Antiobesity Mechanism of CLA Isomer in Human Adipocytes

超出提供的空间。该项目的长期目标是开发新的饮食策略来控制人类肥胖，肥胖是美国最普遍的营养相关疾病。本应用的目的是确定共轭亚油酸(CLA)的异构体特异性机制，共轭亚油酸(CLA)是牛肉和乳制品中发现的可降低某些动物和人类肥胖症的不饱和脂肪酸，通过它改变培养的人(前)脂肪细胞的脂肪代谢。这项研究的中心假设是CLA的反式-10，顺式-12异构体通过促进能量消耗、脂肪分解和脂肪酸氧化来减少甘油三酯(TG)的含量并改变脂滴的形态，从而下调脂肪细胞TG储存的主要调节因子Perilipin-A的表达。这一假设是基于我们在人类(前)脂肪细胞培养中的初步发现提出的，该发现表明，在不影响分化本身的情况下，反式-10，顺-12，而不是顺式-9，反式-11，共轭亚油酸可降低甘油三酯含量、新生脂肪生成、脂肪酸酯化和Perilipin蛋白。这项拟议研究的基本原理是，一旦我们了解了反式-10，顺-12共轭亚油酸如何阻止(前)脂肪细胞中的甘油三酯积累，就可以开发有效的策略，将共轭亚油酸作为一种抗肥胖营养物质用于强化食品或临床试验的补充剂。为了实现这一目标，将在人类分化前脂肪细胞和新分化脂肪细胞的培养中检测以下特定目标：目的#1.确定反式-10，顺式-12CLA降低细胞甘油三酯含量的机制；以及目的#2.确定反式-10，顺式-12CLA降低Perilipin-A表达的机制。在目标1中，将确定脂肪酸类型和剂量对氧消耗、线粒体和过氧化物体的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，将评估脂肪酸类型和剂量对Perilipin-A蛋白和基因表达的影响。使用原代培养的人脂肪细胞作为我们的模型是很重要的，因为人和动物脂肪细胞的脂肪代谢有明显的差异。拟议的研究具有重要意义，因为它们有望导致新的减肥策略的发展。因此，与肥胖相关的健康问题和财务成本有望减少。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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 isomer- specific 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. PERFORMANCE SITE ========================================Section End===========================================