Overexpression of gastric leptin precedes adipocyte leptin during high-fat diet and is linked to 5HT-containing enterochromaffin cells.

OBJECTIVES: In obesity, while hyperleptinemia highly correlates with excess fat mass, the status of gastric leptin remains unknown. Here, we investigated the expression of leptin in stomach biopsies of obese humans and analyzed the temporal changes of gastric leptin expression in response to diet-induced obesity and its impact on 5-hydroxytryptamine (5HT)-producing cells. METHODS: Enterochromaffin (EC) cells and expression of leptin, PAX4 (critical factor for EC specification), tryptophane hydroxylase-1 (TPH1, the peripheral rate-limiting enzyme for 5HT) and 5HT were examined by immunofluorescence, quantitative real-time PCR, radioimmunoassay, respectively, in stomach and duodenum biopsies from 19 obese and 14 normo-weighed individuals, and in mucosa scrapings from C57Bl6/J diet-induced obese mice, leptin-deficient ob/ob mice and intestine-specific leptin receptor isoform B-deficient mice. RESULTS: Gastric mucosa of obese subjects displays an increased expression of leptin (LEP mRNA by fivefold and protein by twofold, P<0.01), TPH1 ((1.75-2.73, 95% confidence interval (CI)) vs (0.38-0.67, 95% CI); P<0.01) and PAX4 ((1.33-2.11, 95%CI) vs (0.62-0.81, 95% CI); P<0.01) as compared with normo-weighed individuals. In diet-induced obese mice, the overexpressions of gastric leptin, antral Pax4, Tph1 and increased EC cell number occurred before the onset of obesity and hyperleptinemia (reflect of adipocyte leptin production). In addition, leptin deficiency was associated with reduced Pax4 mRNA, whereas oral leptin treatment enhanced both Tph1 and Pax4 mRNA. Finally, mice with an intestine-specific deletion of leptin signaling exhibit significant decrease in duodenal mucosa 5HT content. CONCLUSIONS: These data demonstrate that gastric leptin is upregulated in obese individuals. RESULTS from high-fat diet mice showed that overexpression of gastric leptin that is linked to gut '5HT pathway' occurred before the onset of obesity and expansion of fat mass. This may be relevant in the pathophysiology of obesity.

[Characteristics of Low-Level Persistent viraemias in HIV-1 Patients Treated with Second-Line ARVs at the Sourô Sanou Teaching Hospital of Bobo-Dioulasso (Burkina Faso)]. / Caractéristiques des virémies persistantes de bas niveau des patients VIH-1 sous traitement antirétroviral de deuxième ligne au CHU Sourô Sanou de Bobo-Dioulasso (Burkina Faso).

We describe the characteristics of patients infected with HIV-1 as second-line antiretroviral therapy, with persisting low-level viremia. This was a descriptive retrospective study, conducted from January 1, 2010 to December 31, 2016, from the Cohort of the Infectious Diseases Department of Bobo-Dioulasso University Hospital. Patients infected with HIV-1, a second line of stable ARV treatment, with ≥95% compliance for at least 12 months, asymptomatic with CVp between 50 and 1000 copies/ml in two consecutive samplings at least 3 months apart. Out of 244 patients in second-line therapy, 79 met our inclusion criteria. The mean age of the patients was 42±10.2 years. Women (35.8 years) were younger than men (43.8 years) (p=0.001). Most were married (48.1%), 23.5% of whom were polygamous. The majority of patients (38/79) in the study had a CD4 count of <200 cells/ mm3. The median duration of ARV therapy since the beginning of the therapeutic history has been 4.8 (2.5-11 years). CVp greater than 10,000 copies/ml at the start of second-line therapy (p=0.003) and TDF+FTC + DRV + RTV combination (p=0.001) were associated with persistent low viremia. A genotypic resistance test is needed for these patients in order to better adapt the ARV treatment.

