Roles of Sphingosine Kinase 1 in adipocyte thermogenesis

项目摘要 在美国，肥胖是一种影响成人和儿童的健康危机，并导致许多不利的 健康结果。因此，治疗肥胖的新方法引起了人们的浓厚兴趣。棕色和米色 脂肪组织是最近许多与肥胖相关的研究的焦点。棕色和米色脂肪细胞有一种 线粒体含量高，脂肪酸氧化增强。此外，因为这些组织表达 解偶联蛋白1(UCP1)是脂肪酸代谢中很大一部分能量因受热而损失。而当 棕色脂肪在人类中的存在是有争议的，最近的研究集中在 白色脂肪细胞转化为米色的产热脂肪细胞，因为如果这个过程可以故意 如果加以控制，它将导致脂肪组织减少，从而构成一种潜在的肥胖症治疗方法。 本研究旨在阐明鞘氨醇激酶1的一种新功能：β₃肾上腺素能受体 刺激促进白色脂肪细胞转变为米色(“米色”)。我的初步数据显示在活体内 CL 316243(CL)刺激β₃肾上腺素能受体可增加UCP1mRNA和SphK1mRNA的表达。更远的地方， 这些结果在体外被概括，其中β₃肾上腺素能受体刺激白色WT脂肪细胞显示 增加SphK1和Ucp1mRNA的表达，在SphK1缺陷的白色脂肪细胞中这种表达减弱。 此外，SphK1缺失的脂肪细胞不能诱导pGc1α和pGc1β，两者都是共激活因子。 UCP1的转录因子，产热的驱动因素。根据这些初步数据，我假设 SphK1介导白色脂肪细胞褐变，导致线粒体解偶联，导致脂肪组织 生热作用。为了实现这一目标，该项目分为两个目标。目标1将调查 SphK1在体内外脂肪细胞中的表达，目的2将阐明SphK1的作用机制(S) 调节脂肪细胞中的褐变。 这里提出的实验将确定SphK1在白蛋白转化中的重要性 脂肪细胞变成米色及其在体内产热中的作用。此外，这项提案将确定路径 SphK1通过其信号来控制脂肪细胞的产热。因此，我的研究将揭示一个新的联系 SphK1信号转导与脂肪细胞产热，可能成为新的治疗靶点。 减少肥胖。

Project Summary Obesity is a health crisis in America that affects both adults and children and leads to many adverse health outcomes. Therefore, novel approaches to treating obesity are of intense interest. Brown and beige adipose tissue has been the focus of many recent obesity-related studies. Brown and beige adipocytes have a high mitochondria content, and fatty acid oxidation is enhanced. Furthermore, because these tissues express Uncoupling Protein 1 (UCP1), a significant portion of energy from fatty acid metabolism is lost from heat. While the existence of brown adipose in humans is controversial, recent studies have focused on the process by which white adipocytes convert to beige, thermogenic adipocytes, because if this process could be deliberately regulated it would result in decreased adipose tissue and hence constitute a potential treatment for obesity. This proposal aims to shed light on a novel function of Sphingosine Kinase 1. β₃ adrenergic receptor stimulation promotes conversion of white adipocytes to beige (“beiging”). My preliminary data show that in vivo stimulation of β₃ adrenergic receptor with CL 316243 (CL) increases Ucp1 and SphK1 mRNA. Even further, these results were recapitulated in vitro where β₃ adrenergic receptor stimulation of white WT adipocytes showed increased SphK1 and Ucp1 mRNA expression, which was attenuated in SphK1-deficient white adipocytes. Additionally, SphK1 null adipocytes were unable to induce PGC1α and PGC1β, both of which are co-activators of transcription factors for UCP1, the driver for thermogenesis. Based on these preliminary data, I hypothesize that SphK1 mediates beiging of white adipocytes resulting in mitochondrial uncoupling, leading to adipose tissue thermogenesis. This project is divided into two aims to accomplish this goal. Aim 1 will investigate the role of SphK1 in adipocyte beiging in vivo and in vitro, and aim 2 will elucidate the mechanism(s) by which SphK1 regulates beiging in adipocytes. The experiments proposed here will establish the importance of SphK1 in the conversion of white adipocytes to beige and its role in thermogenesis in vivo. Additionally, this proposal will determine the pathway via which SphK1 signals to control adipocyte thermogenesis. Therefore, my study will reveal a new link between SphK1 signaling and adipocyte thermogenesis, which may then serve as a potential novel therapeutic target to reduce obesity.