of prostaglandins.48
Pretreatment of cyclooxygenase inhibitor completely blocks
GALP-induced thermogenesis.52 Moreover, the studies using
IL-1a, IL-1b or IL-1 type-I receptor-deficient mice demonstrates that GALP-induced thermogenesis, body weight loss
and anorexic actions are mediated by IL-1 type-I receptor.63
Table 1
Leptin reduces food intake and body weight, but increases
the core body temperature in rodents, partly through IL-1
system.64 These findings suggest that proinflammatory
cytokines mediate the thermogenesis by GALP.18,65
Brown adipose tissue is recognized as the primary site of
thermogenesis, and potentially functions to regulate body
weight in rodents.66 GALP treatment has been shown to
increase both uncoupling protein-1 mRNA and protein
expression in brown adipose tissue thermogenesis in the
Distribution and physiological function of GALP
Constituent amino acid residues
Receptor
Localization (cell body)
Physiological action
Leptin injection
Insulin injection
Effects of GALP
Reference
60
GALR1 (IC50 ¼ 4.3 nM* or 77 nM**)
GALR2 (IC50 ¼ 0.24 nM* or 28 nM**)
GALR3 (IC50 ¼ 10 nM**)
Specific receptor ?
The arcuate nucleus, the median eminence (rat)
The posterior pituitary gland
Increase in LH secretion (rat, mouse, monkey)
Increase in testosterone secretion (mouse)
Suppression of TSH secretion (rat)
Increase followed by decrease in food intake (rat)
Suppression of food intake (mouse)
Suppression of body weight
Increase in heat production
Suppression of locomotor activity (mouse)
Induction of taste aversion (mouse)
Increase in the gene expression of GALP
Increase in the gene expression of GALP
Ohtaki et al.7
*Ohtaki et al.7, **Lang et al.13
*Ohtaki et al.7, **Lang et al.13
**Lang et al.13
Juréus et al.26, Kerr et al.31, Larm and Gundlach32; Takatsu et al.35
Shen et al.21, Kerr et al.31, Fujiwara et al.34
Seth et al.8, Cunningham et al.50, Krasnow et al.59
Krasnow et al.59
Seth et al.51
Matsumoto et al.49, Lawrence et al.52, Krasnow et al.59
Krasnow et al.59
Lawrence et al.48, Krasnow et al.59
Lawrence et al.48, Lawrence et al.52, Hansen et al.54
Krasnow et al.59
Krasnow et al.59
Fraley et al.23, Juréus et al.26
Fraley et al.23
Abbreviations: GALP, galanin-like peptide; IC50, half maximal inhibitory concentration; LH, luteinizing hormone; TSH, Thyroid-stimulating hormone. *Correspond to
reference 7. **Correspond to reference 13.
Figure 5 Schematic illustration of the putative appetite-regulating neuronal circuit involving GALP in the hypothalamus. GALP neurons modulate body weight,
feeding intake, thermogenesis and reproduction through several neuropeptide and hormones producing neurons. ?, Unknown; 3V, the third ventricle;
Arc, arcuate hypothalamic nucleus; Leptin-R, leptin receptor; LH, lateral hypothalamic area; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; NTS, the
nucleus of the solitary tract; orexin1-R, orexin type-1 receptor; þ , physiological activation; , physiological suppression; VMH, ventromedial hypothalamic nucleus.
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ob/ob mouse.54 These findings suggest that GALP may partly
mediate energy metabolism through thermogenesis by
long-term activation of the sympathetic nervous system.
Polysaccharide was reported to induce GALP mRNA expression in the rat posterior pituitary, suggesting that GALP may
also be involved in exacerbated thermogenesis in response
to inflammatory stress.67 Thus, GALP can have both an
anorectic and a catabolic action.
The hypothalamo–pituitary–thyroid axis and activation of
uncoupling protein-1 by way of sympathetic nervous system
stimulation are known to influence thermogenesis and basal
metabolic rate.68,69 The PVH, which is associated with the
regulation of food ingestion and contains numerous thyrotropin-releasing-hormone-containing neurons,70 acts as the
central hypothalamic regulator of the hypothalamo–pituitary–
thyroid axis. Similar to other orexigenic peptides such as
NPY71 and agouti-related protein,72 administration of GALP
into the PVH decreases the level of plasma thyroid-simulating
hormone within 10 min.51 In other words, orexigenic peptides
exhibit an anabolic action by the suppression of thyroid
hormone release. However, GALP has no effect on the release
of thyroid-simulating hormone directly from dispersed rat
pituitary cells. Although GALP inhibits the release of thyrotropin-releasing hormone from hypothalamic explants in vitro,
GALP-positive nerve terminals are associated with few thyrotropin-releasing hormone neurons in the medial parvocellular
subdivision of the PVH.70 These findings suggest that,
although GALP has an anabolic action during an acute phase,
it may influence the hypothalamo–pituitary–thyroid axis
through an indirect mechanism to suppress circulating
thyroid-simulating hormone levels.
Recently, our group has been investigating the intranasal
delivery of GALP into the brain in order to determine the
potential clinical efficacy based on anorexigenic effect of GALP.
Intranasal infusion provided a 40-to 100-fold improvement in
targeting brain versus peripheral tissue compared with intravenous infusion.73 This study indicates that intranasal administration is an effective route for the delivery of GALP into the
brain.73 We have also been studying the physiological effects of
intranasal infusion of GALP on body weight, food intake, water
intake and locomotor activity in mice. Intranasal infusion of
GALP significantly reduced body weight over the course of a
week. However, food and water intake, as well as locomotor
activity, remained unchanged (Shiba et al., manuscript in
preparation). Our results strongly suggest that intranasal
administration of GALP will be useful for obese people to
control obesity and life-style-related diseases in the future.
However, the authors emphasize that the mechanism of body
weight loss by intranasal administration of GALP remains to be
clarified.
Conclusion
GALP has dichotomous actions on energy balance in rat
(transient hyperphagia followed by reduction of food intake
International Journal of Obesity
and body weight), in contrast to acting as a reducing agent
in both feeding behavior and body weight loss in mouse.
Transient orexigenic actions of GALP are mediated through
NPY and orexin pathway in the rat. The long-term anorectic
and thermogenesis of GALP are mediated through proinflammatory pathway in rodents. The findings of the studies
reviewed here highlight the fact that GALP is involved in
numerous physiological processes, including feeding behavior and energy metabolism (Table 1), through neuronal
networks in the hypothalamus (Figure 5). Further elucidation of the functions of GALP is important for the discovery
of therapeutic drugs, and for the treatment and prevention
of obesity and related disorders.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
We thank Dr Tetsuya Ohtaki of the Takeda Pharmaceutical
Company Ltd. (Japan) and Ms Sachi Kato for their support
in completing this work. We are also grateful to Dr Randeep
Rakwal (Showa University) for his help in reading the
manuscript. This study was supported, in part, by the
High-Technology Research Center Project from the Ministry
of Education, Sports, Science and Technology (Japan).
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