Nous décrivons les caractéristiques des patients infectés par le VIH-1 en deuxième ligne de traitement antirétroviral, avec une virémie persistante de bas niveau. Il s'agissait d'une étude rétrospective à visée descriptive, menée du 1er janvier 2010 au 31 décembre 2016, à partir de la cohorte du service des maladies infectieuses du CHU de Bobo-Dioulasso. Ont été inclus les patients infectés par le VIH-1, en deuxième ligne de traitement ARV stable, ayant une observance ≥ 95 % depuis au moins 12 mois, asymptomatiques, avec une charge virale plasmatique comprise entre 50 et 1 000 copies/ml sur deux prélèvements consécutifs à au moins 3 mois d'intervalle. Sur 244 patients en deuxième ligne de traitement antirétroviral, 79 répondaient à nos critères d'inclusion. L'âge moyen des patients était de 42 ± 10,2 ans. Les femmes (35,8 ans) étaient moins âgées que les hommes (43,8 ans) (p = 0,001). La plupart des patients étaient mariés (48,1 %), parmis lesquels certains vivaient dans des régimes polygames (23,5 %). La majorité des patients (38/79) de l'étude avaient un taux de CD4 ≤ 200 cellules/mm3. La durée médiane du traitement ARV depuis le début de l'histoire thérapeutique était de 4,8 ans (2,5- 11 ans). La charge virale plasmatique supérieure à 10 000 copies/ml au début du traitement (p = 0,003), et la combinaison TDF+FTC+DRV+RTV (p = 0,001) étaient associées à la virémie persistante de bas niveau. La réalisation d'un test génotypique de résistance s'impose pour ces patients afin de mieux adapter le traitement antirétroviral.

PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine.

Dietary proteins are mostly absorbed as di- and tripeptides by the intestinal proton-dependent transporter PepT1. We have examined the effects of leptin on PepT1 function in rat jejunum and in monolayers of the human enterocyte-like 2 cell Caco-2. Leptin is produced by the stomach and secreted in the gut lumen. We show here that PepT1 and leptin receptors are expressed in Caco-2 and rat intestinal mucosal cells. Apical (but not basolateral) leptin increased Caco-2 cell transport of cephalexin (CFX) and glycylsarcosine (Gly-Sar), an effect that was associated with increased Gly-Sar uptake, increased membrane PepT1 protein, decreased intracellular PepT1 content, and no change in PepT1 mRNA levels. The maximal velocity (Vmax) for Gly-Sar transport was significantly increased by leptin, whereas the apparent Michaelis-Menten constant (Km) did not change. Furthermore, leptin-stimulated Gly-Sar transport was completely suppressed by colchicine, which disrupts cellular translocation of proteins to plasma membranes. Intrajejunal leptin also induced a rapid twofold increase in plasma CFX after jejunal perfusion with CFX in the rat, indicating enhanced intestinal absorption of CFX. These data revealed an unexpected action of gastric leptin in controlling ingestion of dietary proteins.

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.

Human apolipoprotein A-IV reduces gastric acid secretion and diminishes ulcer formation in transgenic mice.

We have investigated the involvement of human apolipoprotein A-IV (apoA-IV) in gastric acid secretion and ulcer formation in recently generated apoA-IV transgenic mice. Compared to control littermates, transgenic animals showed a gastric acid secretion decreased by 43-77% whereas only slight variations were observed in the different cell population densities within the gastric mucosa. In addition, no variation in gastrin levels was observed. Transgenics were protected against indomethacin-induced ulcer formation, with lesions diminishing by 45 to 64% compared to controls. These results indicate that endogenous apoA-IV expression can regulate gastric acid secretion and ulcer development.

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.

Leptin decreases feeding and exploratory behaviour via interactions with CCK(1) receptors in the rat.

We assessed the effects of peripheral leptin on anxiety and exploratory behaviour in the elevated plus-maze and in the four-hole box or Y-maze tests, in rats fed 80% of normal daily food intake and rats fed ad libitum. In the Y-maze test, i.p. injection of 0.4 or 1 mg/kg leptin into rationed rats significantly decreased the percentage of spontaneous alternation behaviour and increased the number of visits. In the elevated plus-maze test, rationed rats spent significantly more time in the open arms (aversive part of the maze) than did rats fed ad libitum. This difference in behaviour was abolished by injecting 0.4 mg/kg leptin. In the four-hole box test, i.p. administration of 1 mg/kg leptin significantly reduced the duration and number of hole visits in rationed and ad libitum fed rats. As with leptin inhibition of food intake, these behavioural changes caused by leptin were prevented by a CCK(1) receptor antagonist (L364,718), at a dose that had no effect by itself. Finally, a 20-min stress that increased corticosterone and ACTH levels had no effect on circulating leptin levels and on the leptin content of epididymal fat tissue, stomach and brain. Thus, leptin induces hypoexploration and decreases spontaneous alternation in rats and these effects are partly dependent on nutritional status. These results also suggest that the CCK system may be involved in the induction of these behavioural changes in rats by leptin, via the CCK(1) receptor.

