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: 9706410
• 负责人: Patrick Seale
• 金额: $ 7.54万
• 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/9706410
• 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; 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; recruit; 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.

概括 肥胖是美国慢性病和过早死亡的主要原因。减少肥胖的一个有希望的途径 肥胖和相关疾病是通过增加棕色和米色能量燃烧的活性来实现的 脂肪细胞。除了促进脂肪减少外，棕色脂肪细胞还具有消耗大量脂肪的能力 脂质和葡萄糖，从而减少它们在许多组织中的毒性作用。 PRDM16，锌指转录 该因子在调节棕色和米色脂肪细胞分化中起着关键作用。我们最近发现， 除了驱动棕色脂肪选择性基因程序外，PRDM16 还能强有力地抑制转录 脂肪细胞和组织中对先天免疫 1 型干扰素 (IFN) 信号的反应。此外，我们发现 主要与病毒感染相关的 1 型 IFN 信号在脂肪组织中通过以下方式升高： 高脂肪饮食和 1 型干扰素激活会抑制脂肪细胞中的线粒体功能。这些激动人心的 研究结果使我们推测 PRDM16 介导的 1 型 IFN 信号传导抑制保留了 正常生理条件下棕色脂肪的产热功能。然而，我们推测 高脂肪饮食引起的 1 型干扰素信号持续增加导致棕色人种线粒体功能障碍 脂肪，从而显着促进全身代谢疾病的发展。在这个项目中， 我们将研究 PRDM16 阻断脂肪细胞中 IFN 反应的机制并确定 1 型干扰素在驱动高脂肪饮食引起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 PRDM16 被招募到 IFN 应答基因的机制，并研究 PRDM16 如何 在染色质中发挥作用，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 PRDM16 和 1 型 IFN 信号在调节棕色脂肪中相互作用的遗传模型 功能。在目标 3 中，我们将确定是否可以阻断脂肪中与高脂肪饮食相关的 1 型 IFN 反应 用于减少代谢性疾病。总而言之，这些研究将定义 PRDM16 和 1 型的新作用 调节脂肪生物学和全身代谢的干扰素信号传导。