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; 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 肥胖是美国的健康危机，影响成人和儿童，并导致许多逆境 健康结果。因此，治疗肥胖症的新颖方法具有强烈的兴趣。棕色和米色 脂肪组织一直是许多最近与肥胖有关的研究的重点。棕色和米色脂肪细胞有一个 高线粒体含量和脂肪酸氧化得到了增强。此外，因为这些组织表达 解偶联蛋白1（UCP1），脂肪酸代谢的大部分能量因热而损失。尽管 人类中棕色脂肪的存在是有争议的，最近的研究集中在此过程上 白色脂肪细胞转化为米色，热脂肪细胞，因为如果可以故意此过程 受调节会导致脂肪组织减少，因此构成了对物体性的潜在治疗方法。 该建议旨在阐明鞘氨醇激酶的新功能1。β₃肾上腺素接收器 刺激会促进白色脂肪细胞转化为米色（“存在”）。我的初步数据表明体内 用Cl 316243（Cl）刺激β₃肾上腺素受体会增加UCP1和SPHK1 mRNA。更进一步 这些结果在体外概括，其中β₃肾上腺素受体刺激显示了白色WT脂肪细胞的刺激 SPHK1和UCP1 mRNA表达增加，在SPHK1缺乏的白色脂肪细胞中减弱。 此外，SPHK1无效脂肪细胞无法诱导PGC1α和PGC1β，这两个都是共激活因子 UCP1的转录因子（热生成驱动力）的转录因子。基于这些初步数据，我假设 SPHK1介导的白脂肪细胞变成导致线粒体解偶联的白色脂肪细胞，导致脂肪组织 热发生。该项目分为两个目标，以实现这一目标。 AIM 1将调查 脂肪细胞中的SPHK1成为体内和体外，AIM 2将阐明SPHK1的机制 调节脂肪细胞。 这里提出的实验将确定SPHK1在白色转化中的重要性 脂肪细胞至米色及其在体内生热发生中的作用。此外，该建议将确定路径 通过该通过该SPHK1信号控制脂肪细胞的热发生。因此，我的研究将揭示 SPHK1信号传导和脂肪细胞生成发生，然后可以作为潜在的新型热目标 减少财产。