Endocrinology Vol. 140, No. 10 4406-4410
Copyright © 1999 by The Endocrine Society
Physiological Role of Cholecystokinin B/Gastrin Receptor in Leptin Secretion1
Samir Attoub,
Sandrine Levasseur,
Marion Buyse,
Hélène Goïot,
Jean-Pierre Laigneau,
Laurent Moizo,
Florence Hervatin,
Yannick Le Marchand-Brustel,
J. M. Miguel Lewin and
André Bado
INSERM, U-10, Institut Federatif de Recherche 2 (IFR2)
Cellules Epithéliales, Hôpital Bichat (S.A., S.L., M.B.,
H.G., J.-P.L., L.M., J.M.M.L., A.B.), 75018 Paris; Department de
Radiobiologie et de Radiopathologie-Centre d’Energie Atomique
(DRR-CEA) (F.H.), 92265 Fontenay aux Roses Cedex; and INSERM
EA99–11, Faculté de Médecine (Y.B.), 06107 Nice Cedex 02,
France
Address all correspondence and requests for reprints to: Dr. Miguel J. M. Lewin, INSERM U-10, Hôpital Bichat, 170 boulevard Ney, 75018 Paris, France. E-mail: mjmlewin{at}bichat.inserm.fr
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Abstract
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In the present study, we investigated whether cholecystokinin
(CCK) or its structurally related peptide gastrin participates in long
term regulation of adipocyte leptin secretion. The levels of
circulating leptin observed after 2 and 6 h of refeeding in 18-h
fast rats were significantly lowered by injection of the specific
gastrin/CCK-B receptor antagonist YM022 at doses that did not affect
feeding behavior. Moreover, in normally fed animals, circulating leptin
was markedly decreased by chronic injection of YM022 (from 4 ±
0.6 to 2.1 ± 0.5 ng/ml). Consistent with these observations,
YM022 treatment decreased leptin messenger RNA (mRNA) levels and
increased the leptin content in rat epididymal fat tissue. Rat
adipocytes exclusively contain gastrin/CCK-B receptor mRNA, but not
CCK-A receptor mRNA. Furthermore, adipocyte membranes bound
[125I]CCK-8 in a saturable manner, with kinetics
consistent with a single class of high affinity sites with a
Kd of 0.2 nM. These data argue for a
physiological role for the CCK-B/gastrin receptor in adipocyte leptin
regulation. We therefore propose that gastrin is involved in long term
regulation of leptin expression and secretion in rat fat tissues
through activation of an adipocyte gastrin/CCK-B receptor.
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Introduction
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THE GASTROINTESTINAL polypeptide hormones
gastrin and cholecystokinin (CCK) are related peptides that
share the same C-terminal sequence that carries the biological message.
Eating a meal stimulates gastrin secretion from G cells in the antral
part of the stomach (1) and CCK secretion from duodenal I cells (2, 3, 4, 5).
Both peptides activate the gastrin/CCK-B receptor, whereas only CCK
activates the CCK-A receptor (6). In 1973, Gibbs and co-workers first
reported that CCK, a brain-gut peptide (7, 8), suppressed food intake
in rats, with the animals exhibiting the entire normal behavioral
sequence of satiety (9). Further studies were also consistent with a
physiological role for peripheral CCK in short term regulation of food
intake (for review, see. Ref. 10). The effect is initiated by feeding,
triggered by signals originating from the gastrointestinal tract and
mediated by the vagus nerve (11, 12).
Leptin, the product of the ob gene, was identified as
an adipocyte-secreted protein (13). It is secreted into the blood by
fat tissue to inform the brain about the adipocyte mass and thereby
control appetite and body weight homeostasis (14, 15, 16). In contrast to
that of CCK, the satiety effect induced by circulating leptin is only
effective in the long term. This effect requires leptin cross the
blood-brain barrier (17) to reach specific hypothalamic receptors (18, 19), which, in turn, modulate the action of a set of brain
neuropeptides (20, 21), including neuropeptide Y (22). In addition, it
was reported that leptin can act with CCK through peripheral vagal
pathways to reduce short term food intake in mice (23, 24). We recently
reported that the stomach is another site of leptin production. This
gastric pool is quickly mobilized (within 15 min) by feeding or by
exogenous CCK in the absence of any apparent change in epididymal
leptin content (25). The absence of rapid effect of CCK on adipocyte
leptin is consistent with the storage of leptin, or its lack of
storage, by the adipose cells (26). However, it remained unclear
whether that CCK and the structurally similar gastrin could regulate
adipocyte leptin synthesis and secretion over longer periods of time.
