Central administration of the RFamide peptides, QRFP-26 and QRFP-43, increases high fat food intake in rats
Pyrogultamylated arginine-phenylalanineamide peptide (QRFP) is strongly conserved across species and is a member of the family of RFamide-related peptides, with the motif Arg-Phe-NH(2) at the C-terminal end. The precursor peptide for QRFP generates a 26-amino acid peptide (QRFP-26) and a 43-amino acid peptide (QRFP-43), both of which bind to the G protein-coupled receptor, GPR103. Recently, QRFP has been characterized in rats, mice and humans and has been reported to have orexigenic properties. In rodents, prepro-QRFP mRNA is expressed in localized regions of the mediobasal hypothalamus, a region implicated in feeding behavior. Increased intake of a high fat diet contributes to increased weight gain and obesity. Therefore, the current experiments investigated the effects of QRFP administration in rats and the effects of a high fat diet on prepro-QRFP mRNA and GPR103 receptor mRNA levels. Intracerebroventricular administration of QRFP-26 (3.0nM, 5.0nM) and QRFP-43 (1.0nM, 3.0nM) dose-dependently increased 1h, 2h, and 4h cumulative intake of high fat (55% fat), but not low fat (10% fat) diet. In Experiment 2, hypothalamic prepro-QRFP mRNA levels and GPR103 receptor mRNA levels were measured in rats fed a high fat or a low fat diet for 21 days. Prepro-QRFP mRNA was significantly increased in the ventromedial nucleus/arcuate nucleus of the hypothalamus of rats fed a high fat diet compared to those fed a low fat diet, while GPR103 mRNA levels were unchanged. These findings suggest that QRFP is a regulator of dietary fat intake and is influenced by the intake of a high fat diet.
Primeaux SD, et al. Peptides. 2008 Nov;29(11):1994-2000. Epub 2008 Aug 13.
RF amide peptide QRFP43 causes
obesity with hyperphagia and reduced thermogenesis in mice
QRFP, an RF amide
peptide, was recently identified as an endogenous ligand of
an orphan G protein-coupled receptor, GPR103. Recent investigation
revealed that acute intracerebroventricular (ICV) administration
of QRFP26/P518/26RFa, a constitutive part of QRFP43 (43-amino
acid-residue form of QRFP), increases appetite in mice, but
its role in long-term energy homeostasis remains unknown. In
the present study, we examined the effects of chronic administration
of QRFP43 on feeding behavior, body weight regulation and energy
expenditure in mice. ICV infusion of QRFP43 for 13 days resulted
in a significant increase in body weight and fat mass with hyperphagia.
Weight gain and hyperphagia were more evident when mice were
fed a moderately high-fat diet. Pair-feeding of QRFP43-infused
mice did not increase body weight, but significantly increased
fat mass and plasma concentrations of insulin, leptin and cholesterol
when compared with controls. Moreover, significant decreases
in rectal temperature and expression of brown adipose tissue
uncoupling protein-1 mRNA were observed in QRFP43-infused ad
libitum- and pair-fed mice. The present results suggest that
QRFP plays an important role in energy homeostasis by regulating
appetite and energy expenditure.
Moriya R, et al.
Endocrinology. 2006 Mar 16; [Epub ahead of print]
Antibody
for QRFP western blot and immunohistochemistry
Antibody for QRFP
receptor AQ27 western blot and Immunohistochemistry
Moriya R, et al. Endocrinology.
2006 Mar 16; [Epub ahead of print]
Body composition,
tissue weights and hepatic triglyceride (TG) contents of mice
infused with QRFP43
Data are means ± SE
of 6-11 mice. #, P < 0.05; *, P < 0.01 vs. respective
vehicle-treated group (Student’s t-test or ANOVA
followed by Dunnett’s test). n.t.: not tested.Moriya R,
et al. Endocrinology. 2006 Mar 16; [Epub ahead of print]
Data are means ± SE
of 6-11 mice. FFA, free fatty acid; TG, triglyceride; CHL, Cholesterol
#, P < 0.05; *, P < 0.01 vs. respective vehicle-treated
group (Student’s t-test or ANOVA followed by Dunnett’s
test).Moriya R, et al. Endocrinology. 2006 Mar 16; [Epub ahead
of print]
Data are means ± SE
of 14-15 mice. FFA, free fatty acid; TG, triglyceride; CHL,
Cholesterol #, P < 0.05; *, P < 0.01 vs. vehicle-treated
group (ANOVA followed by Dunnett’s test). Moriya R, et
al. Endocrinology. 2006 Mar 16; [Epub ahead of print]
Effects of ICV-injected QRFP 43 on food
intake in mice Data are means ± SE of 11-13 mice. *, P < 0.01
vs. vehicle-treated group. Moriya R, et al. Endocrinology. 2006
Mar 16; [Epub ahead of print]
Body weight changes (A), daily food
intake (B), cumulative food intake (C) and fat content (D) of
mice chronically infused with vehicle or QRFP43 (30 μg/day)
under regular-diet conditions. Data are means ± SE of 6-7 mice.
