Roles of prolactin-releasing peptide and RFamide related peptides in the control of stress and food intake Yuki Takayanagi and Tatsushi Onaka Division of Brain and Neurophysiology, Depar
Trang 1Roles of prolactin-releasing peptide and RFamide related peptides in the control of stress and food intake
Yuki Takayanagi and Tatsushi Onaka
Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Japan
Introduction
RFamide peptides, defined by their carboxy-terminal
arginine (R) and amidated phenylalanine (F) residues
(hence RFamide), were originally discovered in
inbrates [1] and have recently been identified in
verte-brates [2] The first reported RFamide peptides in
mammals were neuropeptide FF (NPFF) and
neuro-peptide AF, which were later confirmed to be encoded
on a single gene [3] By applying a reverse
pharmaco-logical approach, in which orphan G protein-coupled
receptor ligands were identified by detecting signal
transduction induced in cells expressing a targeted
orphan G protein-coupled receptor after stimulation,
prolactin-releasing peptide (PrRP) was identified to be
a ligand of an orphan G protein-coupled receptor,
GPR10 (hGR3⁄ UHR-1 ⁄ PRLHR) and to belong to the RFamide peptide [4] Subsequently, by utilizing DNA databases, another gene for RFamide peptides was identified in mammals [5,6] The RFamide peptides encoded by the gene were named RFamide related peptide (RFRP)-1⁄ NPSF and RFRP-3 ⁄ NPVF, which were found to be orthologs of avian peptide LPLRFa-mide Thus, RFRPs are allocated into the LPXRFa-mide peptide family (X = L or Q) Several other RFamide peptides also have been discovered by a reverse pharmacological method and by DNA sequence database searching, and there are now five families of RFamide peptides known to exist in mammals: NPFF, PrRP, LPXRFamide, kisspeptin
Keywords
dorsomedial hypothalamus; energy
consumption; energy metabolism; food
intake; nucleus tractus solitarii; oxytocin;
prolactin-releasing peptide; RFamide
peptide; RFamide-related peptide; stress
Correspondence
T Onaka, Division of Brain and
Neurophysiology, Department of Physiology,
Jichi Medical University, Shimotsuke-shi,
Tochigi-ken 329-0498, Japan
Fax: +81 285 44 8147
Tel: +81 285 58 7318
E-mail: tonaka@jichi.ac.jp
(Received 13 June 2010, revised 2
September 2010, accepted 13 October
2010)
doi:10.1111/j.1742-4658.2010.07932.x
Subsequent to the isolation of the first recognized RFamide neuropeptide, FMRFamide, from the clam, a large number of these peptides have been identified There are now five groups of RFamide peptides identified in mammals RFamide peptides show diversity with respect to their N-termi-nal sequence and biological activity RFamide peptides have been impli-cated in a variety of roles, including energy metabolism, stress and pain modulation, as well as effects in the neuroendocrine and cardiovascular systems In the present minireview, we focus on prolactin-releasing peptide (PrRP) and RFamide related peptide (RFRP) with respect to their roles in the control of energy metabolism and stress responses Both food intake and stressful stimuli activate PrRP neurons The administration of PrRP affects energy metabolism and neuroendocrine systems PrRP-deficient or PrRP receptor-deficient mice show abnormal energy metabolism and⁄ or stress responses On the other hand, RFRP neurons are activated by stress-ful stimuli and the administration of RFRP induces neuroendocrine and behavioral stress responses Taken together, these data suggests that PrRP and RFRP neurons play a role in the control of energy metabolism and/or stress responses
Abbreviations
ACTH, adrenocorticotropic hormone; CCK, cholecystokinin-8; CRH, corticotropin-releasing hormone; NPFF, neuropeptide FF;
NTS, nucleus tractus solitarii; PrRP, prolactin-releasing peptide; QFRP, pyroglutamylated RFamide peptide; RFRP, RFamide related peptide.