Here, we address this question using animal experiments. We show that
endogenous gastrin/CCK are involved in long term regulation of leptin
expression and secretion in rat fat tissues through activation of an
adipocyte gastrin/CCK-B receptor.
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Materials and Methods
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Animals, tissues, and leptin measurements
Male Wistar rats (250–350 g), housed in a room at 23 C with
free access to food and water, were used. The animals were accustomed
to eat their food (laboratory Purina chow pellets, Ralston Purina Co., St. Louis, MO) between 1000–1800 h when food was withdrawn
until the next morning, but with water available ad libitum.
Rats were habituated to this feeding schedule until their food
consumption was stabilized (8 days).
A group of rats was allowed to feed on preweighed standard laboratory
pellet chow for 15-min, 2-h, or 6-h periods. Before feeding, the
animals were ip injected with vehicle (control) or CCK-B receptor
antagonist, YM022 (27), in saline containing 1% dimethylsulfoxide. At
appropriate times, food was weighed, and intake was determined. They
were anesthetized, blood was collected from the abdominal aorta and
centrifuged, and plasma was removed and stored at -20 C until leptin
assays. The stomach and epididymal adipose tissues were removed. The
stomach was opened, rinsed with saline, and flattened on a glass plate
with the mucosa upwards, and the epithelium was scraped off and
weighed. The fundic mucosa scrapings and epididymal fat pad tissue were
homogenized using a glass-Teflon homogenizer in Krebs-Ringer buffer
supplemented with HEPES containing 0.1 mg/ml
phenylmethylsulfonylfluoride and 200 IU/ml aprotinin. The homogenates
were centrifuged at 10,000 x g for 10 min. The
resulting supernatant for fundic mucosa, and the infranatant for fat
pad tissue were used for leptin determinations.
In another set of experiments, normally fed rats were chronically
injected once a day for 5 days with vehicle (control) or YM022. Daily
food intake was determined. On day 6, the animals were killed, and
blood was collected for leptin assay.
Plasma, fundic, and epididymal fat pad leptin were estimated using a
mouse leptin RIA kit from Linco Research, Inc. (St.
Charles, MO). Plasma glucose was determined enzymatically by hexokinase
method (Autoanalyzer, Koné Laboratory, Evry, France). Plasma
insulin concentrations were measured using a rat insulin RIA kit from
Linco Research, Inc.
Evidence of CCK receptors on adipose tissue of various
origins
RT-PCR. Total RNA from stomach epithelium scrapings and rat
white adipose tissue of various origins was assayed by RT-PCR. Briefly,
total RNA was extracted using Trizol reagent according the
manufacturer’s procedure (Life Technologies, Inc.,
France). First strand complementary DNA was prepared from 4 µg
total RNA using murine reverse transcriptase according to
Pharmacia Biotech’s procedure. The PCR was performed
using the following primers: for CCK-A receptor (28): forward,
5'-ATGCTCATCATCGTGGTCCTG-3'; and reverse, 5'-AGTGTACACGGGGTAGGGCAC-3';
and for CCK-B receptor (29, 30): forward,
5'-GGCGTGGTCGACAGCCTTCTTATG-3'; and reverse,
5'-CAGGAAGCGGCACATGTTCGCCG-3'. After sample denaturation at 94 C for 3
min, PCR was carried out for 40 cycles consisting of 1 min of
denaturation at 94 C, 1 min of annealing at 60 C, and 2 min of
extension at 72 C. The amplification was terminated by a 10-min final
extension step at 72 C. In controls, reverse transcriptase was omitted,
and H2O was added. Samples were analyzed by 1% agarose gel
electrophoresis ethidium bromide staining to confirm the amplification
of the expected 480- and 532-bp products for the CCK-B and CCK-A
receptor genes, respectively, and 606 bp for the ß-actin gene.
