胆汁改道：一种简单有效的治疗肥胖的方法-猫眼课题宝

胆汁改道：一种简单有效的治疗肥胖的方法

批准号：

9025790

负责人：

Naji N Abumrad

金额：

$20.93万

依托单位：

VANDERBILT UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

2015

资助国家：

美国

项目状态：

已结题

起止时间：

2015-03-01 至 2016-04-29

来源：

https://reporter.nih.gov/project-details/9025790

关键词：

Accounting Anatomy Bariatrics Bile Acids Bile fluid Biliary Binding Biological Models Blood Blood Circulation Body Weight decreased Bypass Cholecystokinin Chylomicrons Comorbidity Data Development Diabetes Mellitus Diet Dietary Fats Distal Duodenum Emulsifying Agents Endocrine Energy Metabolism Enteroendocrine Cell Enterohepatic Circulation FGF1 gene Fasting Fatty acid glycerol esters G-Protein-Coupled Receptors Gallbladder Gastric Bypass Gastrointestinal tract structure Generations Genetically Engineered Mouse Glucose Goals Health Hepatic High Fat Diet Histologic Hormones Human Hydrogen Peroxide Inflammation Inflammatory Insulin Intestinal Hormones Intestines Investigation Knockout Mice Knowledge Lead Leukocytes Lipids Lipopolysaccharides Lipoproteins Liver Lymphocyte Maps Measures Mediating Medical Membrane Metabolic Metabolic Control Methods Molecular Morbid Obesity Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Nutrient Obese Mice Obesity Operative Surgical Procedures Outcome Output Peripheral Physiological Primitive foregut structure Procedures Production Research Resolution Role Roux-en-Y Anastomosis Satiation Signal Transduction Site Therapeutic Intervention Tissues Triglycerides Tyrosine Wild Type Mouse Work absorption bariatric surgery base blood glucose regulation cytokine delivered meals design energy balance glucagon-like peptide glucose disposal glucose tolerance glycemic control ileum improved inflammatory marker innovation insulin sensitivity jejunum lipid metabolism neutrophil novel novel therapeutic intervention obesity management receptor receptor expression reduced food intake response

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英文摘要

DESCRIPTION (provided by applicant): 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.

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