Apelin stimulation of duodenal bicarbonate secretion: feeding-dependent and mediated via apelin-induced release of enteric cholecystokinin.

AIMS: Apelin peptides are the endogenous ligand of the G protein-coupled receptor APJ. Proposed actions include involvement in control of cardiovascular functions, appetite and body metabolism. We have investigated the effects of apelin peptides on duodenal bicarbonate secretion in vivo and the release of cholecystokinin (CCK) from acutely isolated mucosal cells and the neuroendocrine cell line STC-1. METHODS: Lewis × Dark Agouti rats had free access to water and, unless fasted overnight, free access to food. A segment of proximal duodenum was cannulated in situ in anaesthetized animals. Mucosal bicarbonate secretion was titrated (pH stat) and apelin was administered to the duodenum by close intra-arterial infusion. Total RNA was extracted from mucosal specimens, reverse transcripted to cDNA and the expression of the APJ receptor measured by quantitative real-time PCR. Apelin-induced release of CCK was measured using (1) cells prepared from proximal small intestine and (2) STC-1 cells. RESULTS: Even the lowest dose of apelin-13 (6 pmol kg⁻¹ h⁻¹) caused a significant rise in bicarbonate secretion. Stimulation occurred only in continuously fed animals and even a 100-fold greater dose (600 pmol kg⁻¹ h⁻¹) of apelin was without effect in overnight food-deprived animals. Fasting also induced an eightfold decrease in the expression of APJ receptor mRNA. Apelin induced significant release of CCK from both mucosal and STC-1 cells, and the CCK(A) receptor antagonist devazepide abolished bicarbonate secretory responses to apelin. CONCLUSION: Apelin-induced stimulation of duodenal electrolyte secretion is feeding-dependent and mediated by local mucosal release of CCK.

Role of adipokines in obesity-associated hypertension.

It has been well documented that obesity is a major risk factor for the development of the hypertensive state. The correlation between body mass index and blood pressure level is well established. Nevertheless, the exact mechanisms which contribute to obesity-related hypertension remain poorly understood. In the last years, we have realized that the white adipose tissue is not just an inert organ for nutrient storage and isolation but rather depending on the body mass index the biggest endocrinological organ. Thus, the possible contribution of adipokines to the blood pressure elevation becomes an attractive hypothesis to explain the hypertensive state that often occurs in obesity. In this review, we consider direct and indirect effects of main adipokines on structural and functional changes in the cardiovascular system.

Effect of protein, fat, carbohydrate and fibre on gastrointestinal peptide release in humans.

Short-term regulation of food intake controls what, when and how much we eat within a single day or a meal. This regulation results from an integrated response to neural and humoral signals that originate from the brain, gastrointestinal (GI) tract and adipose tissue. In the GI tract, multiple sites including the stomach, duodenum, distal small intestine, colon, and pancreas are involved in this process. Ingested food evokes satiety by mechanical stimulation and by release of peptides in the GI tract. The intestine in particular plays a key role in satiety through various peptides secreted in response to food. Many of the intestinal peptides inhibit also gastric emptying thus enhancing gastric mechanoreceptor stimulation. In this review, the current knowledge about the effects of different macronutrients and fibre on the release of GI satiety-related peptides in humans is discussed.

Duodenal phytohaemagglutinin (red kidney bean lectin) stimulates gallbladder contraction in humans.

AIM: Lectins, carbohydrate-specific proteins without enzymatic activity on the ligand, are daily ingested plant proteins which survive the passage through the gastrointestinal tract in a biologically active form. Their binding to glycan determinants of natural glycoconjugates can trigger biological effects. The lectin phytohaemagglutinin (PHA) is abundantly present in red kidney beans and induces cholecystokinin (CCK) release in rats. The aim of the study was to investigate the effect of intraduodenal administration of PHA on plasma CCK levels and gallbladder contraction in humans and to elucidate potential mechanisms of action. METHODS: Five healthy volunteers underwent four studies. After a basal intraduodenal saline infusion for 30 min, PHA or heat-inactivated PHA was infused in increasing doses: 150 microg, 1.5 mg and 15 mg for 30 min each. Intravenous saline, CCK(1) receptor antagonist dexloxiglumide or atropine were administered in random order. Gallbladder volumes were measured by ultrasonography and plasma CCK levels by radioimmunoassay. RESULTS: Intraduodenal PHA induced gallbladder contraction in a dose-dependent fashion starting with the lowest dose. The highest dose reduced the gallbladder volume to 65.3 +/- 9.4% of basal volume (P < 0.001) whereas heat-inactivated PHA did not have any effect. Blocking CCK(1) or muscarinic receptors completely abolished PHA-stimulated gallbladder contraction (dexloxiglumide 208.7 +/- 23.7%; atropine 104 +/- 7.0% of basal volume) while none of the treatments affected CCK levels. CONCLUSION: Duodenal administration of PHA potently stimulates gallbladder contraction in humans. This contraction is mediated via cholinergic pathway.

