Physiological role of cholecystokinin B/gastrin receptor in leptin secretion.

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.

Prolactin potentiates insulin-stimulated leptin expression and release from differentiated brown adipocytes.

The pituitary hormone prolactin (PRL) exerts pleiotropic effects, which are mediated by a membrane receptor (PRLR) present in numerous cell types including adipocytes. Brown adipose tissue (BAT) expresses uncoupling proteins (UCPs), involved in thermogenesis, but also secretes leptin, a key hormone involved in the control of body weight. To investigate PRL effects on BAT, we used the T37i brown adipose cell line, and demonstrated that PRLRs are expressed as a function of cell differentiation. Addition of PRL leads to activation of the JAK/STAT and MAP kinase signaling pathways, demonstrating that PRLRs are functional in these cells. Basal and catecholamine-induced UCP1 expression were not affected by PRL. However, PRL combined with insulin significantly increases leptin expression and release, indicating that PRL potentiates the stimulatory effect of insulin as revealed by the recruitment of insulin receptor substrates and the activation of phosphatidylinositol 3-kinase. To explore the in vivo physiological relevance of PRL action in BAT, we showed that leptin content was significantly increased in BAT of PRLR-null mice compared with wild-type mice, highlighting the involvement of PRL in the leptin secretion process. This study provides the first evidence for a functional link between PRL and energy balance via a cross-talk between insulin and PRL signaling pathways in brown adipocytes.

Antral gastrin- and somatostatin-producing cells and intraluminal peptide secretion in normal subjects and duodenal ulcer patients with and without vagotomy.

The behaviour of gastrin (G) cells and somatostatin (D) cells in endoscopic antral biopsies and that of intraluminal gastrin (ILG) and somatostatin (ILS) release in the gastric juice were investigated in three groups of patients: control subjects, duodenal ulcer (DU) patients and DU patients treated by a superselective vagotomy (SSV). G and D cell densities were correlated in the three groups of subjects. The G/D cell ratio was significantly increased in SSV patients (P less than 0.001) as compared to control and DU patients. No correlation was found between gastrin or somatostatin cell densities and basal intraluminal levels of the two peptides. ILG output was significantly higher in DU patients than in control or SSV patients (P less than 0.001). ILS output was also higher in DU patients than in controls (P less than 0.001) and in SSV patients (P less than 0.05). It was also significantly augmented in SSV (P less than 0.001) as compared to control patients. ILG and ILS concentrations were only correlated in controls. Within each of the three groups of subjects, ILG and ILS release varied in function of the gastric juice pH. Our results emphasize the necessity to consider the intragastric pH as well as the physiological or pathological state to study intraluminal peptides in man.

The H3 receptor is involved in cholecystokinin inhibition of food intake in rats.

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.

Messenger RNA expression of somatostatin receptor subtypes in human and rat gastric mucosae.

In several tissues including gastric mucosa, somatostatin displays various biological effects. Five seven-transmembrane-domain somatostatin receptor subtypes (SSTR1-5) have been recently cloned and only SSTR1 has been shown to be present in the human stomach. We used the polymerase chain reaction on reverse transcripts (RT-PCR) to characterize further the SSTR's mRNAs in human and rat gastric mucosae and in the human gastric tumoral cell-line HGTL. The SSTR1-5's mRNAs were found in both human fundic and antral mucosae as well as in the HGT1 cell and rat antrum. The four SSTR2-5's mRNA's but not SSTR1's were detected in the rat fundic mucosa. Furthermore, the use of rat isolated and purified fundic mucosal cells allowed us to localize SSTR2-5 in the parietal cell-enriched fraction, whereas SSTR2 and SSTR5 were the only subtypes found in the endocrine cell-enriched fraction. These results are the first to demonstrate the presence of five SSTR's mRNA subtypes in the stomach.

YM022, a highly potent and selective CCKB antagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands.

