DEPENDENCE OF THERMOGENESIS AND BROWN ADIPOSE TISSUE FUNCTION ON FATP1 AND CD36

生热作用和棕色脂肪组织功能对 FATP1 和 CD36 的依赖性

基本信息

批准号：
8256744
负责人：
Andreas Stahl
金额：
$ 36.26万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256744
关键词：
Accounting Adipocytes Adipose tissue Adult Affect Animals Biological Assay Biology Blood Circulation Brown Fat CD36 gene Cell Line Data Defect Dependence Development Diabetes Mellitus Diet Disease Energy Metabolism Equilibrium Exercise Fatty Acids Food Hypertrophy Infant Lead Link Lipids Lipolysis Metabolic Mitochondria Modeling Morphology Mus Muscle Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Output Play Predisposition Process Proteins Regulation Respiration Role Signal Transduction Skeletal Muscle Stable Isotope Labeling Techniques Testing Thermogenesis Tissues Triglycerides base density energy balance fatty acid oxidation fatty acid-transport protein insight lipid metabolism long chain fatty acid loss of function mitochondrial membrane novel overexpression oxidation promoter public health relevance research study scavenger receptor tool uncoupling protein 1 uptake

项目摘要

DESCRIPTION (provided by applicant): Thermogenesis is an important component of energy output and therefore a potential target for altering metabolic balance, which in turn can affect obesity-associated disorders such as diabetes. Brown adipose tissue (BAT) is the primary organ for non-shivering thermogenesis and is found both in infants as well as adult humans. Following cold stimulation BAT increases its uptake of long-chain fatty acids (LCFA) from the circulation and channels them toward uncoupled mitochondrial respiration. Thus, both induction/activation of uncoupling protein 1 (UCP1) and LCFA uptake/activation by BAT are essential to thermogenesis. We have shown that Fatty Acid Transport Protein (FATP) 1 is required for the latter process, as FATP1KO mice are severely cold intolerant, have diminished BAT LCFA uptake, and reduced lipid accumulation. Recent findings have indicated that FATP1 may also localize to mitochondria of skeletal muscle and 3T3 L1 adipocytes, however its role, if any in BAT mitochondria is unknown. Further, we found that CD36, a scavenger receptor involved in LCFA uptake, is expressed by BAT and is also required for non-shivering thermogenesis with CD36KO animals displaying severe thermogenic defects. Surprisingly, we found that LCFA uptake by CD36KO BAT was unchanged while fatty acid oxidation was significantly impaired leading to BAT triglyceride accumulation and hypertrophy. A subfraction of CD36 localizes to mitochondria and we are speculating that CD36 may be required for MAT mitochondrial function. Thus, we propose here to test the mechanism by which FATP1 and CD36 support thermogenesis taking into account potential roles in BAT development, lipid metabolism, and mitochondrial function. Results from these studies could lead to novel insights into the regulation of BAT lipid fluxes, mitochondrial function and thermogenesis in this tissue, and ultimately to a better understanding of how energy expenditure is regulated and how it could be utilized for anti-obesity/diabetes strategies. PUBLIC HEALTH RELEVANCE: Obesity, which has several associated diseases including type-2 diabetes, is a result of energy input, i.e. the amount and kinds of food we consume, and our energy output, e.g. exercise and heat production. We have identified two proteins that are required for heat production and propose to study the mechanisms by which they govern energy expenditure.

描述（由申请人提供）：产热是能量输出的重要组成部分，因此是改变代谢平衡的潜在目标，这反过来又会影响与肥胖相关的疾病，例如糖尿病。棕色脂肪组织（BAT）是非颤抖产热的主要器官，在婴儿和成年人中都有发现。冷刺激后，BAT 会增加对循环中长链脂肪酸 (LCFA) 的吸收，并将其引导至解偶联的线粒体呼吸。因此，解偶联蛋白 1 (UCP1) 的诱导/激活和 BAT 的 LCFA 摄取/激活对于生热作用至关重要。我们已经证明，脂肪酸转运蛋白 (FATP) 1 是后一个过程所必需的，因为 FATP1KO 小鼠严重不耐冷，BAT LCFA 摄取减少，脂质积累减少。最近的研究结果表明，FATP1 也可能定位于骨骼肌和 3T3 L1 脂肪细胞的线粒体，但其在 BAT 线粒体中的作用（如果有的话）尚不清楚。此外，我们发现 CD36（一种参与 LCFA 摄取的清道夫受体）由 BAT 表达，对于表现出严重生热缺陷的 CD36KO 动物的非颤抖生热作用也是必需的。令人惊讶的是，我们发现 CD36KO BAT 对 LCFA 的摄取没有变化，而脂肪酸氧化显着受损，导致 BAT 甘油三酯积累和肥大。 CD36 的一个亚组分定位于线粒体，我们推测 CD36 可能是 MAT 线粒体功能所必需的。因此，我们在此建议测试 FATP1 和 CD36 支持产热的机制，同时考虑到 BAT 发育、脂质代谢和线粒体功能中的潜在作用。这些研究的结果可能会给该组织中 BAT 脂质通量、线粒体功能和产热的调节带来新的见解，并最终更好地理解能量消耗是如何调节的以及如何将其用于抗肥胖/糖尿病策略。公共卫生相关性：肥胖与包括 2 型糖尿病在内的多种相关疾病有关，是能量输入（即我们消耗的食物的数量和种类）以及我们的能量输出（例如，能量输出）的结果。运动和产热。我们已经确定了产生热量所需的两种蛋白质，并建议研究它们控制能量消耗的机制。