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: 10472507
• 负责人: Yolander Valentine
• 金额: $ 4.23万
• 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/10472507
• 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.

项目概要 肥胖是美国的一场健康危机，影响成人和儿童，并导致许多不良后果 健康结果。因此，治疗肥胖的新方法引起了人们的强烈兴趣。棕色和米色 脂肪组织一直是许多近期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 (UCP1) 是脂肪酸代谢产生的大部分能量因热量而损失的。尽管 人类中棕色脂肪的存在是有争议的，最近的研究集中在棕色脂肪的过程上 白色脂肪细胞转化为米色产热脂肪细胞，因为如果这个过程可以故意进行的话 对其进行调节会导致脂肪组织减少，因此构成肥胖症的潜在治疗方法。 该提案旨在阐明鞘氨醇激酶 1 的新功能。β₃ 肾上腺素能受体 刺激促进白色脂肪细胞转化为米色（“米色”）。我的初步数据表明，体内 用 CL 316243 (CL) 刺激 β₃ 肾上腺素能受体会增加 Ucp1 和 SphK1 mRNA。更进一步， 这些结果在体外得到重现，其中白色 WT 脂肪细胞的 β₃ 肾上腺素能受体刺激显示 SphK1 和 Ucp1 mRNA 表达增加，但在 SphK1 缺陷的白色脂肪细胞中表达减弱。 此外，SphK1 无效脂肪细胞无法诱导 PGC1α 和 PGC1β，这两者都是共激活剂 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 介导白色脂肪细胞的米色，导致线粒体解偶联，从而形成脂肪组织 生热作用。为了实现这一目标，该项目分为两个目标。目标 1 将调查的作用 SphK1 在体内和体外脂肪细胞中的表达，目标 2 将阐明 SphK1 的机制 调节脂肪细胞中的 beiging。 这里提出的实验将确定 SphK1 在白色转化中的重要性 脂肪细胞米色及其在体内生热作用中的作用。此外，该提案将确定路径 SphK1 信号通过该信号控制脂肪细胞生热作用。因此，我的研究将揭示两者之间的新联系 SphK1 信号传导和脂肪细胞生热作用，这可能作为潜在的新型治疗靶点 减少肥胖。