Trang 2(previously known as metastin) and pyroglutamylated
RFamide peptide (QFRP) (Table 1) RFamide peptides
show diversity in their N-terminal sequence and, as a
result, a broad pattern of biological activities,
includ-ing the control of energy metabolism and stress, as
well as effects in the neuroendocrine and
cardiovascu-lar systems In the present minireview, we focus on
PrRP and RFRP (Table 2) and review recent progress
in research investigating the roles of these two peptides
in the control of energy metabolism and stress
PrRP
PrRP was considered to serve as a
hypothalamic-releasing factor and to act on the anterior pituitary
to stimulate prolactin release from the pituitary
However, no PrRP immunoreactivity was found in the external layer of the median eminence, from where classic hypothalamic hormones are released into the portal blood to control anterior pituitary hormone release Thus, PrRP is not a classic hypothalamic hor-mone in mammals Instead, PrRP appears to play an important role in the control of energy metabolism and stress [7]
Localization of PrRP and its receptors PrRP neurons are localized mostly in the nucleus trac-tus solitarii (NTS), with modest expression in the ven-trolateral medulla regions of the brainstem, and slight expression in the dorsomedial hypothalamus In the medulla oblongata, PrRP expression is restricted to the
Table 1 Summary of mammalian RFamide peptides and their receptors The effects of administration of RFamide peptides upon stress responses (hormone release) and energy metabolism are also described.
Family
name
Peptide in
Energy metabolism
Food intake
Energy consumption
NPAF
GPR74 (NPFF-2, NPGPR, HLWAR77) Decrease in vasopressin
release
Decrease [51] Increase PrRP PrRP GPR10 (hGR3, UHR-1, PRLHR) Increase in the release
of ACTH, oxytocin, vasopressin and prolactin
Decrease Increase
LPXRF RFRP-1 (NPSF)
RFRP-3 (NPVF)
GPR147 (NPFF-1, OT7T022, RFRPR) Increase in the release
of ACTH, oxytocin and prolactin
Increase
?
?
Table 2 Amino acid sequences of PrRP and RFRP in human, rats and mice are shown *Deduced from the cDNA sequence.
Number of
31
TPDINPAWYASRGIRPVGRF-NH2 SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2
[4]* [4]*
31
TPDINPAWYTGRGIRPVGRF-NH2 SRAHQHSMETRTPDINPAWYTGRGIRPVGRF-NH2
[4]* [4]*
31
TPDINPAWYTGRGIRPVGRF-NH 2
SRAHQHSMETRTPDINPAWYTGRGIRPVGRF-NH2
*
*
12
SLNFEELKDWGPKNVIKMSTPAVNKMPHSFANLPLRF-NH2 MPHSFANLPLRF-NH 2
[5]* [5]*, [54]
12
SVTFQELKDWGAKKDIKMSPAPANKVPHSAANLPLRF-NH2 VPHSAANLPLRF-NH2
[55] [5]*
12
SVSFQELKDWGAKKDIKMSPAPANKVPHSAANLPLRF-NH 2
VPHSAANLPLRF-NH 2
[5]* [5]*
17
VPNLPQRF-NH2 NMEVSLVRRVPNLPQRF-NH2
[5]*, [54] [5]*
Trang 3caudal A2 and A1 noradrenergic neurons
Immunohis-tochemical studies have shown that
PrRP-immunoreac-tive fibers are widely distributed in the brain [8] The
main receptor for PrRP, GPR10, is also widely
expressed in the brain (especially in the reticular
nucleus of the thalamus, bed nucleus of the stria
termi-nalis, preoptic areas, hypothalamic paraventricular
nucleus, periventricular nucleus, dorsomedial
hypothal-amus, NTS and area postrema) [9] In addition to
GPR10, PrRP has a high affinity for NPFF receptor 2
(also known as GPR74⁄ NPGPR ⁄ HLWAR77) NPFF
receptor 2 is expressed in the dorsal horn of the spinal
cord, thalamus, hypothalamus and hippocampus [10]
Although the physiological functions of NPFF
recep-tor 2 activated by PrRP remain to be clarified, a recent
study has proposed that central cardiovascular effects