[125I]CCK8 binding studies. Male
Wistar rats (250–350 g) were killed by a blow on the head. Epididymal
and perirenal adipose tissues were removed, cut into small pieces, and
incubated with 0.1% collagenase in Krebs-Ringer buffer supplemented
with 20 mM HEPES, 1.4 mM
CaCl2, and 3% BSA, pH 7.4, for 60 min at 37 C in a
shaking water bath. Then, the isolated adipocytes were separated by
filtration on a 200-µm mesh and washed three times (400 x
g, 5 min). The adipocytes were lysed at room temperature in
hypotonic medium containing 2 mM Tris-HCl, 2.5
mM MgCl2 1 mM
KHCO3, and 100 µM EGTA, pH 7.5, then
centrifuged for 15 min at 40,000 x g at 15 C. The
pellet was resuspended in a binding buffer consisting of 50
mM Tris-HCl and 0.5 mM
MgCl2 (pH 7.5) and again centrifuged (40,000 x
g for 15 min at 4 C). The resulting pellet was resuspended
in binding buffer and stored at -80 C until subsequent binding
studies. Fifty-microgram aliquots of membrane proteins were each
incubated for 60 min at 30 C in a final volume of 0.3 ml of assay
buffer containing one of a series of concentrations of
[125I]CCK8 (SA, 
2000 Ci/mmol; Amersham Pharmacia Biotech, Orsay, France). The suspensions were chilled on
ice and centrifuged for 1 min at 10,000 x g. The
pellets were washed twice with 1 ml cold binding buffer and counted in
a 
-counter. Specific binding was defined as the difference in
binding in the absence and presence of 1 µM YM022 and
corresponded to more than 70% of the total binding (n = 5
experiments). The computer program EBDA/LIGAND was used for data
analysis.
Northern blot analysis
Total RNA was extracted from the epididymal adipose tissues as
described above. RNA was electrophoresed on 1.2% formaldehyde agarose
gels, blotted, and fixed onto nylon filters (Hybond-N, Amersham Pharmacia Biotech, France). Northern blots were
prehybridized at 65 C for 4 h in a hybridization cocktail. Ob
probe (provided by Dr. M. Guerre-Millo, INSERM U465, Paris, France) was
radiolabeled with [32P]deoxy-CTP (Amersham Pharmacia Biotech) and hybridized at 65 C for 18 h.
Northern blots were rinsed twice in 2 x SSC (standard saline
citrate)-0.1% SDS containing 0.3 M sodium chloride and
0.03 M sodium citrate at 65 C for 30 min and twice in
0.1 x SSC-0.1% SDS at 65 C for 20 min. A
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) probe (provided by Dr.
C. Guillouf, Institut Curie, Paris, France) was used to monitor
messenger RNA (mRNA) integrity and quantity. Biomax MX film
(Eastman Kodak Co., France) was used for
autoradiography. The signal intensity was analyzed by a bioimaging
analyzer (BIOCOM 200, Les Ulis, France). The relative amount of
ob mRNA was determined as the ratio of the density of the
ob band to that of the GAPDH band.
Statistical analysis
Data are expressed as the mean ± 1 SEM. If
ANOVA was significant, a Tukey-Kramer multiple comparisons test was
used. The differences were considered significant for P
< 0.05.
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Results
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Leptin, insulin, and glucose levels in blood and leptin contents in
tissues upon refeeding in rats
An 18-h fast resulted in a plasma leptin level 20% of that in
control animals. The plasma leptin level was increased 2.5-fold after
15 min of refeeding and was fully restored by 6 h. As previously
found, this early increase in plasma leptin was mirrored by an early
decrease in gastric leptin content. After 2 h of refeeding there
was a substantial increase in fundic and epididymal levels of leptin
consistent with leptin neosynthesis in both tissues (Table 1
).
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Table 1. Variations of plasma leptin, insulin, and glucose
levels, and of leptin contents epididymal fat tissue and the stomach
upon refeeding in 18-h fasted rats
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In parallel, circulating insulin levels significantly increased after
15 min of refeeding, then decreased after 2 and 6 h of refeeding
to reach a value 2-fold higher than that in 18-h fasted animals. Plasma
glucose was increased after 15 min of refeeding and remained stable
after 2 and 6 h of refeeding (Table 1
).
