Control of adipose function through a PRDM16/Type 1 Interferon Axis

通过 PRDM16/1 型干扰素轴控制脂肪功能

• 批准号: 9339658
• 负责人: Patrick Seale
• 金额: $ 42.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339658
• 关键词: Adipocytes; Adipose tissue; Animals; Automobile Driving; Binding; Bioenergetics; Biological Assay; Biology; Brown Fat; Cell Culture Techniques; Cell Respiration; Cessation of life; Chromatin; Chronic Disease; Complex; DNA Binding; Deposition; Depressed mood; Development; Distress; FAT gene; Fatty acid glycerol esters; Genes; Genetic Models; Genetic Transcription; Glucose; Goals; Heart Diseases; High Fat Diet; Histones; Human; IFNAR1 gene; IRF1 gene; Immune; Insulin Resistance; Interferon Activation; Interferon Receptor; Interferons; Knock-out; Link; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Methylation; Mitochondria; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Pathway interactions; Physiological; Play; Public Health; Recruitment Activity; Reporter Genes; Role; Signal Transduction; Skeletal Muscle; System; Testing; Tissues; Toxic Actions; Virus Diseases; Weight Gain; Work; Zinc Fingers; adipocyte differentiation; cell type; chromatin immunoprecipitation; feeding; genome editing; in vivo; loss of function; mitochondrial dysfunction; mutant; neutralizing antibody; novel; overexpression; premature; prevent; programs; promoter; response; transcription factor

Summary Obesity is a leading cause of chronic illness and premature death in the U.S. A promising avenue to reduce obesity and associated diseases is through increasing the activity of energy-burning brown and beige adipocytes. In addition to promoting fat loss, brown fat cells have the capacity to consume large amounts of lipid and glucose and thereby reduce their toxic actions in many tissues. PRDM16, a zinc-finger transcription factor plays a critical role in regulating brown and beige adipocyte differentiation. We recently discovered that, in addition to driving a brown fat-selective gene program, PRDM16 powerfully suppresses transcriptional responses to innate immune type 1 Interferon (IFN) signaling in adipose cells and tissues. Moreover, we found that Type 1 IFN signaling, which is primarily associated with viral infection, is elevated in adipose tissues by high fat diet and that type 1 IFN activation represses mitochondrial function in adipocytes. These exciting findings led us to hypothesize that PRDM16-mediated suppression of Type 1 IFN-signaling preserves the thermogenic function of brown fat under normal physiological conditions. However, we speculate that persistent increases in type 1 IFN signaling caused by high fat diet leads to mitochondrial dysfunction in brown fat and, in doing so, contributes significantly to the development of systemic metabolic disease. In this project, we will investigate the mechanisms by which PRDM16 blocks the IFN-response in adipose cells and determine the role of type 1 IFN in driving high fat diet-induced weight gain and systemic insulin resistance. In aim 1, we will determine the mechanism by which PRDM16 is recruited to IFN-responsive genes and study how PRDM16 functions in chromatin to repress the transcription of these genes. In aim 2, we will use cell culture and in vivo genetic models to examine the interaction between PRDM16 and type 1 IFN-signaling in regulating brown fat function. In Aim 3, we will determine if blocking high fat diet-linked type 1 IFN-responses in adipose could be used to reduce metabolic disease. Altogether, these studies will define a novel role for PRDM16 and type 1 IFN signaling in regulating adipose biology and systemic metabolism.

总结 在美国，肥胖是慢性病和过早死亡的主要原因。 肥胖和相关疾病是通过增加活动的能量燃烧棕色和米色 脂肪细胞除了促进脂肪损失，棕色脂肪细胞有能力消耗大量的脂肪， 从而减少它们在许多组织中的毒性作用。PRDM 16，锌指转录 因子在调节褐色和米色脂肪细胞分化中起关键作用。我们最近发现， 除了驱动棕色脂肪选择性基因程序外，PRDM 16还能有效抑制 在脂肪细胞和组织中对先天免疫1型干扰素（IFN）信号传导的应答。此外，我们发现， 主要与病毒感染相关的1型IFN信号传导在脂肪组织中升高， 高脂饮食和1型IFN活化抑制脂肪细胞中线粒体功能。这些令人兴奋 这些发现使我们假设PRDM 16介导的1型IFN信号转导抑制保留了IFN-γ的表达。 正常生理条件下棕色脂肪的产热功能。然而，我们推测， 高脂饮食引起的1型IFN信号持续增加导致棕色人种线粒体功能障碍 脂肪，并在这样做，有助于显着的发展，全身性代谢疾病。在本项目中， 我们将研究PRDM 16阻断脂肪细胞中IFN应答的机制，并确定 1型干扰素在驱动高脂饮食诱导的体重增加和全身胰岛素抵抗中的作用。在目标1中，我们 将确定PRDM 16被招募到IFN应答基因的机制，并研究PRDM 16是如何 在染色质中起作用以抑制这些基因的转录。在目标2中，我们将使用细胞培养和体内 研究PRDM 16和1型IFN信号在调节棕色脂肪中的相互作用的遗传模型 功能在目标3中，我们将确定阻断脂肪中高脂饮食相关的1型IFN-γ应答是否可以 用于减少代谢疾病。总之，这些研究将确定PRDM 16和1型糖尿病的新作用。 IFN信号在调节脂肪生物学和全身代谢中的作用。