Antiobesity Mechanism of CLA Isomer in Human Adipocytes

CLA异构体在人脂肪细胞中的抗肥胖机制

• 批准号: 6561499
• 负责人: MICHAEL K MCINTOSH
• 金额: $ 25.8万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561499
• 关键词: adipocytes; bioenergetics; chemical conjugate; chemical structure function; chemoprevention; clinical research; dietary lipid; dietary supplements; drug design /synthesis /production; female; gene expression; human tissue; isomer; linoleate; lipid metabolism; lipolysis; nutrition related tag; obesity; oxidation; phosphoproteins; spectrometry; tissue /cell culture; transcription factor; triglycerides

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop novel dietary strategies for the control of human obesity, the most prevalent nutrition-related disease in America. The objective of this application is to identify isomerspecific mechanisms by which conjugated linoleic acid (CLA), unsaturated fatty acids found in beef and dairy foods that reduce adiposity in certain animals and humans, alters lipid metabolism in cultures of human (pre)adipocytes. The central hypothesis for the proposed research is that the trans-10, cis-12 isomer of CLA attenuates triglyceride (TG) content and alters lipid droplet morphology by enhancing energy expenditure, lipolysis, and fatty acid oxidation, thereby down-regulating the expression of perilipin-A, a major regulator of adipocyte TG storage. This hypothesis was formulated based on our preliminary findings in human (pre)adipocyte cultures demonstrating that trans-10, cis-12, but not cis-9, trans-11, CLA decreased TG content, de novo lipogenesis, fatty acid esterification, and perilipin protein without affecting differentiation per se. The rationale for the proposed research is that once we understand how trans-10, cis-12 CLA prevents TG accumulation in (pre)adipocytes, effective strategies can be developed using CLA as an antiobesity nutrient in fortified foods or supplements for clinical trials. To accomplish this objective, the following specific aims will be examined in human cultures of differentiating preadipocytes and newly differentiated adipocytes: Aim #1. Determine the mechanism by which trans-10, cis-12 CLA decreases cellular TG content; and Aim #2. Determine the mechanism by which trans-10, cis-12 CLA decreases the expression of perilipin-A. In Aim #1, the impact of fatty acid type and dose on oxygen consumption, mitochondrial and peroxisomal beta-oxidation, lipolysis, fatty acid oxidation, and uncoupling protein expression will be determined. In Aim #2, the influence of fatty acid type and dose on perilipin-A protein and gene expression will be evaluated. Using primary cultures of human adipocytes as our model is important, because there are clear differences between the lipid metabolism of human and animal adipocytes. The proposed studies are significant because they are expected to lead to the development of novel strategies for weight loss. Consequently, reductions in health problems and financial costs related to obesity are expected.

描述（由申请人提供）：该项目的长期目标是开发新的饮食策略，用于控制人类肥胖，这是美国最流行的营养相关疾病。本申请的目的是确定共轭亚油酸（CLA）（牛肉和乳制品中发现的不饱和脂肪酸，可减少某些动物和人类的肥胖）改变人类（前）脂肪细胞培养物中脂质代谢的异构体特异性机制。提出的研究的中心假设是，反式-10，顺式-12异构体的共轭亚油酸减弱甘油三酯（TG）的含量，并通过增强能量消耗，脂解，和脂肪酸氧化改变脂滴形态，从而下调围脂蛋白-A，脂肪细胞TG储存的主要调节剂的表达。这一假设是根据我们在人（前）脂肪细胞培养物中的初步发现制定的，这些发现表明，反式-10，顺式-12，而不是顺式-9，反式-11，CLA降低TG含量，从头脂肪生成，脂肪酸酯化和围脂蛋白，而不影响分化本身。这项研究的基本原理是，一旦我们了解了反式-10，顺式-12共轭亚油酸如何防止（前）脂肪细胞中的TG积累，就可以开发出有效的策略，将共轭亚油酸作为强化食品或补充剂中的抗肥胖营养素用于临床试验。为了实现这一目标，将在分化的前脂肪细胞和新分化的脂肪细胞的人培养物中检查以下具体目标：目标#1。确定反式-10，顺式-12 CLA降低细胞TG含量的机制;以及目标#2。确定反式-10，顺式-12共轭亚油酸降低围脂蛋白-A表达的机制。在目标1中，将确定脂肪酸类型和剂量对耗氧量、线粒体和过氧化物酶体β-氧化、脂解、脂肪酸氧化和解偶联蛋白表达的影响。在目标#2中，将评价脂肪酸类型和剂量对周脂蛋白-A蛋白和基因表达的影响。使用人脂肪细胞的原代培养物作为我们的模型是重要的，因为人和动物脂肪细胞的脂质代谢之间存在明显差异。拟议的研究是重要的，因为它们有望导致新的减肥策略的发展。因此，预计与肥胖有关的健康问题和财务费用将减少。