Bariatric Surgery for Morbid Obesity: Clinical and Pathophysiologic Consequences

病态肥胖的减肥手术：临床和病理生理学后果

基本信息

批准号：
7683738
负责人：
PAUL David BERK
金额：
$ 32.38万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683738
关键词：
ADD-1 protein Abbreviations Adipocytes Adipose tissue Anabolism Animal Model Animals Apolipoprotein A-I Apolipoproteins Apolipoproteins B Atherosclerosis B-Lymphocytes Bariatrics Binding Binding Proteins Biological Assay Biology Blood Blood specimen Body Weight decreased CETP gene Carbohydrates Cardiovascular Diseases Catabolism Cell Size Cessation of life Characteristics Cholesterol Cholesterol Esters Clinical Comorbidity Data Defect Descriptor Diabetes Mellitus Down-Regulation Dyslipidemias Endocrine Enzymes Epidemic Excretory function Fasting Fatty Liver Fatty acid glycerol esters Fatty-acid synthase Functional disorder Gastrectomy Gene Expression Gene Targeting Genes Genetic HDL-triglyceride Harvest Hepatic Hepatocyte High Density Lipoproteins Human Hyperlipidemia Hypertension Hypertriglyceridemia Infiltration Inflammatory Insulin Insulin Resistance Intra-abdominal Kinetics Lead Leptin Lipase Lipolysis Lipoprotein Receptor Lipoproteins Liver Liver diseases Low-Density Lipoproteins Malabsorption Syndromes Measurement Medical Messenger RNA Metabolic syndrome Metabolism Morbid Obesity Morbidity - disease rate Movement Non-Insulin-Dependent Diabetes Mellitus Obesity Oleic Acids Operative Surgical Procedures Outcome PPAR gamma Pathogenesis Pathway interactions Patients Phospholipid Transfer Proteins Physiological Processes Plasma Population Procedures Production Protein Secretion Proteins Protocols documentation RNA Relative (related person)Research Personnel Response Elements Risk Risk Factors Rodent SR-BI receptor Sampling Series Severities Source Staging Stearoyl-CoA Desaturase Stromal Cells Structure of beta Cell of islet Testing Therapeutic Time Transferase Triglycerides Very low density lipoprotein abdominal fat activator 1 protein adiponectin bariatric surgery cost cytokine density falls fatty acid metabolism fatty acid oxidation hepatic lipase high risk insight interest lipoprotein triglyceride liver biopsy long chain fatty acid mRNA Expression macrophage man microsomal triglyceride transfer protein moderate obesity mortality new therapeutic target non-alcoholic fatty liver novel obesity treatment oxidation programs receptor response subcutaneous therapeutic target uptake

项目摘要

Obesity is responsible for more than 300,000 deaths and $117 billion in medical costs annually, but much of our understanding of its pathophysiology derives from studies in rodents. Bariatric surgery offers the best current treatment results in terms of weight-loss and improvement in co-morbidities such as diabetes in patients with moderate obesity, but has been a high risk procedure, with appreciable morbidity and mortality in higher obesity grades. Among obesity co-morbidities, diabetes, hypertension, dyslipidemia, arterio- sclerotic cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD) have common pathogenetic mechanisms involving insulin resistance. This, in turn, relates in incompletely understood ways to the large, metabolically active, intra-abdominal fat depots typical of the "metabolic syndrome" in the obese, the movement of long chain fatty acids (LCFA) between these depots and the liver, and the "lipotoxicity" of LCFA for key non-adipose tissues, e.g. the pancreatic beta-cell. We have developed a novel two-stage laparoscopic surgical approach to high-grade obesity. A restrictive sleeve gastrectomy is followed after a -100 Ib weight loss, when the patient is a better surgical risk, by a second procedure that causes malabsorption. Our initial series of high risk patients (BMI >50) has grown to 100 cases with excellent long term weight loss, minimal morbidity, and no mortality, so that this approach has become our treatment of choice for all patients with BMI > 60 and those with BMI >50 plus other risk factors. The availably in such patients of paired biopsies of liver and of omental & subcutaneous fat at each operation will allow us to study, for the first time in man, the effects of obesity and weight loss on: [A] Key aspects of adipose tissue biology, including depot-specific effects on adipocyte LCFA uptake and lipolysis, endocrine functions of the adipocyte, and the impact of macrophage infiltration and adipokine production on these functions; [B] Patho- genetic mechanisms of NAFLD, including studies of hepatocellular LCFA and triglyceride (TG) uptake, LCFA synthesis and oxidation, lipoprotein synthesis and TG excretion; and [C] Pathogenesis of the atherogenic dyslipidemia (elevated TG, reduced HDL) of obesity. The studies will document important differences in the pathophysiology of obesity between humans and rodents, and should yield novel insights, with potential therapeutic implications, into mechanisms responsible for its key comorbidities.

肥胖症每年造成超过300,000人死亡和1,170亿美元的医疗费用，但大部分我们对其病理生理学的理解源于啮齿动物的研究。减肥手术提供了最好的目前的治疗方法是减肥和改善合并症（例如糖尿病）肥胖症中等的患者，但一直是高风险手术，发病率和死亡率明显在较高的肥胖等级中。肥胖合并症，糖尿病，高血压，血脂异常，动脉 - 硬化心血管疾病和非酒精性脂肪肝疾病（NAFLD）具有常见的病原体涉及胰岛素抵抗的机制。反过来，这与不完全理解的方式有关肥胖中典型的“代谢综合征”的代谢活性，腹内脂肪库，这些仓库和肝脏之间的长链脂肪酸（LCFA）的运动，以及LCFA的“脂毒性” 对于关键的非辅导组织，例如胰腺β细胞。我们已经开发了一个新颖的两个阶段高度肥胖症的腹腔镜手术方法。在 -100 IB体重减轻，当患者是更好的手术风险时，通过第二个手术吸收不良。我们最初的一系列高风险患者（BMI> 50）已增长到100例，长长的病例定期体重减轻，发病率最小，没有死亡率，因此这种方法已成为我们对待所有BMI> 60的患者以及BMI> 50加上其他风险因素的患者的选择。在这种情况下可用每次手术时肝和皮下脂肪的成对活检的患者将使我们能够研究肥胖和体重减轻的影响首次研究：[a]脂肪组织的关键方面生物学，包括对脂肪细胞LCFA摄取和脂解的特异性作用，内分泌功能脂肪细胞，以及巨噬细胞浸润和脂肪因子的产生对这些功能的影响； [b]病情 - NAFLD的遗传机制，包括肝细胞壁LCFA和甘油三酸酯（TG）摄取的研究，LCFA 合成和氧化，脂蛋白合成和TG排泄；和[C]动脉粥样硬化的发病机理肥胖症的血脂异常（TG升高，HDL降低）。研究将记录在人类和啮齿动物之间肥胖的病理生理学，并应产生新颖的见解，并具有潜力治疗意义，使其主要合并症的机制。