Structure-based design of new constrained cyclic agonists of the cholecystokinin CCK-B receptor.

New constrained cyclic pseudopeptide cholecystokinin-B (CCK-B) agonists have been designed on the basis of conformational characteristics of the potent and selective CCK-B agonist Boc-Trp-(NMe)Nle-Asp-Phe-NH2 (Ki = 0.8 nM, selectivity ratio CCK-A/CCK-B > 6000) (Goudreau et al. Biopolymers, 1994, 34, 155-169). These compounds are among the first successful examples of macrocyclic constrained CCK4 analogs endowed with agonist properties and as such may be of value for the development of nonpeptide CCK-B agonists. The affinities and selectivities of these compounds for CCK-B and CCK-A receptors have been determined in vitro by measuring the displacement of [3H]pCCK8 binding to guinea pig cortex and pancreas membranes, respectively. The most potent compound, 8b, N-(cycloamido)-alpha-Me(R)Trp-[(2S)-2-amino-9- ((cycloamido)carbonyl)nonanoyl]-Asp-Phe-NH2, has a Ki value of 15 +/- 1 nM for guinea pig cortex membranes with a good CCK-B selectivity ratio (CCK-A/CCK-B = 147). Furthermore, 8b behaved as a potent and full agonist in a functional assay which measures the stimulation of inositol phosphate accumulation in CHO cells transfected with the rat CCK-B receptor (EC50 = 7 nM). The in vivo affinity of 8b for mouse brain CCK-B receptors was determined following intracerebroventricular injection (ID50 approximately 29 nmol/kg). 8b was also shown to cross the blood-brain barrier (0.16%), after intravenous administration in mice. 8b also increased gastric acid secretion measured in anesthetized rats after intravenous injection. Therefore, 8b appears to be an interesting pharmacological tool and is currently under investigation as a lead for further development of nonpeptide CCK-B agonists.

Gastric leptin.

The recent discovery of gastric leptin has initiated several investigations on the possible role of leptin in digestive physiology. The following clues are currently suggested: leptin might control meal size in cooperation with Cholecystokinin, help cytoprotection of the gastric mucosa, play a role in gut inflammatory processes, regulate secretion of gastric hormones such as gastrin and somatostatin, and modulate intestinal transport of small peptides. The present review is a brief survey of the most significant advances in these issues.

Endogenous opioid peptides in the control of food intake in cats.

In this report, we investigated the role of exogenous and endogenous enkephalins on food intake in the cat, using, respectively, exogenous [D-Ala2-Met5]-enkephalin (DAME) and acetorphan (Ac) in order to inhibit the degradation of endogenous enkephalins. In addition, the selective peripheral antagonist naltrexone methylbromide (NTxMB) and the nonselective antagonist naloxone (Nx) were used in an attempt to discriminate central and peripheral opioid receptors. In 18-hours food-deprived animals, Ac (5 mg/kg IV) increased milk intake during sham feeding (+18%, p less than 0.05), but did not modify it in feeding conditions. Nx (1 mg/kg SC) reduced milk intake in sham-feeding experiments (-67%, p less than 0.01) more than in milk-feeding conditions (-30%, p less than 0.01). NTxMB (1 mg/kg SC) did not modify milk intake in sham-feeding but decreased it in feeding experiments. In nonfasted animals, Ac did not modify food intake. IV infusion of DAME (50 micrograms/kg) resulted in a reduction of daily food intake (-32%, p less than 0.01). Nx (1 mg/kg SC) decreased the earlier 30 min intake followed by reduction of daily intake (-30%, p less than 0.01). NTxMB (1 and 4 mg/kg SC) increased the 30-min intake dose dependently, without significant change in daily intake. In conclusion, Ac increases food intake in sham-feeding conditions, suggesting that endogenous enkephalins are likely to be involved in the stimulation of food intake. The effects of Nx and NTxMB furthermore suggest both a central activation, and a peripheral inhibition of food intake by opiates when food is allowed to proceed normally through the digestive tract.

Acetorphan, an enkephalinase inhibitor, decreases gastric secretion in cats.

