The Importance of the Batf3/Irf4 Pathway in Growth Hormone and Inflammation Mediated Metabolic Changes in Adipose Tissue

Batf3/Irf4 通路在生长激素和炎症介导的脂肪组织代谢变化中的重要性

基本信息

批准号：
10271275
负责人：
Armen I Yerevanian
金额：
$ 7.71万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2022-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10271275
关键词：
3T3-L1 Cells Address Adipocytes Adipose tissue Affect Agonist Anabolism Antigen Presentation Automobile Driving Body Composition Cell Line Cell physiology Cells Cellular biology Clustered Regularly Interspaced Short Palindromic Repeats Colony-Stimulating Factors Cytokine Activation Cytokine Receptors Cytokine Signaling Cytotoxic T-Lymphocytes Data Dendritic Cells Development Epidemic Family Fat Body Fatty acid glycerol esters Foundations Gene Expression Genes Genetic Transcription Goals Growth Growth Hormone Receptor Growth and Development function Hand Hormones Host Defense IRF4 gene Immune Immune response Immune signaling In Vitro Inflammation Inflammatory Infrastructure Insulin Resistance Insulin-Like Growth Factor I Interferons Interleukin-2 Interleukin-6 Interleukins Janus kinase Knock-out Knockout Mice Knowledge Leptin Leukocytes Link Lipolysis Lipopolysaccharides Mammals Mediating Mediator of activation protein Messenger RNA Metabolic Metabolic hormone Metabolism Mitochondria Mus Nuclear Translocation Obesity Pathway interactions Physiology Pituitary Gland Pituitary Hormones Production Proteins Regulator Genes Respiration Response Elements Role STAT protein Signal Pathway Signal Transduction Signaling Molecule Somatotropin Starvation System T cell differentiation Thermogenesis Time Training Transcript Transcriptional Activation Transcriptional Regulation Up-Regulation Visceral Work bZIP Domain base biological adaptation to stress blastomere structure career development common cellular transcription factor ATF cytokine experimental study functional genomics hormonal signals in vivo insight insulin signaling lipid metabolism loss of function metabolic abnormality assessment metabolic phenotype morphogens new therapeutic target novel therapeutics pathogen peptide hormone receptor respiratory response transcription factor

项目摘要

The growth hormone receptor (GHR) is part of a highly conserved set of receptors known as the type I cytokine family. GHR is homologous to many receptors involved in inflammation and host defense including the interleukin-2, interleukin-6 and colony stimulating family of receptors. They share many downstream signaling mechanisms including the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) mechanism of inducing transcriptional regulation of target genes. Growth hormone (GH), a pituitary-derived hormone best known for its role in growth and development, also serves important metabolic functions including mediating lipolysis in adipose tissue during periods of starvation. The precise mechanism by which the JAK/ STAT pathway activation promotes lipolysis in response to GH has yet to be elucidated. Our preliminary data has shown that growth hormone stimulation of adipose tissue leads to the transcriptional upregulation of the basic leucine zipper transcription factor ATF-like 3 (Batf3) gene. This gene is a known response element in the promotion of dendritic cell development and cytotoxic T-cell function in response to pathogens. It is also known to associate with interferon regulatory factors, such as interferon regulatory factor 4 (Irf4) as heterodimers to promote proliferative gene expression in context of inflammatory signals. Recent work has also shown that Irf4 is a key transcription factor in adipose tissue that drives thermogenesis and lipolysis. We have identified that Irf4 transcripts are also induced during GH stimulation. We hypothesize that the Batf3/Irf4 signaling mechanism is conserved in the growth hormone pathway and is important in driving lipolysis, altering mitochondrial respiration and affecting IGF-1/insulin signaling. We will address our hypothesis by performing functional genomics on adipose tissue both in vivo and in vitro. The metabolic consequences of Batf3 and Irf4 induction will be examined by disrupting these genes in adipocytes using CRISPR-based approaches and adipocyte-specific knockout mice. We will examine adipose tissue for lipolytic capacity, body composition and respiratory dynamics to determine the metabolic importance of the Batf3/Irf4 system in adipose tissue under both growth hormone and lipopolysaccharide (LPS) signaling. The goal of these studies is to prove the importance of evolutionarily conserved inflammatory signaling cascades in altering metabolism.

生长激素受体 (GHR) 是一组高度保守的受体（称为 I 型细胞因子）的一部分家庭。 GHR 与许多参与炎症和宿主防御的受体同源，包括白细胞介素 2、白细胞介素 6 和集落刺激受体家族。它们共享许多下游信号机制包括 Janus 激酶 (JAK)/信号转导器和转录激活子 (STAT) 诱导靶基因转录调控的机制。生长激素（GH），一种垂体衍生的激素激素以其在生长和发育中的作用而闻名，还具有重要的代谢功能，包括在饥饿期间介导脂肪组织中的脂肪分解。 JAK/的精确机制 STAT 通路激活促进 GH 响应的脂肪分解尚未阐明。我们的初步数据研究表明，生长激素对脂肪组织的刺激会导致脂肪组织的转录上调碱性亮氨酸拉链转录因子 ATF 样 3 (Batf3) 基因。该基因是已知的反应元件促进树突状细胞发育和细胞毒性 T 细胞功能以应对病原体。据了解，还与干扰素调节因子相关，例如作为异二聚体的干扰素调节因子 4 (Irf4) 在炎症信号背景下促进增殖基因表达。最近的工作还表明 Irf4 是脂肪组织中驱动产热和脂肪分解的关键转录因子。我们已经确定 Irf4 GH 刺激期间也会诱导转录。我们假设 Batf3/Irf4 信号传导机制是在生长激素途径中保守，对于驱动脂肪分解、改变线粒体呼吸很重要并影响 IGF-1/胰岛素信号传导。我们将通过进行功能基因组学来解决我们的假设体内和体外的脂肪组织。将检查 Batf3 和 Irf4 诱导的代谢后果通过使用基于 CRISPR 的方法和脂肪细胞特异性敲除小鼠来破坏脂肪细胞中的这些基因。我们将检查脂肪组织的脂解能力、身体成分和呼吸动力学，以确定 Batf3/Irf4 系统在生长激素和生长激素作用下脂肪组织中代谢的重要性脂多糖（LPS）信号传导。这些研究的目的是证明进化论的重要性保守的炎症信号级联改变代谢。