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：
10589797
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/10589797
关键词：
Affect Biological Models Biology Blood Cardiac Circulation Communication Data Diet Disease 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 Organ Pathway interactions Phenocopy Process Protein Secretion Proteins Proteomics Regulation Research Signal Transduction Snails Source System Testing Therapeutic Tissues Transforming Growth Factor beta Triglycerides 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.

抽象的心脏现在被认为是调节全身脂质稳态的重要器官；然而，我们对 Wingless (Wg) 分子基础的了解仍然有限。心脏中的信号传导控制全身脂质稳态，但是心脏 Wg 信号传导如何控制这一点。在果蝇的遗传筛选中，我们发现 Snail 家族的转录过程尚不清楚。我们的初步结果还表明，Sna TF 在心脏中发挥作用，调节全身脂质代谢。心脏中的 Wg 信号激活 Sna TF 的心脏表达。这些发现使我们得出以下结论。认为心脏中的 Wg-Sna TF 轴以系统方式调节脂质稳态。假设将在目标 1 中得到检验。基于我们之前对果蝇血淋巴（血液）的蛋白质组学分析，我们进一步发现了一种可溶性蛋白硫酯蛋白2（Tep2），这是一种先前的分泌蛋白未知参与脂质代谢，在心脏中通过 Sna 信号传导上调并分泌到我们进一步的初步数据表明，Tep2 突变会改变全身脂质水平，并且两者都会改变。 Sna TF 和 Tep2 控制脂肪体内的 TGF 信号传导，其中 TGF 已知与脂质有关因此，我们认为 Tep2 从心脏分泌到循环中作为一种功能性代谢。 Wg-Sna 轴的效应器通过调节脂肪体内的 TGF 途径来调节脂质系统稳态。假设将在目标 2 中得到检验。此外，我们发现高脂肪饮食 (HFD) 会诱发心脏病 Wg 和 Sna TF 的表达基于我们的初步观察，Sna TF 的激活减少。全身脂质水平，我们追求心脏 Wg-Sna TF-Tep2 轴可以防止 HFD 诱导的这一假设将在目标 3 中得到检验。该提议将共同揭示对心脏的新见解。控制正常脂质系统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。