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Background Roux-en-Y gastric bypass (RYGB) modifies various aspects of eating behavior in morbidly obese individuals to cause marked and lasting weight loss and improvements in metabolic health, but the underlying mechanisms remain poorly understood. Objectives To assess the relative contributions of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY3-36), whose circulating levels are enhanced by RYGB, in the reduced high-fat (HF) food preference that develops postoperatively. Setting University hospital, Wurzburg, Germany. Methods HF diet–induced obese male Wistar rats underwent RYGB (n = 11) or sham (n = 7) surgeries and were subsequently maintained on a choice of low-fat (10% calories from fat) and HF (60% calories from fat) diets. From postoperative weeks 4 to 6, acute feeding studies were performed in which the selective GLP-1 receptor antagonist exendin-9 (30 μg/kg), the second-generation selective Y2 receptor antagonist JNJ-31020028 (10 mg/kg), or a combination of both drugs was administered intraperitoneally. Results During the observational period weight, adiposity and total food intake were lower while postprandial plasma GLP-1 and peptide tyrosine tyrosine levels were higher for RYGB-operated compared with sham-operated rats. There was a gradual shift in preference from HF to low-fat food in RYGB-operated rats by postoperative week 3. Single antagonist treatments had a relatively modest impact on HF food preference in rats from both surgical groups. However, dual antagonist treatment caused a striking increase in HF food preference specifically in RYGB-operated rats. Conclusions GLP-1 and peptide tyrosine tyrosine 3-36 reduce HF food preference additively after RYGB supporting the use of gut hormone combination strategies for healthier feeding behavior.

Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.

Roux-en-Y gastric bypass (RYGB) modifies various aspects of eating behavior in morbidly obese individuals to cause marked and lasting weight loss and improvements in metabolic health, but the underlying mechanisms remain poorly understood.To assess the relative contributions of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYYUniversity hospital, Würzburg, Germany.HF diet-induced obese male Wistar rats underwent RYGB (n = 11) or sham (n = 7) surgeries and were subsequently maintained on a choice of low-fat (10% calories from fat) and HF (60% calories from fat) diets. From postoperative weeks 4 to 6, acute feeding studies were performed in which the selective GLP-1 receptor antagonist exendin-9 (30 μg/kg), the second-generation selective Y2 receptor antagonist JNJ-31020028 (10 mg/kg), or a combination of both drugs was administered intraperitoneally.During the observational period weight, adiposity and total food intake were lower while postprandial plasma GLP-1 and peptide tyrosine tyrosine levels were higher for RYGB-operated compared with sham-operated rats. There was a gradual shift in preference from HF to low-fat food in RYGB-operated rats by postoperative week 3. Single antagonist treatments had a relatively modest impact on HF food preference in rats from both surgical groups. However, dual antagonist treatment caused a striking increase in HF food preference specifically in RYGB-operated rats.GLP-1 and peptide tyrosine tyrosine 3-36 reduce HF food preference additively after RYGB supporting the use of gut hormone combination strategies for healthier feeding behavior.

Roux-en-Y gastric bypass (RYGB) may improve beta cell function by mechanisms other than caloric restriction and body weight loss. We aimed to assess the impact of anatomical and hormonal alterations specific to RYGB on glucose homeostasis, β cell function and morphology.Male Zucker(fa/fa) rats underwent either RYGB (n = 11) or sham surgeries (n = 10). Five of the shams were then food restricted and body weight matched (BWM) to the RYGB rats. Six male Zucker(fa/+) rats underwent sham surgery and served as additional lean controls. Twenty-seven days after surgery, an oral glucose tolerance test (OGTT) was performed and plasma levels of glucose, insulin and glucagon-like peptide-1 (GLP-1) were measured. Immunohistological analysis of pancreatic islets was performed, and GLP-1 receptor and PDX-1 mRNA content were quantified.Shams consumed more food and gained more weight compared to both RYGB and BWM (p 0.001). Hyperglycaemia was evident in ad libitum-fed shams, whilst postprandial glucose levels were lower in RYGB compared to the BWM sham group (p 0.05). During the OGTT, RYGB rats responded with2.5-fold increase of GLP-1. Histology revealed signs of islet degeneration in ad libitum-fed shams, but not in RYGB and sham BWM controls (p 0.001). GLP-1 receptor and PDX-1 mRNA content was similar between the RYGB and BWM shams but higher compared to ad libitum shams (p 0.05).Combined molecular, cellular and histological analyses of pancreatic function suggest that weight loss alone, and not the enhancement of GLP-1 responses, is predominant for the short-term β cell protective effects of RYGB.