of PrRP are mediated via NPFF receptor 2 [11]
Role of PrRP in the control of energy metabolism:
food intake
Intracerebroventricular injection of PrRP reduces food
intake [12] Both PrRP-deficient mice [13] and
GPR10-deficient mice [14] show hyperphagia Acute inhibition
of endogenous PrRP signaling by injections of
neutral-izing monoclonal antibodies against PrRP also induces
hyperphagia [13] From experiments with
PrRP-defi-cient mice or PrRP-neutralizing antibodies, PrRP has
been shown to regulate meal size rather than meal
fre-quency [13] Meal size is regulated by satiety signals
that terminate each meal, and one important satiety
sig-nal is cholecystokinin-8 (CCK) CCK is released from
the intestine in response to meals, and acts via the
CCKAreceptor on afferent vagal fibers that project into
the medulla oblongata, which relays information into
the hypothalamus Food intake [13] or the
administra-tion of CCK [15] activates PrRP neurons in the NTS
The anorectic effects of CCK are impaired in both
PrRP-deficient mice [13] and GPR10-deficient mice [16],
suggesting that PrRP relays satiety signaling of CCK
The downstream actions of PrRP neurons remain to
be clarified However, neurons expressing
corticotro-pin-releasing hormone (CRH) or oxytocin may relay
PrRP signaling to reduce food intake Anatomical
studies have shown that oxytocin neurons in the
hypo-thalamus receive direct projections from PrRP neurons
in the medulla oblongata The administration of PrRP
activates neurons expressing CRH or oxytocin in the
hypothalamus, both of which are anorexic peptides
PrRP-induced anorexia is attenuated by a CRH
recep-tor antagonist or oxytocin receprecep-tor antagonist [16]
Furthermore, an oxytocin receptor antagonist reduces
the anorexic actions of CCK [17,18], and increases
meal size [19] Oxytocin receptor-deficient mice show
an increased meal size [20] Taken together, these results suggest that the PrRP-oxytocin system plays a pivotal role in relaying the satiety signaling of CCK PrRP neurons in the brainstem and hypothalamus express leptin receptors [21] Leptin regulates long-term energy metabolism Leptin induces the expression of phosphorylated signal transducer and activator of transcription protein 3 in PrRP neurons, especially in the dorsomedial hypothalamus [13] (Fig 1) and the anorectic effects of leptin are impaired in PrRP-defi-cient mice [13] These data suggest that the anorectic effects of leptin signaling are mediated, at least in part,
by PrRP
Role of PrRP in the control of energy metabolism: energy expenditure
PrRP has also been associated with energy expendi-ture An intracerebroventricular injection of PrRP
Fig 1 Activation of PrRP and RFRP neurons in the dorsomedial hypothalamus after stressful stimuli and leptin administration The number of PrRP-immunoreactive neurons expressing Fos protein (the protein product of the immediate early gene, c-fos) or phos-phorylated signal transducer and activator of transcription 3 (i.e a transcription factor downstream of leptin) after conditioned fear stimuli or leptin is shown (top) Both conditioned fear stimuli and leptin administration activate PrRP neurons in the dorsomedial hypothalamus The number of RFRP-immunoreactive neurons expressing Fos protein after footshocks is shown (bottom) Foot-shocks activate RFRP neurons in the dorsomedial hypothalamus Data are obtained from previous studies [13,27,48] *P < 0.05,
