A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery
ABSTRACT Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, while short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short-circuiting the normal entero-hepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the mid-distal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis and endoplasmic reticulum (ER) stress were measured. Rats' post-BD lost significantly more weight than the SH-rats. BD rats gained less fat mass post-surgery. BD rats had improved glucose tolerance, increased higher post-prandial GLP-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (CHOP mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/UDCA) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (CHOP mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.
SourceAvailable from: Mouhamad Alloosh[Show abstract] [Hide abstract]
ABSTRACT: Background. Roux-en-Y gastric bypass (RYGB) is the most common bariatric operation; however, the mechanism underlying the profound weight-independent effects on glucose homeostasis remains unclear. Large animal models of naturally occurring insulin resistance (IR), which have been lacking, would provide opportunities to elucidate such mechanisms. Ossabaw miniature swine naturally exhibit many features that may be useful in evaluating the anti diabetic effects of bariatric surgery. Methods. Glucose homeostasis was studied in 53 Ossabaw swine. Thirty-two received an obesogenic diet and were randomized to RYGB, gastrojejunostomy (GJ), gastrojejunostomy with duodenal exclusion (GJD), or Sham operations. Intravenous glucose tolerance tests and standardized meal tolerance tests were performed prior to, 1, 2, and 8 weeks after surgery and at a single time-point for regular diet control pigs. Results. High-calorie-fed Ossabaws weighed more and had greater IR than regular diet controls, though only 70% developed IR. All operations caused weight-loss-independent improvement in IR, though only in pigs with high baseline IR. Only RYGB induced weight loss and decreased IR in the majority of pigs, as well as increasing AUCinsulin/AUCglucose. Conclusions. Similar to humans, Ossabaw swine exhibit both obesity-dependent and obesity-independent IR. RYGB promoted weight loss, IR improvement, and increased AUCinsulin/AUCglucose, compared to the smaller changes following GJ and GJD, suggesting a combination of upper and lower gut mechanisms in improving glucose homeostasis.Journal of Diabetes Research 08/2014; 2014:526972. DOI:10.1155/2014/526972 · 3.54 Impact Factor
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ABSTRACT: The aim of this study was to develop a novel surgical model to test the "hindgut hypothesis" and thereby study the role of the gut in glucose homeostasis and the mechanism of action of bariatric surgery. Sprague-Dawley rats were given a high-fat and high-sugar diet and treated with 25 mg/kg streptozotocin (STZ). The fat-sugar-fed/STZ-treated rats were randomized into mid to distal small bowel resection with the preservation of the terminal ileum (DBRPI) and sham operation (which had a formal celiotomy with bowel manipulation only) groups. Rats were observed for 12 weeks after the operation. The main outcome measures were weight, food intake, non-fasting glucose, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), the levels of fasting and glucose-induced insulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), serum bile acids, and lipid profile. The DBRPI and sham groups exhibited no difference in weight and food intake after surgery. When compared to the sham controls, the DBRPI group displayed an improvement in non-fasting glucose, oral glucose tolerance, and insulin tolerance at 4 and 12 weeks postresection. DBRPI elicited an increased serum insulin, PYY and GLP-1 levels at 12 weeks postoperation; furthermore, DBRPI resulted in higher serum levels of triglyceride, total bile acids, total bilirubin, and direct bilirubin levels and lower free fatty acid level at 12 weeks. This study provides strong evidences for the key role of hindgut in the amelioration of diabetes after bariatric surgery. Moreover, these findings confirm that DBRPI is a simple and effective surgical model for testing the "hindgut hypothesis" and focused study of biliary enterohepatic recycling in the context of bariatric operations.Journal of Gastrointestinal Surgery 04/2014; 18(6). DOI:10.1007/s11605-014-2507-3 · 2.39 Impact Factor
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ABSTRACT: To evaluate the role of bile routing modification on the beneficial effects of gastric bypass surgery on glucose and energy metabolism. Gastric bypass surgery (GBP) promotes early improvements in glucose and energy homeostasis in obese diabetic patients. A suggested mechanism associates a decrease in hepatic glucose production to an enhanced intestinal gluconeogenesis. Moreover, plasma bile acids are elevated after GBP and bile acids are inhibitors of gluconeogenesis. In male Sprague-Dawley rats, we performed bile diversions from the bile duct to the midjejunum or the mid-ileum to match the modified bile delivery in the gut occurring in GBP. Body weight, food intake, glucose tolerance, insulin sensitivity, and food preference were analyzed. The expression of gluconeogenesis genes was evaluated in both the liver and the intestine. Bile diversions mimicking GBP promote an increase in plasma bile acids and a marked improvement in glucose control. Bile bioavailability modification is causal because a bile acid sequestrant suppresses the beneficial effects of bile diversions on glucose control. In agreement with the inhibitory role of bile acids on gluconeogenesis, bile diversions promote a blunting in hepatic glucose production, whereas intestinal gluconeogenesis is increased in the gut segments devoid of bile. In rats fed a high-fat-high-sucrose diet, bile diversions improve glucose control and dramatically decrease food intake because of an acquired disinterest in fatty food. This study shows that bile routing modification is a key mechanistic feature in the beneficial outcomes of GBP.Annals of Surgery 01/2015; DOI:10.1097/SLA.0000000000001121 · 7.19 Impact Factor