Acetorphan is an inhibitor of "enkephalinase" (EC 3.4.24.11) which has been shown to reduce in vivo and in vitro the degradation of enkephalins and other peptides. The effects of acetorphan on gastric secretion were studied in cats fitted with gastric fistulae and Heidenhain pouches. Acetorphan inhibited by 40-60% the acid secretion from the gastric fistulae after stimulation by submaximal doses of pentagastrin, histamine and 2 deoxy-D-glucose. These inhibitions were reduced or suppressed by naloxone. The meal-stimulated secretion from the fistulae was not changed after acetorphan. Acetorphan slightly and progressively reduced the pentagastrin-stimulated acid output from the Heidenhain pouches, and this effect was naloxone resistant. No change was found in the secretion from Heidenhain pouches under histamine stimulation, while meal-induced secretion of the pouches was increased by acetorphan, and this increase was not prevented by naloxone. Endogenous opioids probably exert an inhibitory regulatory control upon the gastric secretion of cats. In addition, non-opioid factors may be involved in the effect of acetorphan on meal-stimulated secretion.

The effects of intravenously administered bombesin on pentagastrin-stimulated acid secretion in cats.

The effects of bombesin (BBS) infusion or BBS injection on the plateau gastric secretion stimulated by pentagastrin (Pg) were compared in cats fitted with gastric fistula (GF) and Heidenhain pouch (HP). Injection of 81 pmol/kg of BBS inhibited Pg-stimulated acid secretion in both GF and HP by 47 +/- 5% and 37 +/- 5% (P less than 0.01), respectively. Infusion of 324 pmol/kg.h of BBS did not significantly modify acid secretion, but as soon as the infusion stopped, an inhibition appeared which lasted 1 h (37 +/- 5% in GF and 53 +/- 4% in HP P less than 0.01). The inhibition was reversed in GF by infusion of BBS 324 pmol/kg.h. In HP, reversion of inhibition required the addition in the Pg infusion of subthreshold dose of carbachol. We suggest that under non-steady state conditions (i.e. injection or after the end of the infusion) a concentration gradient of BBS is created which favors the response of D-cells over that of G-cells, whereas under steady-state conditions (i.e. during infusion) the effects of BBS on G- and D-cells are balanced. This finding argues for a physiological role of BBS in the regulation of gastric acid secretion.

Novel CCK-B receptor agonists: diketopiperazine analogues derived for CCK4 bioactive conformation.

Recently, we proposed a CCK-B agonist bioactive conformation characterized by an 'S' shape of the peptidic backbone which was derived from structure-activity relationships and conformational analysis of CCK4 (Trp-Met-Asp-Phe-NH2) analogues. Using this template, we report here the synthesis of cyclic CCK4 analogues which contain, in place of the Trp-Met dipeptide, a diketopiperazine moiety resulting from a cyclization between Nle and N-substituted (D)Trp residues and coupled with a small linker to Asp-Phe-NH2. Some of these compounds displayed good affinities and selectivities for the CCK-B receptor. The results are discussed in terms of size, hydrophobicity and spatial orientation of the side-chains on the diketopiperazine ring. The most potent ligand exhibited potent and full CCK-B receptor agonist properties in promoting the hydrolysis of inositol phosphates (EC50 = 8 nM) in CHO cells, stably transfected with the rat brain CCK-B receptor. This compound was also shown to be a potent selective CCK-B/gastrin receptor agonist since, it increased gastric acid secretion measured in anesthetized rats on i.v. administration. These compounds provide a rigid template for the design of non-peptide CCK-B agonists, by modification of the remaining peptide moiety.

Proinflammatory role of leptin in experimental colitis in rats benefit of cholecystokinin-B antagonist and beta3-agonist.

Leptin, a hormone primarily secreted from adipocytes, plays a key role in controlling body weight homeostasis. In vitro studies indicate that it is also implicated in immune responses. Hyperleptinaemia has been reported in acute inflammation, especially during the early stages of intestinal inflammation in rats. The present study investigated the possible role of leptin in the pathogenesis of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Since no specific antagonist of leptin is available, a CCK-B antagonist (YM022) and a beta3 agonist (BRL37344) were used in this study to inhibit leptin secretion. Colitis was induced by intracolonic instillation of TNBS in rats. Five TNBS-groups were subcutaneously implanted with micropumps containing: placebo, YM022, BRL37344, BRL37344 and exogenous leptin simultaneously, or leptin alone. At sacrifices, colitis severity was assessed by macroscopic and histological scoring systems and by determination of tissue myeloperoxidase activity. The TNBS-induced hyperleptinaemia was significantly reduced by YM022 and BRL37344 (p<0.05). Inhibition of leptin secretion markedly reduced colonic inflammation, whatever the criteria considered (i.e. macroscopic, histological or biochemical). In contrast, administration of exogenous leptin completely abolished the beneficial effect of leptin-lowering drugs on colitis severity. These results provide the first direct evidence for an important deleterious role of leptin in the pathogenesis of experimental intestinal inflammation and suggest that a pro-inflammatory activity is attributable to leptin in vivo. Further studies are required to determine if these results have clinical significance.

