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

生长激素受体(GHR)是一组高度保守的受体的一部分，称为I型细胞因子 一家人。生长激素受体与许多参与炎症和宿主防御的受体同源，包括 白介素2、白介素6和集落刺激受体家族。它们共享许多下行信令 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)，一种脑下垂体来源的激素 荷尔蒙以其在生长和发育中的作用而闻名，它还具有重要的代谢功能，包括 在饥饿期间调节脂肪组织中的脂肪分解。JAK/的精确机制 STAT通路的激活促进了对GH的脂解反应，目前尚不清楚。我们的初步数据 研究表明，生长激素对脂肪组织的刺激导致转录上调 碱性亮氨酸拉链转录因子ATF-like 3(BATF3)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细胞功能以应对病原体。它也是众所周知的 与干扰素调节因子相关联，如干扰素调节因子4(IRF4)作为异源二聚体 在炎症信号的背景下促进增殖基因的表达。最近的研究还表明，IRF4 是脂肪组织中的关键转录因子，驱动产热和脂肪分解。我们已经确定了IRF4 转录本也在生长激素刺激过程中被诱导。我们假设BATF3/IRF4信号机制是 在生长激素途径中保守，在驱动脂肪分解、改变线粒体呼吸方面很重要 并影响IGF-1/胰岛素信号转导。我们将通过执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。BATF3和IRF4诱导的代谢后果将被检测 通过使用基于CRISPR的方法和脂肪细胞特异性基因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肪分解能力、身体成分和呼吸动力学，以确定 生长激素和胰岛素样生长因子共同作用下BATF3/IRF4系统在脂肪组织中的代谢重要性 脂多糖(LPS)信号转导。这些研究的目标是证明进化的重要性 保守的炎症信号在改变新陈代谢的过程中级联。

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.