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

• 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
• 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

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.

摘要 心脏被认为是调节全身脂质平衡的重要器官; 然而，我们对分子基础的了解仍然有限。无翼（Wingless，Wg） 心脏中的信号传导控制全身脂质稳态。然而，心脏Wg信号传导如何控制这一点， 过程未知。在果蝇的基因筛选中，我们发现转录的Snail家族 这些因子（Sna TF）在心脏中起作用以调节全身脂质代谢。我们的初步结果还显示 心脏中的Wg信号激活了Sna TF的心脏表达。这些发现使我们 假设心脏中的Wg-Sna TF轴以系统方式调节脂质稳态。这 假设将在目标1中得到检验。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，可溶性蛋白含硫酯蛋白2（Tep 2），一种先前分泌的蛋白， 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 流通我们进一步的初步数据表明，Tep 2突变改变了全身脂质水平， Sna TF和Tep 2控制脂肪体中的TGF β信号传导，其中已知TGF β与脂质代谢有关。 新陈代谢.因此，我们假设从心脏分泌到循环的Tep 2作为一种功能性调节因子， Wg-Sna轴通过调节脂肪体中TGF β通路调节全身脂质稳态效应子。这 假设将在目标2中得到检验。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的激活减少， 我们假设心脏Wg β Sna TF-Tep 2轴保护HFD诱导的 肥胖目标3将检验这一假设。总之，这一建议将揭示新的见解， 控制正常的全身脂质稳态，并提供可能有助于指导未来治疗的知识 人类肥胖症及其并发症的研究。