[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.

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.

[Prevalence of albuminuria in children from 5 to 15 years in the town of Kaya (Burkina Faso)]. / Prevalence de l'albuminurie chez des enfants de 5 a 15 ans de la ville de Kaya (Burkina Faso).

INTRODUCTION: Albuminuria, an important marker of kidney damage, is still insufficiently studied in sub-Saharan Africa. The aim of this study is to describe the epidemiology of albuminuria in the town of Kaya in Burkina Faso. METHODS: We conducted a cross-sectional study in the town of Kaya. Simple random sampling was done. It concerned all households with children 5-15 years old of urban area of the town of Kaya. Selected children or their parents were interviewed. Anthropometric measurements and urinary samples were performed. RESULTS: Two hundred six children (113 girls and 93 boys) participated in the study. Albuminuria was found in 18 children whether 8.7% of cases. The mean systolic and diastolic blood pressures of children with albuminuria (107.2 ± 13.6 and 74.7 ± 11.4 mm Hg) were not significantly different from those of children without albuminuria (110.3 ± 14 and 73.1 ± 11.5 mmHg). Sociodemographic factors were not associated with the occurrence of albuminuria in children. DISCUSSION: The prevalence of albuminuria in the strip involved nearly a tenth of children, which is important. CONCLUSION: The results of this study are a first population database of kidney disease in the country. The study should be completed by the identification of cases of persistent albuminuria in this population.

INTRODUCTION: L'albuminurie, important marqueur d'atteinte rénale, est encore insuffisamment étudiée en Afrique subsaharienne. Par la présente étude, nous voulons connaître l'épidémiologie de l'albuminurie dans la ville de Kaya au Burkina Faso. MÉTHODES: Nous avons mené une étude transversale dans la ville de Kaya. Un échantillonnage aléatoire simple a été effectué à partir d'une base de sondage constituée par l'ensemble des ménages ayant des enfants de 5 à 15 ans du milieu urbain de la ville de Kaya. Les enfants sélectionnés ou leurs parents ont été interviewés. Les mesures anthropométriques et des prélèvements urinaires ont été effectués. RÉSULTATS: Deux cent six enfants (113 filles et 93 garçons) ont participé à l'étude. L'albuminurie a été trouvée chez 18 enfants soit 8,7% des cas. Les moyennes des pressions artérielles systolique et diastolique des enfants avec albuminurie (107,2±13,6 et 74,7±11,4 mm Hg) n'étaient pas significativement différentes de celles des enfants sans albuminurie (110,3±14 et 73,1±11,5 mm Hg). Les facteurs sociodémographiques n'étaient pas associés à la survenue de l'albuminurie chez l'enfant. DISCUSSION: La prévalence de l'albuminurie à la bandelette a concerné près d'un dixième des enfants, ce qui est important. CONCLUSION: Les résultats de cette étude constituent pour le pays une première base de données en population sur la maladie rénale. L'étude doit être complétée par l'identification des cas d'albuminurie persistante dans cette population.

Long-term results of adjustable gastric banding in a cohort of 186 super-obese patients with a BMI≥ 50 kg/m2.

