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：
8109127
负责人：
Andreas Stahl
金额：
$ 42.26万
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/8109127
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 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）：热发生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，这反过来会影响肥胖相关的疾病，例如糖尿病。棕色脂肪组织（BAT）是非震动热发生的主要器官，在婴儿和成年人中都被发现。在冷刺激后，从循环中增加了其对长链脂肪酸（LCFA）的吸收，并将其引导到线粒体呼吸无偶联的情况下。因此，通过BAT诱导/激活解偶联蛋白1（UCP1）和LCFA摄取/激活对于热生成至关重要。我们已经表明，后一个过程需要脂肪酸转运蛋白（FATP）1，因为FATP1KO小鼠严重冷，蝙蝠LCFA的摄取减少，脂质累积减少。最近的发现表明，FATP1也可能定位于线粒体的骨骼肌和3T3 L1脂肪细胞，但是其作用，如果蝙蝠线粒体中有任何作用，则尚不清楚。此外，我们发现CD36是一种参与LCFA摄取的清道夫受体，由BAT表达，对于表现出严重的热缺陷的CD36KO动物的不动动生成也是必需的。令人惊讶的是，我们发现CD36KO BAT的LCFA吸收不变，而脂肪酸氧化显着受损，导致蝙蝠甘油三酸酯的积累和肥大。 CD36的亚限度本地化为线粒体，我们猜测CD36可能需要用于MAT线粒体功能。因此，我们在这里提议测试FATP1和CD36支持热生成的机制，这些机制考虑了在BAT发育，脂质代谢和线粒体功能中潜在的作用。这些研究的结果可能导致对蝙蝠脂质通量的调节，线粒体功能和该组织中的热发生的新见解，并最终更好地了解如何调节能量消耗以及如何用于抗肥胖/糖尿病策略。公共卫生相关性：肥胖症患有多种相关疾病，包括2型糖尿病，是能源投入的结果，即我们消耗的食物的数量和种类，以及我们的能量输出，例如运动和热量产生。我们已经确定了两个蛋白质的蛋白质，这些蛋白质是热量产生所需的，并建议研究它们控制能量消耗的机制。