A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery

1Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Endocrinology (Impact Factor: 4.5). 04/2013; 154(7). DOI: 10.1210/en.2012-2069
Source: PubMed


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.

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    • "Postoperative effects on glycemic control and insulin resistance have been shown to precede significant weight reduction [3] and occur at least partially in a weight-independent fashion [4], generating controversy surrounding the mechanisms of RYGB's antidiabetic effects [5]. Hypotheses include the operation's impact on intestinal hormones [6, 7], bile acids [8, 9], gut flora [10, 11], and intestinal glucose sensing [12] and metabolism [13]; however, no definitive mechanism has emerged. "
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    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.
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