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目标，这反过来可以影响肥胖相关的疾病，如糖尿病。褐色脂肪组织（BAT）是非寒颤产热的主要器官，在婴儿和成人中都有发现。在冷刺激后，BAT从循环中增加对长链脂肪酸（LCFA）的摄取，并将其引导至非偶联线粒体呼吸。因此，BAT对解偶联蛋白1 （UCP1）的诱导/激活和LCFA的摄取/激活对于产热至关重要。我们已经证明，脂肪酸转运蛋白（FATP） 1是后一过程所必需的，因为FATP1KO小鼠严重不耐冷，减少了BAT LCFA的摄取，减少了脂质积累。最近的研究表明，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线粒体中的作用尚不清楚。此外，我们发现CD36，一种参与LCFA摄取的清除率受体，由BAT表达，并且在CD36KO动物表现出严重的产热缺陷的非寒颤产热中也是必需的。令人惊讶的是，我们发现CD36KO BAT对LCFA的摄取没有变化，而脂肪酸氧化明显受损，导致BAT甘油三酯积累和肥大。CD36的一个亚片段定位于线粒体，我们推测CD36可能是MAT线粒体功能所必需的。因此，我们在此提出测试FATP1和CD36支持产热的机制，考虑到BAT发育、脂质代谢和线粒体功能的潜在作用。这些研究的结果可能会对BAT脂质通量、线粒体功能和该组织产热的调节产生新的见解，并最终更好地了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。

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.