We investigated the effects of the novel CCKB/gastrin antagonist YM022 on gastric acid secretion in vivo and in vitro, compared to CI-988 and L365,260 as reference antagonists. In the anaesthetized rat, pentagastrin-induced stimulation of gastric acid secretion was dose-dependently and up to 100% inhibited by i.v. administration of YM022 with an ID50 of 0.009 +/- 0.0006 mumol/kg h in comparison to 0.6 +/- 0.03 and 3.40 +/- 0.05 mumol/kg h for CI-988 and L-365,260, respectively. In the gastric fistula cat, i.v. administration of YM022 produced a similar inhibitory effect with an ID50 of 0.02 mumol/kg in comparison to 1.6 and 2.5 mumol/kg for CI-988 and L-365,260, respectively. Furthermore, bolus injection of 0.6 mumol/kg YM022 produced 100% inhibition within 30 min and 85% inhibition was still observed after 3 h. In the isolated rabbit gastric glands, CCK8-stimulated 14C-aminopyrine uptake was inhibited according to the following rank order of potency: YM022 (IC50 = 0.0012 microM) > > CI-988 (IC50 = 0.2 microM) > > L365,260 (IC50 = 2.8 microM). Unlike with L365,260, no influence of CI-988 and YM022 on histamine-stimulated acid output was shown in this study. Thus, YM022 is a highly potent and selective gastric CCKB/gastrin receptor antagonist and has a long-lasting inhibitory effect on gastric acid secretion.

Helicobacter pylori stimulates gastric acid secretion via platelet activating factor.

Platelet activating factor (PAF) is a phospholipid mediator known as potent ulcerogenic agent but its physiological role is still unknown in the gastrointestinal tract. Lyso PAF the immediate PAF procursor has no deleterious effect in the gastrointestinal tract. We have previously reported that lyso PAF is produced by gastric mucosa in basal condition and in response to gastrin in healthy men. Helicobacter pylori metabolises lyso PAF to produce PAF. The aim was to study the effect of PAF on the gastric acid secretion. Isolated rabbit glands were used as a model and acid secretion was assessed by (14C) Aminopyrine (AP) uptake. PAF and histamine stimulated AP accumulation time- and dose-dependently. PAF-induced AP accumulation was supressed by omeprazole and Fura 2. BN50727 a specific PAF antagonist inhibited PAF-induced AP accumulation. The presence of a PAF receptor transcript was investigated by reverse transcriptase polymerase chain reaction (RT-PCR) from total mRNA using two primers in which oligonucleotides were synthetized from the human leucocyte PAF receptor cDNA. A single RT-PCR band of the transcript with expected size was detected in the crude isolated cell fraction. These results and others from our laboratory suggest that PAF stimulates gastric acid secretion via specific receptor on the parietal cells and H. pylori produces PAF which may induce mucosal injury directly or indirectly via acid pathway.

Persistence of circadian rhythms in gastric acid, gastrin, and pancreatic polypeptide secretions despite loss of cortisol and body temperature rhythms in man under stress.

During organic stress, severe dysfunctions of fundamental biological phenomena, such as modification of vagal tone, have been described. These dysfunctions could induce changes in the rhythm of acid secretion and/or its hormonal control. We therefore analyzed the effects of acute respiratory failure on the 24 h variations in intragastric pH, serum gastrin, and pancreatic polypeptide levels, taken as a marker of vagal tone. Body temperature and plasma cortisol circadian rhythms were used as marker rhythms. Twelve patients with chronic obstructive pulmonary disease complicated with acute respiratory failure were studied before and during continuous enteral nutrition; half of the patients received ranitidine, a H2 blocker. During the 3 days of the study, intragastric pH was below 2.5 for only one third of the time. No difference was observed between the placebo and the ranitidine groups. Plasma pancreatic polypeptide was within normal ranges despite increased cortisol levels. Gastrin levels reflected changes in intragastric pH over the 24 h time frame and were noted to increase during ranitidine and enteral nutrition. Despite the loss of cortisol and body temperature circadian rhythmicity all throughout the study, circadian rhythms were maintained or restored during the different therapeutic regimens for intragastric pH, serum gastrin, and pancreatic polypeptide levels. Moreover, an ultradian rhythm for gastrin before any treatment, a circadian rhythm for intragastric pH on enteral nutrition, a circadian rhythm for intragastric pH, plasma gastrin and plasma pancreatic polypeptide on ranitidine regimen were observed. Thus during acute respiratory failure, certain physiological circadian rhythms persisted despite the disappearance of "marker" rhythms. Furthermore, these rhythms for digestive secretions could be pharmacologically restored.