**P < 0.01, ***P < 0.001.
Trang 4increases body temperature and oxygen consumption
[12,22], although neither PrRP-deficient [13], nor
GPR10-deficient male mice [23] show significant difference in
oxygen consumption under basal conditions
PrRP-deficient mice also show no significant difference in
core body temperature either at room temperature or
after cold exposure [13] Pair-fed PrRP-deficient mice
show no obese phenotype and no significant difference
in oxygen consumption [13], suggesting that
endoge-nous PrRP is not important for regulating energy
expenditure under resting conditions On the other
hand, obese GPR10-deficient female mice show slightly
reduced oxygen consumption [23], suggesting that
GPR10 might be important for regulating energy
expenditure in females Obesity has been reported to
be more pronounced in female than in male
GPR10-deficient mice It is interesting to note that PrRP
neu-rons in the brainstem express estrogen receptors and
that PrRP expression in the brainstem is higher in
female than in male rats [24] Thus, the function of
PrRP-GPR10 system in the control of energy
con-sumption might differ between sexes
PrRP has been suggested to be involved in energy
consumption under stressful conditions Stressful
stim-uli increase oxygen consumption This increase in
oxy-gen consumption after stressful stimuli is lower in
PrRP-deficient mice [25] Stressful stimuli activate
PrRP neurons, and thus it is possible that PrRP
increases energy consumption under the conditions in
which PrRP neurons are activated
Roles of PrRP in the control of stress responses
PrRP neurons in the medulla oblongata and⁄ or in the
dorsomedial hypothalamus are activated by a variety
of stressful stimuli [26], including restraint of body
movement, conditioned fear [27] (Fig 1), footshocks,
hemorrhage [28], exercise [29] and inflammatory stress
(e.g lipopolysaccharide injection) [30] PrRP neurons
have been suggested to be involved in neuroendocrine
responses to stress PrRP neurons project directly to
CRH neurons and oxytocin neurons in the
hypothala-mus [31] An intracerebroventricular injection of PrRP
activates CRH neurons and oxytocin neurons in the
hypothalamus, and facilitates adrenocorticotropic
hor-mone (ACTH) and oxytocin release into the systemic
circulation Blockade of endogenous PrRP signaling by
the administration of PrRP-neutralizing antibodies
reduces the activation of hypothalamic paraventricular
neurons after noxious stimuli (formalin injection) [30]
or reduces oxytocin release in response to conditioned
fear [27], suggesting that endogenous PrRP has
facilita-tive roles in neuroendocrine stress responses On the
other hand, the administration of PrRP-neutralizing antibodies facilitates ACTH release in response to exercise, suggesting that PrRP inhibits ACTH release
in response to exercise [29] Corticosterone release in response to restraint stress has been reported to be enhanced in PrRP-deficient mice [32] These data sug-gest that PrRP has inhibitory effects on neuroendo-crine responses to stress At present, the mechanisms underlying these apparent discrepant data remain to
be clarified However, the roles of PrRP in the control
of stress responses may depend upon the nature of stressful stimuli used
Stressful stimuli affect food intake and increase energy expenditure On the other hand, food intake affects stress responses [33] PrRP-deficient mice show
a lower increase in oxygen consumption after stressful stimuli [25], although the effects of stress on food intake and the effects of food intake on stress responses have not yet been examined in PrRP-defi-cient mice PrRP might be involved in the integration
in the control of energy metabolism and stress responses, whereas the underlying detailed mechanisms need further investigation
RFRP
The mammalian members of the LPXRFamide peptide family are 1 and 3 1 and
RFRP-3 are derived from a single precursor protein Immu-nohistochemical studies have shown that single cells contain both RFRP-1 and RFRP-3 RFRP-1 and RFRP-3 bind with high affinity to a G protein-coupled receptor, GPR147 (also known as OT7T022, NPFF receptor 1 or RFRP receptor)
In birds, peptides of the LPXRFamide family are termed gonadotropin inhibitory hormones RFRPs have also been reported to serve a similar function in mammals [34] The administration of RFRP-3 sup-presses plasma luteinizing hormone or follicle-stimulat-ing hormone concentrations in mammals However, the mechanisms are not fully understood RFRP-3 inhibits the activity of gonadotropin-releasing hormone neurons in the hypothalamus [35–37] RFRP-3 has been also reported to act on pituitary gonadotrophs to inhibit luteinizing hormone or follicle-stimulating hor-mone release [38–40], although it is currently a matter
of controversy as to whether RFRP-3 exerts a hypo-physiotropic role in mammals [37,41] RFRP mRNA expression is not affected either by estrogen [42] or tes-tosterone [43], whereas RFRP neurons have been reported to express estrogen receptors [35] The precise physiological roles of RFRP in the mammalian repro-ductive system need further investigation
Trang 5Localization of RFRPs and their receptors
The RFRP gene is expressed in the caudal