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.

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.

Exposure to ionizing radiation modifies circulating gastrin levels and gastrointestinal endocrine cell densities in the rat.

PURPOSE: Gastrointestinal functions, controlled partly by gut peptides, are disturbed by ionizing radiation exposure. The effect of whole-body irradiation on circulating gastrin levels, densities of gastrointestinal endocrine cells and gastric acid secretion was investigated. MATERIALS AND METHODS: Rats were exposed to 2 or 6 Gy gamma-radiation. They were killed 3 or 7 days later and compared with shams. Plasma gastrin and basal acid output were measured. Endocrine cells were identified by argyrophilia or immunohistochemistry and their densities estimated. RESULTS: Radiation exposure significantly increased gastrinaemia and gastric acid output at the times studied (p<0.05-p<0.001). Endocrine cells displayed different sensitivities to irradiation. In the gastric mucosa, a 6 Gy dose induced a decrease in fundic argyrophil cell, antral gastrin and somatostatin cell densities, always accentuated 7 days after irradiation, while in the intestinal mucosa it induced an increase, with highest values often at 7 days post-irradiation (p<0.01-p<0.001). This was true for neurotensin cells in the jejunum and ileum, substance P cells in ileum and enteroglucagon cells in the descending colon. CONCLUSIONS: Whole-body irradiation in rats significantly alters plasma gastrin levels, and several gut endocrine cell densities. This has repercussions on hormonal function, such as that exerted on acid secretion, and may explain gastrointestinal dysfunction observed following radiation exposure.

Cholecystokinin suppresses food intake in cats: structure-activity characterization.

Our experimental models in this study were cats fitted with gastric fistulae. Intravenous infusion of sulfated CCK 8 and nonsulfated Boc CCK 7 inhibited both sham-feeding and feeding in fasted cats. The threshold dose (1.2 pmol/kg.hr) required for inhibition of sham-feeding was identical to that required to inhibit feeding in the same animals. However, the gastric secretory studies indicated that this dose was 90 times lower than the threshold dose stimulating gastric acid secretion (109 pmol/kg.hr). In nonfasted animals, sulfated CCK 8 and nonsulfated Boc CCK 7 (219 and 875 pmol/kg.hr) are both capable of decreasing the food intake at different intervals following the infusion with no significant effect on daily food intake. Our findings clearly show that there is no difference in the sensitivity of CCK's ability to inhibit sham-feeding and feeding, suggesting that CCK's suppressive effect on food intake does not solely involve gastric distension mechanisms. In contrast to gastric acid secretion, the sulfate group is not a "restrictive" factor for peripherally-induced CCK satiety.

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.

[Gastrin-17 and G17-gly induce proliferation of LoVo cells through the CCK B/gastrin receptor]. / La G17 et la G17-gly stimulent la prolifération des cellules LoVo par l'intermédiaire du récepteur CCK B/gastrine.

BACKGROUND AND METHODS: Recent studies suggest that glycine-extended gastrin (G17-gly) stimulates in vitro proliferation of the pancreatic cell line AR4-2J, through selective receptors distinct from the CCK-B/G-receptor mediating the effects of amidated gastrin (G17). The aims of our study were to examine the effects of G17 and G17-gly on the growth of the colorectal cancer cell line LoVo and to determine the receptor involved by using selective receptor-antagonist. RESULTS: Both G17 and G17-gly stimulated [3H]-thymidine incorporation in a concentration-dependent fashion. Maximal stimulation (153 +/- 18% and 166 +/- 17% of control, p < 0.01) was achieved with 10 nM G17 and 100 nM G17-gly, respectively. These stimulations were fully prevented by the presence of 10 pM YM022, a G/CCK B receptor-antagonist, but unaffected by L364,718, a CCK A receptor-antagonist. Basal growth of LoVo cells was inhibited by YM022 and stimulated by L364,718. CCK A and G/CCK B receptors mRNA were detected in the cells. Gastrin immunoreactivity was detected in the cells (16 pM) and in the extracellular medium (4.5 pM). CONCLUSION: Both G17 and G17-gly stimulate LoVo cells growth through the activation of a gastrin/CCK B receptor. The evidence for secreted gastrin and CCK A and B receptors mRNA may further suggest the existence of an autocrine loop involving a stimulatory gastrin/CCK B receptor.