Functions of orexins in peripheral tissues.

Orexin A (OXA) and orexin B were originally isolated as hypothalamic peptides regulating sleep, wakefulness and feeding. However, growing evidence suggests that orexins have major functions also in the peripheral tissues. Central orexigenic pathways originating from medulla activate the hypothalamus-pituitary axis and can influence the sympathetic tone. Orexins and their receptors are widely dispersed throughout the intestine, where orexin receptors are regulated by the nutritional status, affect insulin secretion and intestinal motility. Although the primary source of the peptide has not been elucidated, OXA is detected in plasma and its level varies in response to the metabolic state. In this review, we focus on the current knowledge on peripheral functions of orexins and discuss possible endocrine, paracrine and neurocrine roles.

TRPA1 channel activation induces cholecystokinin release via extracellular calcium.

TRPA1 channels are non-selective cation channels activated by plant derived pungent products including allyl isothiocyanate (AITC) from mustard. Therefore, possible intestinal secretory functions of these channels were investigated. We detected TRPA1 mRNA in mouse and human duodenal mucosa and in intestinal mouse neuroendocrine STC-1 cells. Stimulation of STC-1 cells with AITC increased intracellular calcium ([Ca(2+)](i)) and significantly stimulated cholecystokinin secretion by 6.7-fold. AITC induced cholecystokinin release was completely blocked by TRPA1 antagonist ruthenium red and depletion of extracellular calcium and reduced by 36% by nimodipine and nifedipine. This suggests that spices in our daily food might stimulate digestive functions.

Effect of total colectomy and PYY infusion on food intake and body weight in rats.

PYY (3-36) is postulated to act as a satiety factor in the gut-hypothalamic pathway to inhibit food intake and body weight gain in humans and rodent models. We determined the effect of 14-day continuous intravenous infusion of PYY (3-36) (175 microg/kg/day) on food intake and body weight gain in colectomized male Wistar rats. Colectomy caused an increase in plasma PYY levels at 7 days which was reduced at 14 days but still significantly elevated compared to basal preoperative values. Animals treated with continuous PYY (3-36) infusion had significantly elevated PYY levels compared to the control group throughout the whole experiment, but showed a similar pattern of food intake and body weight gain. In conclusion, although continuous intravenous infusion is the most physiologically relevant method to mimic high postprandial PYY levels, we did not observe any significant effect on food intake and body weight gain in non-food deprived colectomized animals. This suggests that PYY has, if at all, only a minor role in food intake in rats.

Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding.

UNLABELLED: Maintenance of human energy homeostasis is regulated by a complex network. Peptides secreted from the gastrointestinal tract (GI) are signaling to the brain and other organs initiating or terminating food intake and energy expenditure. In the present study we investigated basal plasma levels of apelin, orexin-A, and leptin in morbid obese patients. In addition, we measured in a subgroup of these patients in the same individual orexin-A and leptin plasma levels one year after gastric banding surgery. METHODS: Basal plasma values were determined in obese patients (BMI=48+/-1 kg/m2n=32) after an overnight fast and compared to healthy, normal weighted (BMI=22+/-2 kg/m2n=12) controls. In addition, blood samples were collected in a subgroup of patients (BMI=48+/-1 kg/m2n=8) the day before surgery and 1 year after the operation. Apelin, orexin-A, and leptin levels were analysed using ELISAs. RESULTS: One year after the operation obese patients significantly lost weight (from 48+/-2 kg/m2 to 39+/-2 kg/m2; p<0,001). Apelin, orexin-A and leptin levels in obese patients were significantly higher compared to control individuals (736+/-50 pg/ml vs. 174+/-14 pg/ml, p<0.0001; 75.3+/-24.1 pg/ml vs. 0.8+/-0.4 pg/ml, p<0.0001; 79.0+/-2.4 ng/ml vs. 5.8+/-0.8 ng/ml, p<0.0001, respectively). Apelin and leptin plasma concentrations also correlated significantly with BMI (r=0.769, p<0.0001; r=0.778; p<0.0001, respectively), while orexin-A correlation was rather weak (r=0.335, p<0.03). No difference between pre- and post-operative orexin-A levels was observed, while leptin plasma levels significantly decreased from 45.1+/-5.4 ng/ml to 27.3+/-6.0 ng/ml (p=0.015). CONCLUSIONS: Apelin, orexin-A, and leptin plasma levels correlated positively with the BMI. One year after gastric banding with significant loss in BMI basal plasma levels of leptin decreased, while orexin-A remained unchanged.