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

• 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
• 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

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的一部分，被称为I型细胞因子 家人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）/信号转导和转录激活因子（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 激素以其在生长和发育中的作用而闻名，也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解。JAK/ STAT通路激活促进响应于GH的脂解尚未阐明。我们的初步数据 已经表明，生长激素刺激脂肪组织导致转录上调， 碱性亮氨酸拉链转录因子ATF样3（Batf 3）基因。该基因是一种已知的反应元件， 促进树突状细胞发育和细胞毒性T细胞功能以响应病原体。另据了解 与干扰素调节因子如干扰素调节因子4（Irf 4）结合为异二聚体， 促进炎症信号背景下的增殖基因表达。最近的研究还表明，Irf 4 是脂肪组织中驱动产热和脂解的关键转录因子。我们已经确定Irf 4 在GH刺激期间也诱导转录物。我们假设Batf 3/Irf 4信号传导机制是 在生长激素途径中是保守的，在驱动脂解、改变线粒体呼吸中是重要的 并影响IGF-1/胰岛素信号传导。我们将通过对以下动物进行功能基因组学研究来解决我们的假设： 在体内和体外的脂肪组织中。将检查Batf 3和Irf 4诱导的代谢结果 通过使用基于CRISPR的方法和脂肪细胞特异性敲除小鼠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 Batf 3/Irf 4系统在脂肪组织中的代谢重要性， 脂多糖（LPS）信号转导。这些研究的目的是证明进化的重要性 保守的炎症信号级联改变代谢。