Effect of YM022 on plasma and epididymal fat tissue leptin
Intraperitoneal injection of YM022 into 18-h fasted rats dose
dependently prevented the increase in leptin levels in plasma after a
2-h refeeding. The inhibition was 20% and 50% (P <
0.01 vs. control) with 0.1 and 1 mg/kg YM022, respectively,
and was maintained for 6 h (Fig. 1a). However, food intake was not
affected by this treatment (not shown). YM022 treatment markedly
increased epididymal leptin content after refeeding, by 30% at 2
h and 65% at 6 h (Fig. 1b). In these experimental conditions,
circulating insulin and glucose levels were not significantly different
in the various groups refed with and without YM022 (data not
shown).
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Figure 1. Effects of a CCK-B receptor antagonist, YM022, on
feeding-induced changes in plasma leptin (a) and in epididymal fat
tissue leptin content (b) in fasted rats. Data are expressed as the
mean ± 1 SEM for eight rats in each group. Data were
analyzed by a Tukey-Kramer multiple comparisons test after a
significant ANOVA. *, P < 0.05; **,
P < 0.01 vs. vehicle; #,
P < 0.05 vs. fasted rats.
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In control (normally fed) animals, injection of 3 mg/kg YM022 once a
day for 5 days resulted in a decrease in plasma leptin levels (Fig. 2a). Neither daily food intake (Fig. 2b)
nor body weight (not shown) was significantly affected. These effects
of YM022 suggest an regulation of the ob gene by endogenous
gastrin.
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Figure 2. Effects of chronic treatment of normally fed rats
with a CCK-B receptor antagonist, YM022, on plasma leptin on day 6 (a)
and on cumulative daily food intake (b). Data are expressed as the
mean ± 1 SEM for eight rats in each group. Data were
analyzed by Student’s t test. *, P
< 0.05 vs. vehicle.
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This was assessed by Northern analysis of total RNA extracted from the
epididymal fat pad of rats treated with or without the CCK-B receptor
antagonist. As shown in Fig. 3, the
amount of leptin mRNA in epididymal fat tissue was very much lower
after an 18-h fast than that in controls. The level returned to control
levels after 2 h of refeeding. However, prior treatment with YM022
dose dependently inhibited this recovery.
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Figure 3. Effects of CCK-B receptor antagonist, YM022, on
feeding-induced ob gene expression. a, A representative
Northern blot of ob and GAPDH mRNAs in rat epididymal
adipose tissue. b, Mean (±1 SEM) relative levels of
ob mRNA under the various conditions. Lane 1, Normally
fed rat; lane 2, 18-h fast rat; lanes 3–5, 2-h refeeding in 18-h
fasted rats; lane 3, vehicle; lane 4, plus 0.1 mg/kg YM022; lanes 5,
plus 1 mg/kg YM022, ip. Data were analyzed by a Tukey-Kramer multiple
comparisons test after a significant ANOVA. *, P <
0.05 vs. vehicle; #, P < 0.05
vs. 18-h fasted rats.
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Evidence for CCK-B/gastrin receptor on rat fat tissues
We next examined whether the adipose cells are endowed with CCK
receptors. Oligonucleotides deduced from the rat CCK-A (28) and human
gastrin/CCK-B receptor (29, 30) genes were used for RT-PCR screening of
total RNA from various adipose tissues. One gastrin/CCK-B RT-PCR
product with the expected size of 480 bp was detected in all of the
adipose tissues tested (Fig. 4b). That
this RT-PCR product corresponded to the gastrin/CCK-B receptor gene
transcript was confirmed by complementary DNA sequencing (ESGS,
Montigny le Bretonneux, France). However, no CCK-A RT-PCR product was
found in any fat tissue sample compared with the stomach as positive
control (Fig. 4a).