BACKGROUND: There are conflicting results concerning the bariatric effectiveness of adjustable gastric banding in super-obese patients with a Body Mass Index (BMI) more or equal to 50 kg/m(2). METHOD: A cohort of 186 patients with a BMI greater or equal to 50 kg/m(2) who underwent adjustable gastric banding (AGB) at the Bichat-Claude-Bernard University Hospital (Paris, France) were prospectively entered into a database. The following data were recorded: BMI, percentage of BMI loss, percentage of excess weight lost (%EWL), complications, and surgical re-interventions. Loss of greater than 50% of excess weight was considered a success (primary endpoint). A %EWL of less than 25% after one year, or the removal of the gastric band was considered a failure. RESULTS: Thirty-five men (18.8%) and 151 women (81.2%), with a mean age of 38.9 years (range: 16-65) underwent AGB between September 1995 and December 2007. The mean BMI was 55.06 kg/m(2) (range: 50-74.4). Mean follow-up was 112.5 months with a minimum of 28 months and a maximum of 172 months. The follow-up rate was maintained at 89% at ten years. The technique of AGB was by "peri-gastric dissection" in the first 115 patients (61.82%) and by "pars flaccida dissection" in 71 patients (38.17%). The gastric band was removed in 87 of 186 patients (46.8%); band ablation was due to a complication of the gastric band in 62 of these cases (33.3%), to failure of weight loss in 23 cases (12.4%), and to patient request in two cases (1%). The major complications requiring re-operation were: chronic dilatation of the proximal gastric pouch (27 patients - 14.5%), acute dilatation (21 patients - 11.3%), intragastric migration of the prosthesis (six patients - 3.2%), reflux esophagitis (six patients - 3.2%), infection of the gastric band (one patient - 0.5%), and Barrett's esophagus (one patient - 0.5%). No statistically significant difference was found between the two operative techniques with regard to the possibility of preserving the gastric band for ten years. For patients who underwent band removal, no further follow-up analysis of patient data after band ablation was performed. The results were best at two years after AGB with a median BMI of 42.72 kg/m(2), a band removal rate of 8.6% (16 of 186 patients), and a failure rate of 16.4% (28 of 170 patients) of those patients who still had their band in place. However, at 10 years, the picture was completely reversed with a band removal rate of 52.2% (47 of 90 patients), a failure rate of 22% (seven of 33 patients) of those who still had their band in place, and a median BMI of 43.43 kg/m(2). CONCLUSION: Laparoscopic gastroplasty using the adjustable gastric band appeared to be a promising intervention for super-obese patients when the results at two years were analyzed - fairly simple to perform, with perioperative morbidity and mortality near zero. However, these results do not persist in the long-term for super-obese patients. At ten years, only 11% of patients (nine of 80) have successful bariatric results (%EWL>50%) and we were forced to remove the gastric band in 52.2% of patients (47 of 90) because of complications, regardless of the initial operative technique used. Given these results, AGB gastroplasty is not a recommended method for super-obese patients and we believe that a BMI greater or equal to 50 kg/m(2) is a contra-indication for this procedure.

Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis.

BACKGROUND AND PURPOSE: Pentoxifylline is in clinical trials for non-alcoholic fatty liver disease and diabetic nephropathy. Metabolic and hepatic effects of pentoxifylline were assessed in a murine model of obesity and type 2 diabetes. EXPERIMENTAL APPROACH: Pentoxifylline (100 mg·kg(-1) ·day(-1)) was administered for 4 days or 3 weeks in lean and obese/diabetic ob/ob mice. Plasma lipids, glucose, other metabolites and relevant enzymes were measured by standard assays. Hepatic lipids in vivo were assessed with magnetic resonance spectroscopy and by histology. Hepatic extracts were also analysed with RT-PCR and Western blotting. KEY RESULTS: Four days of pentoxifylline treatment slightly increased liver lipids in ob/ob mice. After 3 weeks, pentoxifylline exacerbated fatty liver and plasma transaminases in ob/ob mice but did not induce liver steatosis in lean mice. Plasma glucose was highest in fed, but not fasted, ob/ob mice treated with pentoxifylline. During the first 10 min of an oral glucose tolerance test, blood glucose increased more rapidly in pentoxifylline-treated mice. Jejunal expression of glucose transporter 2 isoform was increased in pentoxifylline-treated obese mice. Hepatic activity of carbohydrate response element binding protein (ChREBP) increased after pentoxifylline in ob/ob, but not lean, mice. Hepatic expression of lipogenic enzymes was highest in pentoxifylline-treated ob/ob mice. However, pentoxifylline reduced markers of oxidative stress and inflammation in ob/ob liver. CONCLUSION AND IMPLICATIONS: Pentoxifylline exacerbated fatty liver in ob/ob mice through enhanced intestinal glucose absorption, increased postprandial glycaemia and activation of hepatic lipogenesis. Long-term treatment with pentoxifylline could worsen fatty liver in some patients with pre-existing hyperglycaemia.

Dichloromethane-methanol extract from Borassus aethiopumn mart. (Arecaceae) induces apoptosis of human colon cancer HT-29 cells.