hypothala-mus, including the dorsomedial hypothalamus and the
periventricular nucleus Immunohistochemical studies
have shown that RFRP-immunoreactive fibers are
widely distributed within the brain [44] Expression of
the main receptor for RFRP, GPR147, is broadly
dis-tributed within the brain, including the septal areas,
amygdala, bed nucleus of the stria terminalis,
hypotha-lamic paraventricular nucleus, dorsomedial
hypothala-mus, ventromedial hypothalamus and the anterodorsal
thalamic nucleus
Roles of RFRP in the control of food intake and
stress responses
The dorsomedial hypothalamus plays an important
role in the control of energy metabolism [45] Indeed,
RFRPs have been suggested to contribute not only to
the control of the reproductive system, but also to the
control of energy balance RFRP neurons project
directly to cells expressing neuropeptide Y or
pro-opio-melanocortin in the arcuate nucleus of the
hypothala-mus, both of which are key molecules in the control of
energy balance [46] The administration of RFRPs
induces Fos protein in the arcuate nucleus, which is a
center for food intake, and stimulates food intake in
rats [36,38] However, food restriction does not change
the expression of RFRP in Siberian hamsters [47] The
effects of RFRP upon energy consumption or oxygen consumption are not known The downstream and physiological significance of orexigenic actions by RFRP remain to be determined
The involvement of RFRP in the control of stress responses has also been reported The dorsomedial hypothalamus where RFRP neurons exist plays an important role in the control of stress responses as well
as food intake [45] Subsequent to stressful stimuli, the percentage of RFRP neurons expressing Fos protein [48] (Fig 1) and the expression of RFRP mRNA in the hypothalamus are increased [49] RFRP fibers are observed in the hypothalamic paraventricular nucleus and appear to project directly to cells containing CRH
or oxytocin [46] in the hypothalamus The administra-tion of RFRP increases Fos expression in the hypotha-lamic paraventricular nucleus and in hypothahypotha-lamic oxytocin neurons, and facilitates the release of ACTH and oxytocin into the peripheral circulation Similar patterns of Fos expression and hormone release are observed after stressful stimuli Furthermore, the cen-tral application of RFRP-1 or RFRP-3 induces anxi-ety-related behavior [48] Taken together, these data are consistent with the view that stressful stimuli acti-vate RFRP neurons and that RFRP-1 and RFRP-3 are involved in neuroendocrine and behavioral responses to stressful stimuli
RFRP neurons express glucocorticoid receptors and the administration of glucocorticoid increases the expression of RFRP mRNA in the hypothalamus [49]
Fig 2 Possible neural pathways controlling stress and food intake by PrRP and RFRP The PrRP and RFRP systems influence energy homeostasis and stress responses The dorsomedial hypothalamus has direct connections to and from the limbic areas, other hypothalamic nuclei and the brainstem, which are involved in stress and energy balance AMY, amygdala; ARC, arcuate nucleus; BST, bed nucleus of the stria terminalis; DMH, dorsomedial hypothalamus; LHA, lateral hypothalamic area; NTS, nucleus tractus solitarii (A2 noradrenergic region); PBN, parabrachial nucleus; POA, preoptic area; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; VLM, ventrolateral medulla (A1 noradrenergic region); VMH, ventromedial hypothalamus.
Trang 6RFRP neurons also express serotonin receptors and
the number of RFRP neurons is increased after
chronic administration of a selective serotonin
reup-take inhibitor, citalopram [50] Glucocorticoid and
serotonin play major roles in the control of food
intake and stress responses The physiological
func-tions of these receptors expressed in RFRP neurons
remain to be determined
Conclusions
Epidemiological studies have shown that both stress
and obesity cause deleterious effects on human health
Obesity is caused by a positive energy balance
Stress-ful stimuli affect neurons in the brainstem and
hypo-thalamus, and induce neuroendocrine and behavioral
responses Food intake also activates the brainstem
and hypothalamus, resulting in the termination of
meals and the induction of energy consumption
Energy homeostasis and stress interact with each other
Stress affects food intake and energy expenditure On
the other hand, energy balance conditions affect stress
responses As described in the present minireview,
neu-rons expressing RFamide peptides receive information
concerning both internal metabolic states and
environ-mental conditions, and play a role in energy
homeosta-sis and stress responses (Fig 2) Thus, it is interesting
to speculate that RFamide peptides are pivotal in
interactions between stress and energy metabolism
Other neuropeptides, including GALP [57–59] and
relaxin-3 [60], also may play a role in these
tions The detailed mechanisms underlying the
interac-tions between stress and energy metabolism remain to
be clarified
Acknowledgements
The present work was supported by KAKENHI
(20590237, 20020023, 20790194, 22120512, 22659050)
from MEXT and JSPS
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