After Roux-en-Y gastric bypass surgery (RYGB), patients report consuming fewer fatty and dessert-like foods, and rats display blunted sugar and fat preferences. Here we used a progressive ratio task (PR) in our rat model to explicitly test whether RYGB decreases the willingness of rats to work for very small amounts of preferred sugar- and/or fat-containing fluids. In each of two studies, two groups of rats - one maintained on a high-fat diet (HFD) and standard chow (CHOW) and one given CHOW alone - were trained while water-deprived to work for water or either Ensure or 1.0 M sucrose on increasingly difficult operant schedules. When tested before surgery while nondeprived, HFD rats had lower PR breakpoints (number of operant responses in the last reinforced ratio) for sucrose, but not for Ensure, than CHOW rats. After surgery, at no time did rats given RYGB show lower breakpoints than SHAM rats for Ensure, sucrose, or when 5% Intralipid served postoperatively as the reinforcer. Nevertheless, RYGB rats showed blunted preferences for these caloric fluids versus water in 2-bottle preference tests. Importantly, although the Intralipid and sucrose preferences of RYGB rats decreased further over time, subsequent breakpoints for them were not significantly impacted. Collectively, these data suggest that the observed lower preferences for normally palatable fluids after RYGB in rats may reflect a learned adjustment to altered postingestive feedback rather than a dampening of the reinforcing taste characteristics of such stimuli as measured by the PR task in which postingestive stimulation is negligible.

Perineal wound healing disorders are one of the major complications following abdominoperineal rectum extirpation.We evaluated the impact of an "incisional negative pressure wound therapy" (iNPWT) system after abdominoperineal rectum extirpation in six patients. All patients had a neoadjuvant radiochemotherapy with 50.4 Gy and 5-FU. Five of the six patients (83%) experienced complication-free healing of the perineal wound after 5 to 12 days of iNPWT. One patient developed a wound healing disorder 8 days after abdominoperineal rectum extirpation during current iNPWT.Use of an iNPWT system can be of favor after abominoperineal rectum extirpation.

Background Reductions in urinary protein excretion after Roux-en-Y gastric bypass (RYGB) surgery in patients with diabetic kidney disease have been reported in multiple studies. Objectives To determine the weight loss dependence of the effect of RYGB on urinary protein excretion by comparing renal outcomes in Zucker diabetic fatty rats undergoing either gastric bypass surgery or a sham operation with or without weight matching. Setting University laboratories. Methods Zucker diabetic fatty rats underwent surgery at 18 weeks of age. A subgroup of sham operated rats were weight matched to RYGB operated rats by restricting food intake. Urinary protein excretion was assessed at baseline and at postoperative weeks 4 and 12. Renal histology and macrophage-associated inflammation were assessed at postoperative week 12. Results Progressive urinary protein excretion was attenuated by both RYGB and diet-induced weight loss, albeit to a lesser extent by the latter. Both weight loss interventions produced equivalent reductions in glomerulomegaly, glomerulosclerosis, and evidence of renal macrophage infiltration. Conclusion Weight loss per se improves renal structure and attenuates renal inflammatory responses in an experimental animal model of diabetic kidney disease. Better glycemic control post-RYGB may in part explain the greater reductions in urinary protein excretion after gastric bypass surgery.

Background Evidence on bariatric surgery induced weight loss and its possible impact on cancer risk is limited, but also controversial. We used obese Zuckerfa/fa and lean Zuckerfa/+ to investigate the association between obesity, oxidative stress and genomic damage after weight loss induced either by Roux-en-Y gastric bypass surgery (RYGB) or caloric restriction. Methods Male Zuckerfa/fa rats underwent RYGB (n=15) or sham surgery (n=17). Five shams were food restricted and body weight matched (BWM) to RYGB. Twelve Zuckerfa/+ rats served as lean controls. Body weight and food intake were measured daily. An oral glucose tolerance test was performed on day 27. DHE staining and western blots of HSP70 and HO-1 were used to evaluate oxidative stress and anti-3-nitrotyrosine antibody staining for nitrative stress detection in colon and kidney. Lipid peroxidation products in urine were quantified by TBARS assay. LC/MS/MS was applied to measure urinary excretion of 8-oxoGua (oxidized DNA derived base), 8-oxodG (oxidized DNA derived nucleoside) and 8-oxoGuo (oxidized RNA derived nucleoside). DNA double strand breaks (DSBs) and cell proliferation (PCNA) were detected by immunohistochemistry. Results Sham-operated rats showed impaired glucose tolerance, elevated plasma insulin levels as well as elevated oxidative stress and nitrative stress markers, which were less severe after weight loss by RYGB or caloric restriction. Cell proliferation showed similar trends but no significant alteration. DNA DSBs were more frequent in sham-operated compared to all other groups. DNA damage in Zuckerfa/fa rats positively correlated with basal plasma insulin values (Spearman's correlation coefficient for colon, 0.634 and for kidney, 0.525). Conclusions RYGB and caloric restriction were sufficient to significantly reduce elevated oxidative/nitrative stress and genomic damage in obese Zuckerfa/fa rats. Further investigations are needed to elucidate the underlying mechanism of these genome protective effects.

