Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB), is the most effective and durable treatment for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following RYGB approaches 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood. We hypothesize that the altered enterohepatic circulation of bile acids (BA) after RYGB mediates the metabolic improvements that underlie the resolution of T2D after the procedure. In this proposal we will determine how BA contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after RYGB. We will apply a novel surgical procedure to diet-induced obese (DIO) mice where bile is diverted from the gallbladder (GB) to the duodenum (GB-D, a sham procedure), the jejunum (GB-J), or ileum (GB-IL). The biliary diversion (BD) procedure permits examination of altered bile flow, similar to that observed after RYGB, independent of alterations in gastrointestinal tract anatomy. Remarkably, the GB-IL procedure, but not GB-D or GB-J, recapitulates many of the beneficial metabolic and physiologic outcomes observed after RYBG.
Specific Aim 1 will elucidate the contribution of altered fat absorption, chylomicron generation and clearance in the efficacy of GB-IL or RYGB. Studies in Specific Aim 2 are designed to define the role of membrane-bound BA receptor, TGR5, on glucose homeostasis after RYGB and GB-IL.
In Specific Aim 3 we extend our investigations to the nuclear BA receptor, farnesoid x receptor (FXR), investigating the efficacy of RYGB and BD in mice genetically-engineered for intestine- and liver-specific FXR deficiency. The long-term goal of this work is to understand the mechanisms of metabolic improvement after bariatric procedures and to develop technically simple procedures and pharmacologic strategies to treat obesity and its sequelae.

Public Health Relevance

Roux-en Y gastric bypass (RYGB) increases circulating bile acids which reroutes dietary nutrients to the mid or distal intestine. BA have been implicated in the metabolic improvements after this bariatric procedure. As model systems we will compare a novel gallbladder biliary diversion (BD) procedure without GI tract rearrangement and RYGB applied to wild-type and genetically-engineered mice lacking the bile acid receptors, TGR5 and FXR. Findings from these studies may lead to development of innovative, minimalistic and better tolerated surgical interventions to treat diabetes/obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105847-02
Application #
9025790
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Maruvada, Padma
Project Start
2015-03-01
Project End
2016-04-29
Budget Start
2016-03-01
Budget End
2016-04-29
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
Guo, Yan; Xiong, Yanhua; Sheng, Quanghu et al. (2016) A micro-RNA expression signature for human NAFLD progression. J Gastroenterol 51:1022-30
Albaugh, Vance L; Flynn, C Robb; Tamboli, Robyn A et al. (2016) Recent advances in metabolic and bariatric surgery. F1000Res 5:
Sharifnia, Torfay; Antoun, Joseph; Verriere, Thomas G C et al. (2015) Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 309:G270-8
Albaugh, Vance L; Flynn, Charles Robb; Cai, Steven et al. (2015) Early Increases in Bile Acids Post Roux-en-Y Gastric Bypass Are Driven by Insulin-Sensitizing, Secondary Bile Acids. J Clin Endocrinol Metab 100:E1225-33
Flynn, Charles Robb; Albaugh, Vance L; Cai, Steven et al. (2015) Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery. Nat Commun 6:7715