Roles of Sphingosine Kinase 1 in adipocyte thermogenesis

鞘氨醇激酶 1 在脂肪细胞生热作用中的作用

• 批准号: 10315416
• 负责人: Yolander Valentine
• 金额: $ 4.16万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315416
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic beta-Agonists; Adult; Affect; Americas; Attenuated; Brown Fat; Cell physiology; Centers for Disease Control and Prevention (U.S.); Child; Data; Emergency Situation; Enzymes; Fatty Acids; Fatty acid glycerol esters; Generations; Glucose; Goals; Health; High Fat Diet; Human; In Vitro; Incidence; Infant; Inner mitochondrial membrane; Light; Link; Lipids; Maintenance; Mediating; Messenger RNA; Metabolic; Mitochondria; Mus; Obesity; Outcome; Oxidative Phosphorylation; Oxygen Consumption; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Process; Proteins; Protons; Research; Role; SPHK1 enzyme; Scheme; Signal Pathway; Signal Transduction; Sphingolipids; Testing; Thermogenesis; Tissues; Transcription Coactivator; United States; Weight Gain; base; beta-adrenergic receptor; comorbidity; experimental study; fatty acid metabolism; fatty acid oxidation; gene induction; in vivo; interest; mRNA Expression; new therapeutic target; novel; novel strategies; obesity treatment; programs; response; transcription factor; uncoupling protein 1

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.

项目摘要 肥胖是美国的一个健康危机，它影响着成年人和儿童，并导致许多不良后果。 健康成果。因此，治疗肥胖症的新方法受到强烈关注。棕色和米色 脂肪组织是近来许多肥胖相关研究的焦点。棕色和米色脂肪细胞具有 线粒体含量高，脂肪酸氧化增强。此外，由于这些组织表达 解偶联蛋白1（UCP 1），脂肪酸代谢中的一大部分能量从热量中损失。而 人类棕色脂肪的存在是有争议的，最近的研究集中在这个过程中， 白色脂肪细胞转化为米色产热脂肪细胞，因为如果这一过程可以被有意地 调节它将导致脂肪组织减少，因此构成肥胖症的潜在治疗。 该提案旨在阐明鞘氨醇激酶1的新功能。β-肾上腺素能受体 刺激促进白色脂肪细胞转化为米色（“米色”）。我的初步数据显示， 用CL 316243（CL）刺激β-肾上腺素能受体可增加Ucp 1和SphK 1 mRNA。更进一步， 这些结果在体外被概括，其中白色WT脂肪细胞的β 1肾上腺素能受体刺激显示 增加SphK 1和Ucp 1 mRNA表达，而在SphK 1缺陷的白色脂肪细胞中减弱。 此外，SphK 1缺失的脂肪细胞不能诱导PGC 1 α和PGC 1 β，两者都是共激活剂 UCP 1的转录因子，产热的驱动程序。基于这些初步数据，我假设 SphK 1介导白色脂肪细胞的染色，导致线粒体解偶联，导致脂肪组织 产热作用该项目分为两个目标，以实现这一目标。目标1将研究 本研究旨在探讨SphK 1在体内和体外脂肪细胞中的作用机制， 调节脂肪细胞中的beiging。 这里提出的实验将确定SphK 1在白色转化中的重要性 脂肪细胞变米色及其在体内产热中的作用。此外，该提案将确定 SphK 1通过该信号来控制脂肪细胞产热。因此，我的研究将揭示一个新的联系， SphK 1信号传导和脂肪细胞产热，这可能是一个潜在的新的治疗靶点， 减少肥胖。