Background: Bariatric surgery rapidly improves type 2 diabetes mellitus (T2DM). Our objective was to profile and compare the extent and duration of improved glycemic control following Roux-en-Y gastric (RYGB) bypass surgery and vertical sleeve gastrectomy (SG) and compare against caloric restriction/weight loss and medical combination therapy based approaches using the Zucker diabetic fatty rat (ZDF) rodent model of advanced T2DM. Methods: Male ZDF rats underwent RYGB (n=15) or SG surgery (n=10) at 18 weeks of age and received postsurgical insulin treatment as required to maintain mid light phase glycemia within a predefined range (10-15 mmol/L). In parallel, further groups of animals underwent sham surgery with ad libitum feeding (n=6), with bodyweight (n=8) or glycemic matching (n=8) to the RYGB group using food restriction or a combination of insulin, metformin and liraglutide respectively. Results: Both bariatric procedures decreased the daily insulin dose required to maintain mid light phase blood glucose levels below 15 mmol/L as compared to those required by bodyweight or glycemic matched rats (p < 0.001). No difference was noted between RYGB and SG with regard to initial efficacy. SG was however associated with higher food intake, weight regain and higher insulin requirements versus RYGB at study end (p < 0.05). Severe hypoglycemia occurred in several rats after RYGB. Conclusions: RYGB and SG significantly improved glycemic control in a rodent model of advanced T2DM. Whilst short-term outcomes are similar, long-term efficacy appears marginally better after RYGB although this is tempered by the increased risk of hypoglycemia.

Bariatric surgery is currently the most effective treatment for severe obesity, and Roux-en-Y gastric bypass (RYGB) is the most common approach in the United States and worldwide. Many studies have documented the changes in body weight, food intake, and glycemic control associated with the procedure. Although dehydration is commonly listed as a postoperative complication, little focus has been directed to testing the response to dipsogenic treatments after RYGB. Accordingly, we used a rat model of RYGB to test for procedure-induced changes in daily water intake and in the response to three dipsogenic treatments: central administration of ANG II, peripheral injection of hypertonic saline, and overnight water deprivation. We did not find any systematic differences in daily water intake of sham-operated and RYGB rats, nor did we find any differences in the response to the dipsogenic treatments. The results of these experiments suggest that RYGB does not impair thirst responses and does not enhance any satiating effect of water intake. Furthermore, these data support the current view that feedback from the stomach is unnecessary for the termination of drinking behavior and are consistent with a role of orosensory or postgastric feedback.

Objective: To evaluate clinical, quality-of-life (QoL) and dynamic magnetic resonance imaging (dMRI) results in patients with pelvic organ prolapse (POP) preoperatively, and 4 and 12 weeks after anterior and/or posterior mesh repair. Study design: Thirty-six patients (mean age 65 years) with symptomatic pelvic floor descent underwent mesh repair. The prolapse was quantified using the POP-Q system. Before surgery as well as 4 and 12 weeks after surgery, the pelvic organ positions were measured on dynamic magnetic resonance imaging during Valsalva manoeuvre in relation to the pubococcygeal and mid-pubic lines to assess surgery outcome. Patients also completed the P-QOL questionnaire to evaluate subjective changes at each visit. Results: Four and 12 weeks after surgery patients showed improvement of the POP on clinical examination and on dynamic MRI. The latter demonstrated high significance (p < 0.001) especially in bladder and vaginal cuff/cervix positions during maximal straining. All quality-of-life domains and some symptom questions of the P-QOL questionnaire significantly improved (p < 0.05) 12 weeks after surgery. Conclusion: Significant anatomical and quality-of-life improvement was demonstrated after anterior and/or posterior mesh repair for POP using dynamic MRI and the P-QOL questionnaire.

Background— Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss–independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1–dependent mechanism. Methods and Results— Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin 9-39 (10 μg·kg −1 ·h −1 ). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDL-mediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. Conclusions— RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1–mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity.

Purpose: Roux-en-Y Gastric Bypass (RYGB) reduces weight and cardiovascular risk in obese patients. The mechanism of RYGB cardiovascular protection (CV) seems to be partly weight-independent, but still unclear. Glucagon Like Peptide 1 (GLP-1) exerts endothelial protective actions, through endothelial-NO-Synthase (eNOS) activation. Thus, we investigated the role of GLP-1 in obesity-induced endothelial dysfunction in rats after RYBG, prior to significant weight loss. Methods: After 7 weeks of high fat-high-cholesterol diet, obese Wistar male rats underwent RYGB and were compared to sham-operated rats fed Ad Lib (AL) or body weight-matched (BWM) to rats receiving RYGB. Thoracic aortic rings were suspended for isometric tension recording; cumulative relaxation responses were performed to peptide GLP-1 (7–36) amide (10-12-10-6mol/L) after submaximal contraction with norepinephrine (10-6mol/L) and repeated after preincubation with GLP-1 receptor antagonist exendin (9-39) (10-7 mol/L) and eNOS-inhibitor (L-NAME, 10-4mol/L). Western blotting of aortic lysates using GLP-1 receptor (GLP-1r), eNOS, Protein Kinase A (PKA) and c-Jun N-terminal Protein Kinase (JNK) antibodies was performed to address the role of GLP-1 signaling in endothelial function. GLP-1 and bile acids plasma fasting levels were measured. Results: 8 days post-surgery body weight difference among the 3 groups was not yet significant. GLP-1-induced vasorelaxation was impaired in sham AL and BWM compared with RYGB rats (max relaxations: 17±3.1% and 15±2.8 vs 36±4.8, respectively, n=6-8, p