#, P < 0.05 vs. vehicle-treated group (Student’s t-test).
Moriya R, et al. Endocrinology. 2006 Mar 16; [Epub ahead of print]
Body weight changes (A), daily food
intake (B), cumulative food intake (C) and fat content (D) of
mice chronically infused with vehicle or QRFP43 (3, 10, 30 μg/day)
under MHF-diet conditions. Data are means ± SE of 9-11 mice. #,
P < 0.05; *, P < 0.01 vs. respective vehicle-treated group
(ANOVA followed by Dunnett’s test). Moriya R, et al. Endocrinology.
2006 Mar 16; [Epub ahead of print]
Body weight changes (A), cumulative
food intake (B) and fat content (C) of mice chronically infused
with vehicle, QRFP43/ad lib-fed (10 μg/day) or QRFP43/pair-fed
(10 μg/day) under MHF-diet conditions. Data are means ± SE
of 14-15 mice. *, P < 0.01 vs. vehicle-treated group (ANOVA
followed by Dunnett’s test). Moriya R, et al. Endocrinology.
2006 Mar 16; [Epub ahead of print]
Rectal temperature (A) and BAT UCP1 mRNA expression
(B) of mice infused with vehicle, QRFP43/ad lib-fed (10 μg/day)
or QRFP43/pair-fed (10 μg/day).
Data are means ± SE of 14-15 mice. #, P < 0.05; *, P <
0.01 vs. vehicle-treated group (ANOVA followed by Dunnett’s
test). Moriya R, et al. Endocrinology. 2006 Mar 16; [Epub
ahead of print]
Identification and characterization
of a novel RF-amide peptide ligand for orphan G-protein coupled
receptor SP9155
Orphan G-protein coupled receptors are a large class of receptors
whose cognate ligands are unknown. SP9155 (also referred to as
AQ27 and GPR103) is an orphan G-protein coupled receptor originally
cloned from a human brain cDNA library. SP9155 was found to be
predominantly expressed in brain, heart, kidney, retina and testis.
Phylogenetic analysis shows that SP9155 shares high homology with
Orexin, NPFF and CCK receptors, but identification of the endogenous
ligand for SP9155 has not been reported. In this study, we have
used a novel method to predict peptides from genome databases.
From these predicted peptides, a novel RF-amide peptide, P52 was
shown to selectively activate SP9155-transfected cells. We subsequently
cloned the precursor gene of the P52 ligand and characterized
the activity of other possible peptides encoded by the precursor.
This revealed an extended peptide, P518, which exhibited high
affinity for SP9155 (EC50 = 7 nM). mRNA expression analysis revealed
that the peptide P518 precursor gene is predominantly expressed
in various brain regions, coronary arteries, thyroid and parathyroid
glands, large intestine, colon, bladder, testes and prostate.
These results indicate the existence of a novel RF-amide neuroendocrine
peptide system, and suggest that SP9155 is likely the relevant
G-protein coupled receptor for this peptide. Jiang
Y, et al., J Biol Chem 2003 Apr 24; [epub ahead of print].
A new peptidic ligand and its receptor regulating adrenal
function in rats SUMMARY We searched for peptidic ligands for orphan G protein-coupled
receptors utilizing a human genome database and identified a
new gene encoding a preproprotein that could generate a peptide.
This peptide consisted of 43 amino acid residues that starting
from N-terminal pyroglutamic acid and ending at C-terminal arginine-phenylalanin-amide.
We therefore named it QRFP after pyroglutamylated arginine-phenylalanine-amide
peptide. We subsequently searched for its receptor and found
that Chinese hamster ovary cells expressing an orphan G protein-coupled
receptor, AQ27, specifically responded to QRFP. We analyzed
tissue distributions of QRFP and its receptor mRNAs in rats
utilizing quantitative reverse transcription-polymerase chain
reaction and in situ hybridization. QRFP mRNA was highly expressed
in the hypothalamus and its receptor mRNA in the adrenal gland.
The intravenous administration of QRFP caused the release of
aldosterone, suggesting that QRFP and its receptor have a regulatory
function in the rat adrenal gland.
Fukusumi S, et al. J Biol Chem. 2003 Sep
5 [Epub ahead of print].
