Role of Ileum in Reducing Obesity Related Comorbidities

回肠在减少肥胖相关合并症中的作用

• 批准号: 7707234
• 负责人: Rohit Kohli
• 金额: $ 15.04万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707234
• 关键词: ASBT protein; Acids; Adolescent; Adult; Anatomy; Animals; Back; Bariatrics; Bile Acids; Bile fluid; Biliary; Biliopancreatic Diversion; Blood Vessels; Body Weight decreased; CYP7A1 gene; Catheterization; Childhood; Cholesterol; Cholic Acids; Clinical; Coenzyme A; Comorbidity; Data; Diabetes Mellitus; Distal; Enterohepatic Circulation; Fatty Liver; Figs - dietary; Gastric Bypass; Gastroenterologist; Gastrointestinal tract structure; Goals; Hepatic; Hydroxycholesterols; Intervention; Intestinal Absorption; Intestines; Isotopes; K-Series Research Career Programs; Laboratories; Length; Ligaments; Ligands; Link; Lipids; Liver; Malabsorption Syndromes; Mass Fragmentography; Measurement; Measures; Mediating; Medical; Mentors; Metabolic; Metabolism; Modeling; Morbid Obesity; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutritional; Obesity; Obesity associated hypercholesterolemia; Operative Surgical Procedures; Oxidoreductase; Pathway interactions; Plasma; Portal vein structure; Positioning Attribute; Prevalence; Procedures; Production; Rattus; Reporting; Research; Resected; Resolution; Role; Serum; Sterols; Stomach; Stress; Surgical Models; Techniques; Testing; Therapeutic; Time; Training; Translating; United States; Weight; Work; absorption; bariatric surgery; bile acid transporter; bile duct; bile salts; cholesterol absorption; experience; feeding; glucose tolerance; hypercholesterolemia; ileum; improved; in vivo; inhibitor/antagonist; jejunum; novel; obesity in children; professor; public health relevance; receptor; research study; reuptake; sham surgery

DESCRIPTION (provided by applicant): The prevalence of obesity is increasing at alarming rates in the United States such that bariatric surgery has become an accepted therapeutic option for adults and adolescents with morbid obesity. Bariatric surgery provides significant metabolic benefits, including resolution of type-2 diabetes and marked reduction in hypercholesterolemia, that precede the weight loss produced by these surgeries. The mechanisms responsible for these weight-independent metabolic benefits are poorly understood. Dr. Kohli's long-term research objective is to characterize the mechanisms behind these weight-loss-independent metabolic benefits of bariatric surgical procedures and translate those observations into more scalable non-invasive therapeutic measures. In this proposal Dr. Kohli will focus on the benefits of bariatric surgery to obesity related hypercholesterolemias by using a unique surgical procedure called "Ileal Transposition" in a rat model. This weight loss surgery has been previously shown to produce improved glucose tolerance similar to roux-en-y- gastric bypass without gastric size restriction or malabsorption. Dr. Kohli has generated exciting preliminary data using this surgical model that include a significant reduction in cholesterol levels that is independent of weight loss. The specific aims of his proposal will examine the mechanistic links between bile acid entero-hepatic circulation and cholesterol absorption, sensing, and endogenous production in this bariatric surgery model. He will also investigate the role of adaptation of the transposed segment of the ileum in reduction of cholesterol. These studies build on Dr. Kohli's prior work as a fellow investigating the mechanisms involved in lipid-induced nutritional stress producing hepatic steatosis. The primary goal of this mentored career development award is to provide a pathway for Dr. Kohli, a trained pediatric gastroenterologist and hepatologist, to achieve scientific independence. By developing an expertise in lipid and bile acid metabolism using small-animal surgical-obesity-intervention models, he will distinguish himself from his mentor, Professor Randy Seeley, and be well-positioned to make significant scientific and medical contributions to the understanding of obesity in children and adolescents. PUBLIC HEALTH RELEVANCE: Bariatric surgery is now an accepted treatment for the morbidly obese adult or adolescent. Certain benefits of these surgeries, such as reduced cholesterol and resolution of diabetes, occur even prior to weight loss. This proposal seeks to identify the key mechanisms involved in these weight-loss-independent improvements in cholesterol levels and then translate those findings to non-invasive more scalable treatment options.

描述（由申请人提供）： 在美国，肥胖症的患病率以惊人的速度增加，使得减肥手术已经成为患有病态肥胖症的成人和青少年的可接受的治疗选择。减肥手术提供了显着的代谢益处，包括2型糖尿病的解决和高胆固醇血症的显着减少，这些手术产生的体重减轻之前。负责这些与体重无关的代谢益处的机制知之甚少。Kohli博士的长期研究目标是描述减肥手术的这些减肥独立代谢益处背后的机制，并将这些观察结果转化为更可扩展的非侵入性治疗措施。在本提案中，Kohli博士将通过在大鼠模型中使用称为“回肠转位”的独特手术程序，重点关注减肥手术对肥胖相关高胆固醇血症的益处。这种减肥手术以前已经显示出产生类似于roux-en-y-胃旁路术的改善的葡萄糖耐量，而没有胃大小限制或吸收不良。Kohli博士使用这种手术模型产生了令人兴奋的初步数据，其中包括胆固醇水平的显着降低，这与体重减轻无关。他的建议的具体目标将检查在这个减肥手术模型中胆汁酸肠肝循环和胆固醇吸收、传感和内源性生产之间的机械联系。他还将研究回肠转位段的适应性在降低胆固醇中的作用。这些研究建立在Kohli博士之前的工作基础上，他研究了脂质诱导的营养应激产生肝脂肪变性的机制。这个指导职业发展奖的主要目标是为Kohli博士提供一条途径，Kohli博士是一名训练有素的儿科胃肠病学家和肝病学家，可以实现科学独立。通过使用小动物药物肥胖干预模型开发脂质和胆汁酸代谢方面的专业知识，他将与他的导师Randy塞利教授区分开来，并能够为儿童和青少年肥胖的理解做出重大的科学和医学贡献。 公共卫生相关性：减肥手术现在是病态肥胖的成人或青少年接受的治疗方法。这些手术的某些好处，如降低胆固醇和解决糖尿病，甚至发生在减肥之前。该提案旨在确定这些与减肥无关的胆固醇水平改善所涉及的关键机制，然后将这些发现转化为非侵入性的更可扩展的治疗方案。