[Release of pancreatic polypeptide in response to the intragastric administration of a meal is not different in duodenal ulcer patients and normal subjects]. / La libération de polypeptide pancréatique en réponse à l-administration intra-gastrique d'un repas n'est pas différente chez des ulcéreux duodénaux et des sujets normaux.

The high basal and meal-induced acid secretions in duodenal ulcer patients has led to the concept that vagal hyperactivity is a common factor in the pathogenesis of peptic ulcer. For these reasons, since pancreatic polypeptide secretion is known to be under vagal control, we studied the pancreatic polypeptide release after intragastric administration of two protein meals (10 and 20 g protein in 400 ml) in 18 duodenal ulcer patients and in 17 normal subjects. After a 10 g protein meal was administered, gastric pH was either maintained at pH 4.5 or allowed to decrease. The 20 g protein meal induced a higher pancreatic polypeptide release than did the 10 g protein meal (p less than 0.05): the integrated pancreatic polypeptide responses were 1.07 +/- 0.5 and 3.21 +/- 0.58 nmol/l/60 min respectively in the duodenal ulcer group and 0.46 +/- 0.21 and 2.67 +/- 0.69 nmol/l/60 min respectively in the control group. On the other hand, the responses to the two protein meals in duodenal ulcer patients were not different from those obtained in normal subjects, despite the higher meal-induced acid secretions in the duodenal ulcer group. pancreatic polypeptide increase was not larger when gastric pH was fixed than when it was allowed to decrease, 0.56 +/- 0.21 and 1.7 +/- 0.63 nmol/l/60 min respectively in normal subjects and 1.07 +/- 0.5 and 1.07 +/- 0.49 nmol/l/60 min respectively in duodenal ulcer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequential somatostatin and gastrin releases in response to secretin in rat in vivo.

Secretin in known to inhibit gastric acid secretion. Exogenous secretin has also been shown to have a biphasic effect on acid secretion, being stimulatory then inhibitory. To explain this effect, we studied the timing of gastrin, somatostatin, and HCl releases in the gastric lumen in response to an i.v. bolus of secretin (360 pmol) or saline in conscious rats provided with a chronic double gastric fistula and having had or not antrectomy. After secretin but not saline, an immediate and transient increase in acid and gastrin secretions was first observed. After a 4 min lag, a dramatic increase in somatostatin secretion was then observed, together with a 90 percent inhibition of acid secretion and a return of gastrin release to basal level. Twenty min after secretin administration, a rebound increase in acid and gastrin outputs occurred, whereas somatostatin output returned to basal level. The secretin-induced somatostatin release was higher in rats with antrectomy than in those without antrectomy suggesting that the observed somatostatin output mostly originated from the fundus. This present study suggests that a bolus of secretin induced a gastrin release and thus could stimulate acid secretion. These pharmacological findings could provide an explanation for the so-called paradoxical secretin-induced stimulation of gastrin secretion in particular conditions.

Decreased expression of Intestinal I- and L-FABP levels in rare human genetic lipid malabsorption syndromes.

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.

Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc(Min/+) mice.