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Figure 4. RT-PCR analysis of CCK-A (AR) and CCK-B (BR)
receptor gene expression in rat adipose tissue. a, Wistar rat stomach
as a positive control; b, Wistar rat adipose tissues: mesenteric (lanes
1 and 2), epididymal (lanes 3 and 4), and perirenal (lanes 5 and 6).
Lane M, Marker ladders. Arrows indicate the expected
sizes of the PCR products (480- and 532-bp products for CCK-B and CCK-A
receptor, respectively).
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At the protein level, we performed a [125I]CCK8 assay to
assess the presence of the receptor protein. The adipocyte membranes
bound [125I]CCK8 in a saturable manner (Fig. 5). Scatchard analysis (Fig. 5, inset) indicated a single class of high affinity sites with
an equilibrium dissociation constant (Kd) of 0.21 ±
0.04 nM and a maximal binding capacity of 5.95 ± 0.9
fmol/mg protein.
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Figure 5. Binding of [125I]CCK8 to adipocyte
membranes. Membranes (50 µg) were incubated at 37 C with each of a
series of concentrations of [125I]CCK8. A typical
experiment, representative of four experiments, is shown.
Inset, Scatchard transformation of the binding isotherm.
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Discussion
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Our study provides strong evidence that leptin synthesis and
secretion in rat adipocytes are regulated by an adipocyte gastrin/CCK-B
receptor. Gastrin/CCK-B receptors have been found in the brain (CCK-B),
on smooth muscle cells, and on parietal cells (gastrin receptors).
However, we report molecular and kinetic data showing that such a
receptor is also present on adipose cells. Indeed, transcripts for
gastrin/CCK-B receptor were detected in rat fat tissue, and CCK-8
binding to adipocyte membranes was specifically displaced by the
selective gastrin/CCK-B receptor antagonist YM022. Furthermore, the
value for the equilibrium dissociation constant, Kd, of 0.2
nM is consistent with those reported for the brain (31) and
parietal cell gastrin/CCK-B receptors (32, 33). We previously reported
that exogenous CCK failed to acutely affect the epididymal fat pad
leptin content. This finding is consistent with the current idea that
adipocytes do not store leptin (26).
As previously reported (34, 35), we found that adipocyte leptin
expression and secretion rose within 2 h of refeeding in 18-h
fasted rats, with normal levels recovered after 6 h. Our findings
indicate that this refeeding increase is at least partly mediated by a
gastrin/CCK-B receptor. The inhibitory effect of the selective
antagonist YM022 is consistent with this view. Interestingly, this
effect is long lasting, as it was still observed 6 h after the
injection. Furthermore, it was maintained for 5 days by chronic (daily)
injections. As circulating CCK does not penetrate the blood-brain
barrier (36), its putative action on adipocyte leptin may be assumed to
be peripheral. However, the fasting plasma CCK levels range from
0.3–2.6 pM, and peak postprandial levels range from
4.6–11.2 pM in humans (37), rats (4, 5, 38), and dogs
(39), whereas the values for plasma gastrin are 10- to 20-fold higher
(40). Furthermore, exogenous administration of gastrin increases
circulating levels of leptin in fasted rats (Buyse, M., S. Attoub, and
A. Bado, unpublished results). Therefore, it is likely that gastrin is
the primary physiological stimulus of the adipocyte gastrin/CCK-B
receptor (Kd = 0.2 nM).
In conclusion, we provide another element for the understanding of
leptin regulation by gastrointestinal hormones; in addition to the fast
CCK mobilization of the gastric leptin store as previously reported
(25), gastrin appears to mediate a delayed stimulation of adipocyte
leptin secretion through a gastrin/CCK-B receptor. These in
vivo data argue for a physiological role of the gastrin/CCK-B
receptor in leptin regulation in the rat. It is very likely, but not
proven to date, that both effects act to stop food intake and maintain
the energy balance. It is also possible that gastrin/CCK regulation of
adipocyte leptin could have another, as yet unidentified, function.
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Footnotes
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1 This work was supported by INSERM, the Ministère de
l’Education et de la Recherche Scientifique (Grant 94.G0155 to A.B.;
grants to S.L. and M.B.), and a grant from the Fondation de la
Recherche Médicale (to S.A.). 
Received February 15, 1999.
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Top
Abstract
Introduction