Borassus aetihiopum MART (Arecaceae) is a plant used in traditional herbal medicine for the treatment of various diseases (bronchitis, laryngitis, antiseptic). In particular, their male inflorcscences were reported to exhibit cicatrizing, antiseptic and fungicidal properties. In the present study, the biological activity of E2F2, an apolar extract from Borassus aethiopum male inflorescence was investigated on colon cancer HT29 cells. Phytochemical screening was carried according to methodology for chemical analysis for vegetable drugs. Cells proliferation was determined by the MTT assay and cells cycle distribution was analysed by using laser flow cytometer (Beckman coulter). The cytoskeleton organisation was examined under a laser scanning confocal microscope (Zess). Preliminary phytochemical analysis of E2F2 extract revealed the presence of sterols, triterpenes and saponosids. E2F2 extract (1 microg and 100 microg mL(-1)) significantly inhibited cell proliferation by blocking cell population in G0/G1 phase. Flow Cytometric analysis of E2F2-treated HT29 cells showed that hypoploïd cell population (sub G1 phase) increased with processing time exposures. Immunofluorescence confocal analysis revealed a disrupt actin microfilaments network in E2F2 treated-cells with a significant reduction in actin stress fibres and appearance of a random, non-oriented distribution of focal adhesion sites. These data indicate that E2F2 extract has anti-proliferative and pro-apoptotic activities. Further studies are required to unravel the mechanisms of action of E2F2 extract.

Metformin-induced regulation of the intestinal D-glucose transporters.

Metformin is an orally administered drug that lowers blood glucose and improves insulin sensitivity in patients with non insulin-dependent diabetes. Although the antihyperglycemic effect of metformin has been extensively studied, its cellular mechanism(s) of action (including the effect on enterocyte) remains to be defined. This study was designed to examine the effect of metformin on glucose transporters in enterocyte. Na(+)-dependent glucose transporter-1 (SGLT-1) activity was followed as glucose-induced short-circuit current (Isc) in Ussing chambers. The effect of metformin (10 micromol/L, 3 min) on transmural glucose transport was studied in isolated rat jejunal loops. Its impact on abundance of transporters SGLT-1 and GLUT2 in jejunal brush border membranes (BBM) and its effect on the phosphorylation of AMP-activated protein kinase (AMPK) alpha2 subunit was studied by western blot. Acute effect of metformin was also measured in vivo by oral glucose tolerance test (OGTT). Metformin markedly inhibited glucose-induced Isc (approximately 77%) after mucosal addition. In addition, metformin reduced the glucose-induced abundance of SGLT-1 in BBM and increased those of GLUT2, concomitantly increasing the phosphorylation of intracellular AMPKalpha2. This effect of metformin was also observed using non-metabolizable sugar alpha3-O-methyl glucose. Transmural glucose transport measured in vitro was increased by 22% under metformin. Finally, oral metformin markedly increased glucose tolerance in OGTT. In conclusion, metformin slightly increases intestinal glucose absorption by inducing a re-distribution of glucose transporters in BBM through AMPK control in enterocyte. In addition to its action to other splanchnic tissues, this could constitute a peripheral signal contributing to the beneficial effect of metformin on glucose tolerance.

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.

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.

Admixture and diversity in West African cattle populations.

We present a population genetic analysis of microsatellite variation in 16 West African cattle populations. West Africa represents a unique juxtaposition of different climatic and ecological zones in a relatively small geographical area. While more humid coastal regions are inhabited by the tsetse fly, a vector which spreads trypanosomiasis among cattle, the disease is not transmitted in the drier areas outside this zone. This is the most thorough study of genetic diversity in cattle within this area, which contains genetically important trypanotolerant Bos taurus breeds. Genetic relationships among the many breeds are examined and levels of diversity are assessed. Admixture levels were determined using a variety of methods. Ancestry informative or population-associated alleles (PAAs) were selected using populations from India, the Near East and Europe. Multivariate analysis, the admix program and model-based Bayesian admixture analysis approaches were also employed. These analyses reveal the direct impact of ecological factors and the profound effect of admixture on the cattle of this region. They also highlight the importance of efforts to prevent further dilution of African taurine breeds by B. indicus cattle.

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.

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.

Expression and regulation of leptin receptor proteins in afferent and efferent neurons of the vagus nerve.