BACKGROUND AND AIMS: Leptin, the product of the ob gene, has been suggested to increase the risk of colon cancer. However, we have shown that although leptin stimulates epithelial cell proliferation it reduces the development of carcinogen induced preneoplastic lesions in the rat colon. Here, we explored the effect of leptin in vitro on proliferation of human colon cancer cells, and in vivo on the growth of HT-29 xenografts in nude mice and the development of intestinal tumours in Apc(Min/+) mice. METHODS: Proliferation of HT-29, LoVo, Caco2, and SW 480 cells was assessed in the absence or presence of leptin (20-500 ng/ml) by 3H-thymidine incorporation and cell count. Leptin (800 microg/kg/day) or its vehicle was delivered for four weeks to nude mice, inoculated with HT-29 cells on day 0, and for six weeks to Apc(Min/+) mice. RESULTS: Leptin dose dependently stimulated cell DNA synthesis and growth in all cell lines. In nude mice, leptin caused a 4.3-fold increase in plasma leptin levels compared with pair fed controls. This hyperleptinaemia, despite leptin receptor expression in tumours, did not induce significant variation in tumour volume or weight. Tumour Ki-67 index was even inhibited. In leptin treated Apc(Min/+) mice, a 2.4-fold increase in plasma leptin levels did not modify the number, size, or distribution of intestinal adenomas compared with pair fed controls. CONCLUSIONS: Leptin acts as a growth factor on colon cancer cells in vitro but does not promote tumour growth in vivo in the two models tested. These findings do not support a pivotal role for hyperleptinaemia in intestinal carcinogenesis.

H3-receptor regulation of vascular gastrin and somatostatin releases by the isolated rat stomach.

We have studied the effects of the H3-receptor agonist (R) alpha-methylhistamine [(R) alpha-MeHA] and the H3-receptor antagonist thioperamide (Thiop) on basal- and carbachol-stimulated vascular gastrin release (GR) and somatostatin release (SR) by the isolated rat stomach. Carbachol dose-dependently stimulated and inhibited GR and SR, respectively. Maximal stimulation of GR (500 +/- 112 percent of basal; p < .01), and maximal inhibition of SR (-62 +/- 9 percent under basal; p < .01) were obtained with 1 micron carbachol. Neither (R)alpha-MeHA nor Thiop, up to 10 microns, affected GR. However, SR was dose-dependently enhanced by Thiop (25 +/- 8 percent for 10 microns). Carbachol stimulation of GR was strongly inhibited by Thiop (30 +/- 7 percent for 100 nM and 73 +/- 14 percent for 1 microgram), whereas it was potentiated by (R)alpha-MeHA. Carbachol inhibition of SR was reversed by Thiop and (R)alpha-MeHA. However, the reversal effect of (R)alpha-MeHA was prevented by the CCKB/gastrin receptor antagonist PD134308. These results support H3-receptor regulation of basal and cholinergically-stimulated GR and SR.

Neurotensin and oxyntomodulin-(30-37) potentiate PYY regulation of gastric acid and somatostatin secretions.

The present study was designed to investigate, in cats provided with both a gastric fistula and a denervated fundic Heidenhain pouch, the effect of peptide YY (PYY) on pentagastrin-stimulated gastric acid and somatostatin secretions and to determine whether neurotensin (NT) and the COOH-terminal octapeptide of oxyntomodulin [Oxm-(30-37)] would modify these secretions. Intravenous infusion of PYY (0.1 nmol.kg-1.h-1), NT (15 nmol.kg-1.h-1), or Oxm-(30-37) (60 nmol.kg-1.h-1) did not affect basal acid secretion. However, they significantly inhibited pentagastrin-stimulated gastric acid output up to 50% (P < 0.01) in the main stomach. Furthermore, they significantly increased gastric somatostatin release by +750, +1,700, and +600% over basal level (P < 0.01) for (in nmol.kg-1.h-1) 0.1 PYY, 15 NT, and 60 Oxm-(30-37), respectively. On the other hand, the effects of 0.1 nmol.kg-1.h-1 PYY were potentiated by subthreshold doses of NT (5 nmol.kg-1.h-1) or Oxm-(30-37) (15 nmol.kg-1.h-1). These findings suggest that there could be a cooperation between the three peptides in the intestinal regulation of gastric secretions.

