A cardiac Wingless-Snail-Tep2 axis directs normal lipid homeostasis and protects against diet-induced obesity

心脏 Wingless-Snail-Tep2 轴指导正常的脂质稳态并防止饮食引起的肥胖

基本信息

批准号：
10371186
负责人：
Hui-Ying Lim
金额：
$ 36.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371186
关键词：
Affect Biological Models Biology Blood Blood Circulation Cardiac Communication Data Diet Drosophila genus Dyslipidemias Energy Metabolism Family Fat Body Future Genetic Epistasis Genetic Screening Heart Hemolymph High Fat Diet Homeostasis Human Impairment Knowledge Link Lipids Maintenance Mediating Messenger RNA Metabolic Metabolic Diseases Metabolism Modeling Molecular Mutation Myocardial dysfunction Obesity Obesity associated disease Organ Pathway interactions Phenocopy Process Proteins Proteomics Regulation Research Signal Transduction Snails Source Sum System Testing Therapeutic Tissues Transforming Growth Factor beta Triglycerides base comorbidity diet-induced obesity fly genetic manipulation insight knock-down lipid biosynthesis lipid metabolism novel novel therapeutic intervention overexpression protective effect public health relevance thioester transcription factor

项目摘要

Abstract The heart is now recognized as an important organ in the regulation of systemic lipid homeostasis; however, our understanding of the molecular basis remains limited. It was recently shown that Wingless (Wg) signaling in the heart controls systemic lipid homeostasis. However, how cardiac Wg signaling controls this process is unknown. In a genetic screen in Drosophila, we discovered that the Snail family of transcription factors (Sna TFs) act in the heart to regulate systemic lipid metabolism. Our preliminary results also showed that Wg signaling in the heart activates the cardiac expression of Sna TFs. These findings led us to hypothesize that a Wg-Sna TF axis in the heart regulates lipid homeostasis in a systemic manner. This hypothesis will be tested in Aim 1. Building on our previous proteomic analysis of fly hemolymph (blood), we further discovered that a soluble protein thioester-containing protein 2 (Tep2), a secreted protein previously unknown to be involved in lipid metabolism, is up-regulated in the heart by Sna signaling and secreted to the circulation. Our further preliminary data showed that Tep2 mutation alters systemic lipid levels and that both Sna TF and Tep2 control TGF signaling in the fat body, in which TGF is known to be implicated in lipid metabolism. We therefore hypothesize that Tep2 secreted from heart to circulation serves as a functional effector of Wg-Sna axis in regulating systemic lipid homeostasis by modulating TGF pathway in fat body. This hypothesis will be tested in Aim 2. Furthermore, we found that high fat diet (HFD) induces the cardiac expression of Wg and Sna TFs. Based on our preliminary observation that activation of Sna TFs decreases systemic lipid levels, we hypothesize that a cardiac WgSna TF–Tep2 axis protects against HFD-induced obesity. This hypothesis will be tested in Aim 3. Together, this proposal will reveal novel insights into the heart control of normal systemic lipid homeostasis and provide knowledge that may help guide future therapeutics for human obesity and its comorbidities.

抽象的现在，心脏被认为是系统性脂质稳态调节的重要器官。但是，我们对分子基础的理解仍然有限。最近显示无翼（WG）心脏中的信号控制系统性脂质稳态。但是，心脏WG信号如何控制此过程未知。在果蝇的遗传屏幕中，我们发现了蜗牛转录家族因素（SNA TF）在心脏中起作用，以调节系统性脂质代谢。我们的初步结果也显示了心脏中的WG信号传导激活了SNA TF的心脏表达。这些发现导致我们假设心脏中的WG-SNA TF轴以系统的方式调节脂质稳态。这假设将在AIM 1中进行检验。基于我们先前对苍蝇血淋巴（血液）的蛋白质组学分析，我们进一步发现含有固体蛋白硫酯的蛋白2（TEP2），一种分泌的蛋白 SNA信号在心脏中涉及脂质代谢的未知数未知，并分泌给圆圈。我们进一步的初步数据表明，Tep2突变改变了系统性脂质水平，并且都会改变脂肪体中的SNA TF和TEP2控制TGF信号传导，其中tgf在脂质中隐含代谢。因此，我们假设从心脏到循环分泌的TEP2用作功能 WG-SNA轴在调节系统性脂质体内稳态中的效应子，通过调节脂肪体中的TGF途径。这假设将在AIM 2中进行检验。此外，我们发现高脂饮食（HFD）诱导心脏 WG和SNA TF的表达。根据我们的初步观察，SNA TF的激活下降了系统性脂质水平，我们假设心脏WGSNATF – TEP2轴可预防HFD诱导的肥胖。该假设将在AIM 3中进行检验。该提议将揭示对心脏的新见解控制正常的全身性脂质稳态，并提供可能有助于指导未来治疗的知识用于人类肥胖及其合并症。