Leptin, the product of the ob gene, plays a key role in the regulation of food intake via a cross-talk between hypothalamic leptin receptors and neuropeptides that affect feeding behaviour. Recent studies have shown a synergistic interaction between leptin and cholecystokinin (CCK) leading to suppression of food intake, which involves CCK-1 receptors and capsaicin-sensitive vagal fibres. In this study, we have investigated the presence of leptin receptors in afferent and efferent neurons of the vagus nerve. By using reverse transcription-polymerase chain reaction, mRNAs encoding long (Ob-Rb) and short (Ob-Ra) leptin receptor isoforms were detected in the rat nodose ganglion, which contains the cell bodies of the vagal afferent neurons. Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk. Immunohistochemistry showed the presence of leptin receptors and the leptin-induced transcription factor STAT3 in the cytoplasm of nodose ganglion cells. In cervical vagal segments, levels of leptin receptor protein displayed physiological regulation, with decreased amounts after feeding and increased levels after food restriction. In addition, leptin receptor and STAT3 immunoreactivities were detected in neurons of the nucleus of tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNX) by immunofluorescence histochemistry. Furthermore, direct double-labelling demonstrated colocalization of Ob-Rb and STAT3 immunoreactivities in cholinergic vagal efferent cell bodies of the DMNX. It is speculated that vagal leptin receptors, apart from being activated by adipocyte-derived leptin, may also be influenced by leptin produced by the stomach. This may explain the synergistic action of leptin and CCK on neuronal activity in the NTS and on food intake.

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.

Insulin and glucocorticoids differentially regulate leptin transcription and secretion in brown adipocytes.

Leptin, the ob gene product, is produced by adipose tissue and is submitted to a complex hormonal and metabolic regulation. Leptin plays a critical role in the balance of body weight. Here we report on secretion and hormonal regulation of leptin by brown adipocytes. Using the recently established T37i cell line, we show that leptin expression and secretion occurred as a function of cell differentiation. In differentiated T37i cells, insulin induced leptin release ( approximately 0.25 ng/10(6) cells/h) in a concentration-dependent manner (EC50=0.1 nM), and this was totally suppressed by beta3-adrenergic ligand, thiazolidinedione, cycloheximide, or actinomycin D. Insulin induced a strong, rapid (within 2 h) but transient fivefold increase in leptin mRNA levels. This transcriptional control of ob gene expression by insulin involved both phosphatidylinositol 3-kinase- and MAP kinase-dependent pathways. Glucocorticoids inhibited both insulin-stimulated leptin secretion and ob gene expression without affecting leptin mRNA stability (t(1/2)=3h05). Altogether, our results demonstrate that brown adipocytes express and secrete leptin, whose hormonal regulation clearly differs from that described in white adipose tissue. These findings point to tissue-specific molecular mechanisms and suggest that leptin might exert direct effects on energy homeostasis through an autocrine mechanism.

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.

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.

Leptin secretion and leptin receptor in the human stomach.

BACKGROUND AND AIM: The circulating peptide leptin produced by fat cells acts on central receptors to control food intake and body weight homeostasis. Contrary to initial reports, leptin expression has also been detected in the human placenta, muscles, and recently, in rat gastric chief cells. Here we investigate the possible presence of leptin and leptin receptor in the human stomach. METHODS: Leptin and leptin receptor expression were assessed by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and western blot analysis on biopsy samples from 24 normal individuals. Fourteen (10 healthy volunteers and four patients with non-ulcer dyspepsia and normal gastric mucosa histology) were analysed for gastric secretions. Plasma and fundic mucosa leptin content was determined by radioimmunoassay. RESULTS: In fundic biopsies from normal individuals, immunoreactive leptin cells were found in the lower half of the fundic glands. mRNA encoding ob protein was detected in the corpus of the human stomach. The amount of fundic leptin was 10.4 (3.7) ng leptin/g mucosa, as determined by radioimmunoassay. Intravenous infusions of pentagastrin or secretin caused an increase in circulating leptin levels and leptin release into the gastric juice. The leptin receptor was present in the basolateral membranes of fundic and antral gastric cells. mRNA encoding Ob-RL was detected in both the corpus and antrum, consistent with a protein of approximately 120 kDa detected by immunoblotting. CONCLUSION: These data provide the first evidence of the presence of leptin and leptin receptor proteins in the human stomach and suggest that gastric epithelial cells may be direct targets for leptin. Therefore, we conclude that leptin may have a physiological role in the human stomach, although much work is required to establish this.

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.