Pharmacological characterization of histamine H3 receptors in isolated rabbit gastric glands.

The effects of the specific H3 agonist (R)-alpha-methylhistamine (alpha-MeHA) and the specific H3 antagonist thioperamide were examined on histamine release and acid secretion [( 14C]-aminopyrine (AP) accumulation) by isolated rabbit gastric glands. Thioperamide significantly enhanced basal histamine release from the glands (+50% at 30 min for 10(-7) M thioperamide; P less than 0.01), and this increase was prevented by alpha-MeHA. Histamine-elicited AP accumulation was increased by 18% (P less than 0.05) by 10(-7) M thioperamide and decreased by 70% (P less than 0.01) by 10(-6) M of the H2 antagonist ranitidine. Thioperamide alone significantly enhanced AP accumulation in a dose-dependent manner, whereas alpha-MeHA had no effect of its own on this accumulation. Thioperamide stimulation of basal AP accumulation was not modified by ranitidine but was 50% decreased by alpha-MeHA. Furthermore, carbachol-induced AP accumulation was decreased by alpha-MeHA and increased by thioperamide; the latter effect was not blocked by ranitidine. These findings support that H3 receptors pharmacologically distinct from H2 receptors are involved in the regulation of histamine-stimulated acid secretion. They further suggest that these gastric H3 receptors occur in the gastric glands as 1) H3 autoreceptors located on the histamine-secreting cells and acting to downregulate histamine release from these cells and 2) H3 (or H3-like) receptors located on the parietal cell and regulating in a negative manner the acid secretory process.

Possible mediation by luminal somatostatin of bombesin-induced satiety in the cat.

Intravenous bombesin produced a dose-related stimulation of luminal gastric somatostatin output and a concomitant dose-dependent inhibition of food intake in the gastric fistula cat. Maximal food intake inhibition was observed at 1,280 pmol.kg-1.h-1 and corresponded to 65 +/- 7% (P less than 0.01). These effects of bombesin were dose dependently abolished by the specific bombesin-receptor antagonist, [Leu13-psi(CH2NH)-Leu14]bombesin. Furthermore, intragastric administration of somatostatin-14, at doses corresponding to those found in the gastric lumen in response to intravenously administered bombesin, significantly inhibited the first 30 min of food intake. This administration had however no effect on total (daily) food intake. We therefore suggest that luminal gastric somatostatin could at least account for bombesin-induced short-term satiety.

H3-receptor activation inhibits cholinergic stimulation of acid secretion in isolated rabbit fundic glands.

We previously reported evidence for H3-receptor inhibition of cholinergic stimulation of acid secretion by isolated rabbit gastric glands. Because this inhibition was unsensitive to H2 antagonists, we postulated that the parietal cell should bear a H3-receptor. In the present study, we investigated the effects of M1-M3 muscarinic receptors antagonists on carbachol- and thioperamide-induced acid secretion (14CAP uptake) by isolated rabbit gastric glands. Furthermore, we examined whether H3-receptor ligands could affect [3H]-N-methylscopolamine binding to the isolated rabbit parietal cells. Both carbachol and thioperamide concentration-dependently stimulated 14CAP uptake in the glands with maximal responses being achieved for 100 microM and 0.1 microM, respectively. These stimulations were concentration-dependently inhibited by the H3-receptor agonists R(alpha)-methylhistamine and imetit. Maximal inhibitions did not exceed 60% for 1 microM. The muscarinic receptor antagonists, hexa-sila-difenidol p-fluoro analog (M3), pirenzepine (M1) and gallamine (M2) inhibited carbachol-induced 14CAP uptake with IC50 of 50 nM, 10 microM and >> 100 microM, respectively. Thioperamide-induced 14CAP uptake was also inhibited by hexa-sila-difenidol p-fluoro analog and pirenzepine with IC50 of 90 nM and 12 microM, respectively; whereas gallamine had no effect. [3H]-N-methylscopolamine binding to isolated parietal cells was inhibited by atropine and pFHHSiD with IC50 of 15 nM and 132 nM, respectively. Neither R(alpha)-MeHA nor thioperamide did affect this binding although a H3-receptor inhibitory effect was observed on carbachol-induced 14CAP uptake by the cells. These data support that H3-receptor activation inhibits M3-mediated cholinergic stimulation of acid secretion through mechanisms operating downstream to the receptors sites.

