Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: a mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet.

OBJECTIVE: Food intake normally stimulates release of satiety and insulin-stimulating intestinal hormones, such as glucagon-like peptide (GLP)-1. This response is blunted in obese insulin resistant subjects, but is rapidly restored following Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised this to be a result of the metabolic changes taking place in the small intestinal mucosa following the anatomical rearrangement after RYGB surgery, and aimed at identifying such mechanisms. DESIGN: Jejunal mucosa biopsies from patients undergoing RYGB surgery were retrieved before and after very-low calorie diet, at time of surgery and 6 months postoperatively. Samples were analysed by global protein expression analysis and Western blotting. Biological functionality of these findings was explored in mice and enteroendocrine cells (EECs) primary mouse jejunal cell cultures. RESULTS: The most prominent change found after RYGB was decreased jejunal expression of the rate-limiting ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGCS), corroborated by decreased ketone body levels. In mice, prolonged high-fat feeding induced the expression of mHMGCS and functional ketogenesis in jejunum. The effect of ketone bodies on gut peptide secretion in EECs showed a ∼40% inhibition of GLP-1 release compared with baseline. CONCLUSION: Intestinal ketogenesis is induced by high-fat diet and inhibited by RYGB surgery. In cell culture, ketone bodies inhibited GLP-1 release from EECs. Thus, we suggest that this may be a mechanism by which RYGB can remove the inhibitory effect of ketone bodies on EECs, thereby restituting the responsiveness of EECs resulting in increased meal-stimulated levels of GLP-1 after surgery.

The human duodenal mucosa harbors all components for a local renin angiotensin system.

The renin-angiotensin system (RAS) is present in the gastrointestinal (GI) tract but remains to be fully characterized, particularly in man. The duodenum plays a role in both the upper and lower GI regulation, as well as in distant organs. The present study investigates the presence and functional potential of RAS in the human duodenal mucosa of healthy individuals. Endoscopically acquired mucosal biopsies from healthy volunteers were examined using western blot, immunohistochemistry, and ELISA. Functionality was examined by using Ussing chambers and recording duodenal transmucosal potential difference (PD) and motility in vivo Angiotensinogen, Angiotensin II (AngII) and its receptors (AT1R, AT2R) as well as to the RAS associated enzymes renin, ACE, and neprylisin were detected in all samples of duodenal mucosa. Migrating motility complex induced elevations of transmucosal PD were significantly larger after per-oral administration of the AT1R receptor antagonist candesartan. Fasting duodenal motility per se was not influenced by candesartan. The epithelial current produced by duodenal mucosae mounted in Ussing chambers increased significantly after addition of AngII to specimens where the AT1R was blocked using losartan. The epithelial current also increased after addition of the AT2R-selective agonist C21. Immunostaining and pharmacological data demonstrate the presence of a local RAS in the human duodenal mucosa with capacity to influence epithelial ion transport by way of particulary the AT2R.

Changes in the mucosa of the Roux-limb after gastric bypass surgery.

AIMS: Roux-en-Y gastric bypass surgery is the most efficient treatment of morbid obesity, but the mechanisms of action are still poorly understood. The aim of this study was to explore the Roux-limb mucosa after gastric bypass surgery, focusing upon basic morphology and inflammation. METHODS AND RESULTS: Jejunal mucosal samples from the Roux-limb were gathered from eight patients at time of surgery and 6-8 months postsurgery. Histological evaluation of inflammation and morphometric investigations were performed, cell proliferation was assessed using immunohistochemistry and inflammatory markers and angiotensin (Ang) II receptors were detected using Western blot. Cell proliferation increased and villous surface area decreased in the Roux-limb mucosa but no signs of active inflammation were observed after surgery. Protein analyses showed increased levels of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, myeloperoxidase (MPO) and the Ang II type 1(AT(1)) receptor after surgery, whereas the levels of inducible nitric oxide synthase (iNOS), nitrotyrosine and the Ang II type 2(AT(2)) receptor remained constant. CONCLUSION: These results indicate that the phenotype of the jejunal mucosa changes once exposed to undigested food and the increased microbial load in the Roux-limb after surgery.

Angiotensin II receptors are expressed and functional in human esophageal mucosa.

Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT(1)) and type 2 (AT(2)) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT(1) and AT(2) receptors. Immunoreactivity to AT(1) and AT(2) was localized to stratum superficiale and spinosum in the epithelium. ACE, AT(1), and AT(2) were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT(1) receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was -6.4 mV, epithelial current (I(ep)) 34 muA/cm(2), and epithelial resistance (R(ep)) 321 Omega.cm(2). Serosal exposure to Ang II increased PD as a result of increased I(ep), whereas R(ep) was constant. Ang II given together with the selective AT(1)-receptor antagonist losartan, or AT(2) agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT(2)-receptor antagonist PD123319 did not influence PD, but I(ep) decreased and R(ep) increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT(2)-receptor stimulation increases epithelial ion transport, whereas the AT(1) receptor inhibits ion transport and increases R(ep).

Candesartan improves survival following severe hypovolemia in pigs; a role for the angiotensin II type 2 receptor?

OBJECTIVE: To investigate the involvement of intestinal angiotensin II type 2 receptors in the outcome of acute severe hypovolemia as well as systemic and regional mesenteric hemodynamics and intestinal mucosal functions in anesthetized pigs. DESIGN AND SETTING: Prospective, interventional animal study in a university research laboratory. SUBJECTS: 53 landrace pigs, 28-35 kg. INTERVENTIONS: 30+30% or 20+20% hemorrhage of estimated total blood volume followed by retransfusion performed in untreated controls, in animals treated with the angiotensin II type 1 receptor blocker candesartan or with a combination of candesartan and the angiotensin II type 2 receptor blocker PD123319. MEASUREMENTS AND RESULTS: Following 30+30% hemorrhage the candesartan-treated animals attained a significantly higher survival rate than controls and animals treated with PD123319 in combination with candesartan. Less pronounced hemorrhage (20+20%) resulted in no mortality and functional variables were assessed. A significantly higher output of jejunal intraluminal nitric oxide occurred during hypovolemia in the candesartan treated group than in controls and animals that received PD123319 in combination with candesartan. Jejunal transmucosal potential difference was significantly better preserved after retransfusion in candesartan-treated animals than in controls. Expression of angiotensin II type 2 receptors in intestinal tissue was significantly higher in animals surviving the 30+30% hemorrhage than in nonsurvivors. CONCLUSIONS: Lethal circulatory failure is possibly influenced by use of angiotensin receptor ligands, and activation of intestinal angiotensin II type 2 receptors may play a significant role in improving the outcome of severe hypovolemia.