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

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靶点，进而影响肥胖相关疾病，如糖尿病。棕色脂肪组织（BAT）是非颤抖性产热的主要器官，在婴儿和成年人中都有发现。在冷刺激后，BAT增加其从循环中摄取长链脂肪酸（LCFA），并将其引导至非偶联线粒体呼吸。因此，解偶联蛋白1（UCP 1）的诱导/激活和BAT对LCFA的摄取/激活对产热至关重要。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FATP 1 KO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，FATP 1也可能定位于骨骼肌和3 T3 L1脂肪细胞的线粒体，但它的作用，如果有的话，在BAT线粒体是未知的。此外，我们发现，CD 36，清道夫受体参与LCFA的摄取，是由BAT表达，也是所需的非颤抖产热与CD 36 KO动物显示严重的产热缺陷。令人惊讶的是，我们发现CD 36 KO BAT的LCFA摄取没有变化，而脂肪酸氧化显著受损，导致BAT甘油三酯积累和肥大。CD 36的亚组分定位于线粒体，我们推测CD 36可能是MAT线粒体功能所需的。因此，我们建议在这里测试FATP 1和CD 36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导致对BAT脂质通量，线粒体功能和该组织中产热的调节的新见解，并最终更好地了解能量消耗如何调节以及如何将其用于抗肥胖/糖尿病策略。 公共卫生相关性：肥胖症与包括2型糖尿病在内的几种相关疾病有关，它是能量输入的结果，即我们消耗的食物的数量和种类，以及我们的能量输出，例如运动和产热。我们已经确定了两种蛋白质是所需的热量生产，并建议研究的机制，它们管理的能量消耗。

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.