Antral mucosa expresses functional leptin receptors coupled to STAT-3 signaling, which is involved in the control of gastric secretions in the rat.

BACKGROUND & AIMS: Leptin is a circulating hormone that communicates the peripheral nutritional status to the hypothalamus, which controls food intake, energy expenditure, and body weight. This study characterizes leptin receptors and leptin-sensitive STAT proteins in the antrum and investigates the effects of leptin on gastric secretions. METHODS: The effects of leptin on gastrin messenger RNA (mRNA), plasma gastrin, gastric acid in vivo in the rat, and on somatostatin and gastrin secretions by isolated antral cells were determined in vitro. Leptin receptors were investigated in isolated rat antral cells by reverse transcription-polymerase chain reaction and binding of [(125)I]-leptin studies. The effects of in vivo and in vitro leptin on transduction signal STAT proteins were investigated by immunoblotting antral extracts. RESULTS: Peripheral injection of leptin inhibited in a dose-dependent manner, basal gastric secretion, gastrinemia, and mucosal gastrin mRNA in vivo. mRNAs encoding the long (Ob-Rb) and short (Ob-Ra) receptor forms were detected in rat antral mucosa, as were STAT-1, -3, and -5b immunoreactive proteins. Isolated antral cells specifically bound [(125)I]-leptin, and addition of leptin to these cells inhibited the release of somatostatin and increased the release of gastrin. These effects were associated with an increase in nuclear STAT-3 proteins in vitro and in vivo. CONCLUSIONS: This study provides the first molecular evidence for the coexpression of leptin receptors and STAT-3 in antral mucosa. It provides further evidence for the involvement of leptin in the control of gastric secretions.

Characterization of a beta 3-adrenoceptor stimulating gastrin and somatostatin secretions in rat antrum.

The beta 3-adrenoceptor (beta 3-AR) agonist SR-58611A {ethyl-[(7s)-7-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]5, 6,7,8-tetrahydronaphth-2-yl]oxyacetate hydrochloride} stimulated somatostatin and gastrin releases in isolated rat gastric antral epithelial cells. Stimulation was a concentration-dependent process with 50% effective concentrations of 2.7 +/- 1.1 and 3.8 +/- 1.9 nM compared with 209 +/- 71 and 230 +/- 51 nM for isoproterenol, respectively. It was inhibited by selective beta-AR antagonists with the following rank order of potency: SR-59230A 3-(2-ethylphenoxy)1-[(1S)-1,2,3,4-tetrahydronaphth- 1-ylamino]-(2S)-2-propranol oxalate; beta 3-AR antagonist > ICI-118551[erythro-(+/-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride; beta 2-AR antagonist > CGP-20712A[(+/-)-[2-(3-carbarmoyl-4-hydroxyphenoxy)-et hyl- amino]-3-[4 (1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]- 2-propranol; beta 1-AR antagonist]. Furthermore, specific binding of 125I-cyanopindolol to the isolated cells was demonstrated and was displaced by the beta-AR antagonists according to the same rank order of potency and with apparent dissociation constants consistent with the 50% inhibitory concentrations for SR-58611A-stimulated somatostatin and gastrin releases. In addition, the presence of beta 3-AR mRNA was detected by reverse transcriptase polymerase chain reaction. These findings provide the first evidence for a gastric beta 3-AR mediating catecholamine stimulation of gastrin and somatostatin releases from antral cells.