Florian Seyfried

Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study.

BACKGROUND Bariatric surgery improves arterial hypertension and renal function; however, the underlying mechanisms and effect of different surgical procedures are unknown. In the present prospective study, we compared the 12-month follow-up results after Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and laparoscopic sleeve gastrectomy on weight loss, hypertension, renal function, and inflammatory status. METHODS A total of 34 morbidly obese patients were investigated before, one and 12 months after Roux-en-Y gastric bypass (n = 10), laparoscopic adjustable gastric banding (n = 13), and laparoscopic sleeve gastrectomy (n = 11) for hypertension, kidney function, urinary and serum cytokine levels of macrophage migration inhibitory factor, monocyte chemotactic protein-1, and chemokine ligand-18. RESULTS At 12 months after surgery, the patients in all 3 treatment arms showed a significant decrease in the mean body mass index, mean arterial pressure, and urinary and serum inflammatory markers (all P < .001). The reduction in urinary and serum cytokine levels correlated directly with body weight loss (P < .05). Patients with impaired renal function at baseline (corresponding to serum cystatin C >.8 mg/L) had a marked improvement in renal function 12 months after surgery (P < .05). CONCLUSION Surgically induced weight loss is associated with a marked decrease in renal and systemic inflammation and arterial hypertension and improvement in renal function in patients with pre-existing renal impairment. These effects appear to be independent of surgical procedure. The improvement in renal inflammation could be 1 of the mechanisms contributing to the beneficial effects of bariatric surgery on arterial blood pressure, proteinuria, and renal function.

Lessons Learned from Gastric Bypass Operations in Rats

Numerous studies using gastric bypass rat models have been recently conducted to uncover underlying physiological mechanisms of Roux-en-Y gastric bypass. Reflecting on lessons learned from gastric bypass rat models may thus aid the development of gastric bypass models in mice and other species. This review aims to discuss technical and experimental details of published gastric bypass rat models to understand advantages and limitations of this experimental tool. The review is based on PubMed literature using the search terms ‘animal model’, ‘rodent model’, ‘bariatric surgery’, ‘gastric bypass’, and ‘Roux-en-Y gastric bypass’. All studies published up until February 2011 were included. 32 studies describing 15 different rat gastric bypass models were included. Description of surgical technique differs in terms of pouch size, limb lengths, preservation of the vagal nerve, and mortality rate. Surgery was carried out exclusively in male rats of different strains and ages. Pre- and postoperative diets also varied significantly. Technical and experimental variations in published gastric bypass rat models complicate comparison and identification of potential physiological mechanisms involved in gastric bypass. In summary, there is no clear evidence that any of these models is superior, but there is an emerging need for standardization of the procedure to achieve consistent and comparable data.

Roux-en-Y gastric bypass operation in rats.

Currently, the most effective therapy for the treatment of morbid obesity to induce significant and maintained body weight loss with a proven mortality benefit is bariatric surgery. Consequently, there has been a steady rise in the number of bariatric operations done worldwide in recent years with the Roux-en-Y gastric bypass (gastric bypass) being the most commonly performed operation. Against this background, it is important to understand the physiological mechanisms by which gastric bypass induces and maintains body weight loss. These mechanisms are yet not fully understood, but may include reduced hunger and increased satiation, increased energy expenditure, altered preference for food high in fat and sugar, altered salt and water handling of the kidney as well as alterations in gut microbiota. Such changes seen after gastric bypass may at least partly stem from how the surgery alters the hormonal milieu because gastric bypass increases the postprandial release of peptide-YY (PYY) and glucagon-like-peptide-1 (GLP-1), hormones that are released by the gut in the presence of nutrients and that reduce eating. During the last two decades numerous studies using rats have been carried out to further investigate physiological changes after gastric bypass. The gastric bypass rat model has proven to be a valuable experimental tool not least as it closely mimics the time profile and magnitude of human weight loss, but also allows researchers to control and manipulate critical anatomic and physiologic factors including the use of appropriate controls. Consequently, there is a wide array of rat gastric bypass models available in the literature reviewed elsewhere in more detail. The description of the exact surgical technique of these models varies widely and differs e.g. in terms of pouch size, limb lengths, and the preservation of the vagal nerve. If reported, mortality rates seem to range from 0 to 35%. Furthermore, surgery has been carried out almost exclusively in male rats of different strains and ages. Pre- and postoperative diets also varied significantly. Technical and experimental variations in published gastric bypass rat models complicate the comparison and identification of potential physiological mechanisms involved in gastric bypass. There is no clear evidence that any of these models is superior, but there is an emerging need for standardization of the procedure to achieve consistent and comparable data. This article therefore aims to summarize and discuss technical and experimental details of our previously validated and published gastric bypass rat model.

Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats

Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.

Is There a Role for Anything Other Than a Nissen’s Operation?

BackgroundThe Nissen fundoplication is the most frequently applied antireflux operation worldwide. The aim of this review was to compare laparoscopic Nissen with partial fundoplication.MethodsNine randomized trials comparing several types of wraps were analyzed, four for the comparison Nissen vs. Toupet and five for the comparison Toupet or Nissen vs. anterior fundoplication. Similar comparisons in nonrandomized studies were also included.ResultsDysphagia rates and reflux recurrence were not related to preoperative esophageal persistalsis independent of the selected procedure. Overall, Nissen fundoplication revealed slightly better reflux control, but was associated with more side effects, such as early dysphagia and gas bloat. Advantages of an anterior approach were only reported by one group. A significantly higher reflux recurrence rate for anterior fundoplication was observed in all other comparisons.ConclusionTailoring antireflux surgery according to esophageal motility is not indicated. At present, the relevant factor for selection of a Nissen or Toupet fundoplication is personal experience. Anterior fundoplication offers less effective long-term reflux control.

Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery

Background/Objectives:Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear.Subjects/Methods:We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery.Results:The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs.Conclusions:The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting.

Effects of preoperative exposure to a high-fat versus a low-fat diet on ingestive behavior after gastric bypass surgery in rats

BackgroundThe consumption of high fat and sugar diets is decreased after gastric bypass surgery (GB). The mechanisms remain unclear, with tests of motivated behavior toward fat and sugar producing conflicting results in a rat model. These discrepancies may be due to differences in presurgical maintenance diets. The authors used their GB rat model to determine whether the fat content of preoperative maintenance diets affects weight loss, calorie intake, and macronutrient selection after surgery.MethodsMale Wistar rats were either low-fat diet fed (LFDF) with normal chow or high-fat diet fed (HFDF) before randomization to GB or sham surgery. In food preference test 1, the animals were offered the choice of a vegetable drink (V8) or a high-calorie liquid (Ensure), and in food preference test 2, they could choose normal chow or a solid high-fat diet.ResultsThe GB groups did not differ significantly in terms of body weight loss or caloric intake. In food preference test 1, both groups responded similarly by reducing their preference for Ensure and increasing their preference for V8. In food preference test 2, the HFDF-GB rats reduced their preference for a solid high-fat diet gradually compared with the immediate reduction observed in the LFDF-GB rats.ConclusionThe consumption of presurgical maintenance diets with different fat contents did not affect postoperative weight loss outcomes. Both the LFDF-GB and HFDF-GB rats exhibited behaviors consistent with the possible expression of a conditioned taste aversion to a high-fat stimulus. These results suggest that for some physiologic parameters, low-fat-induced obesity models can be used for the study of changes after GB and have relevance to many obese humans who consume high-calorie but low-fat diets.

Urinary phenotyping indicates weight loss-independent metabolic effects of Roux-en-Y gastric bypass in mice.

Patients with a body mass index (BMI) above 35 kg/m(2) with metabolic diseases benefit from Roux-en-Y gastric bypass (RYGB) independently of their final BMI and the amount of body weight lost. However, the weight loss independent metabolic effects induced by RYGB remain less well understood. To elucidate metabolic changes after RYGB, (1)H NMR spectroscopy-based urine metabolic profiles from RYGB (n = 7), ad libitum-fed sham (AL, n = 5), and body-weight-matched sham (BWM, n = 5) operated mice were obtained. Gut morphometry and fecal energy content were analyzed. Food intake and body weight of RYGB mice were significantly reduced (p = 0.001) compared to sham-AL. There was a strong tendency that BWM-shams required less food to maintain the same body weight as RYGB mice (p = 0.05). No differences were found in fecal energy content between the groups, excluding malabsorption in RYGB animals. Unlike RYGB-operated rats, gut hypertrophy was not observed in RYGB-operated mice. Urinary tricarboxylic acid cycle intermediates were higher in the sham groups, suggesting altered mitochondrial metabolism after RYGB surgery. Higher urinary levels of trimethylamine, hippurate and trigonelline in RYGB mice indicate that the RYGB operation caused microbial disturbance. Taken together, we demonstrate for the first time that there are RYGB specific metabolic effects, which are independent of food intake and body weight loss. Increased utilization of TCA cycle intermediates and altered gut microbial-host co-metabolites might indicate increased energy expenditure and microbial changes in the gut, respectively.

Impact of weight loss induced by gastric bypass or caloric restriction on oxidative stress and genomic damage in obese Zucker rats

BACKGROUND Evidence on bariatric surgery induced weight loss and its possible impact on cancer risk is limited, but also controversial. We used obese Zucker(fa/fa) and lean Zucker(fa/+) 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 Zucker(fa/fa) rats underwent RYGB (n=15) or sham surgery (n=17). Five shams were food restricted and body weight matched (BWM) to RYGB. Twelve Zucker(fa/+) 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 Zucker(fa/fa) rats positively correlated with basal plasma insulin values (Spearmans 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 Zucker(fa/fa) rats. Further investigations are needed to elucidate the underlying mechanism of these genome protective effects.

Increased energy expenditure in gastric bypass rats is not caused by activated brown adipose tissue

Objective: To investigate whether gastric bypass induces a higher activity of brown adipose tissue and greater levels of the brown adipose tissue-specific protein uncoupling protein-1 (UCP-1) in rats. Methods: Gastric bypass rats and sham-operated controls (each n = 8) underwent whole body 1H-MR spectroscopy for analysis of body composition and 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (18F-FDG PET/CT) imaging for measurement of the metabolic activity of brown adipose tissue. Brown adipose tissue was harvested and weighed, and UCP-1 mRNA content was measured by Northern Blot technique. Results: Gastric bypass rats had a significantly lower percentage of whole body adipose tissue mass compared to sham-operated rats (p = 0.001). There was no difference in brown adipose tissue activity between the two groups (standardised uptake value sham 2.81 ± 0.58 vs. bypass 2.56 ± 0.46 ; p = 0.73). Furthermore, there was no difference in the UCP-1 mRNA content of brown adipose tissue between the two groups (sham 49.5 ± 13.2 vs. bypass 43.7 ± 13.1; p = 0.77). Conclusion: Gastric bypass does not increase the activity of brown adipose tissue in rats suggesting that other mechanisms are involved to explain the increased energy expenditure after bypass surgery. Our results cannot justify the radiation dose of 18F-FDG PET/CT studies in humans to determine potential changes in brown adipose tissue after gastric bypass surgery.