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

摘要 心脏现在被认为是调节全身脂质稳态的重要器官； 然而，我们对分子基础的了解仍然有限。最近有研究表明，无翼(Wg) 心脏中的信号控制着全身的脂质平衡。然而，心脏Wg信号如何控制这一点 进程未知。在果蝇的基因筛查中，我们发现蜗牛转录家族 因子(SNA、TF)在心脏中起作用，调节全身的脂类代谢。我们的初步结果还显示 心脏中的Wg信号激活了SNA转录因子的心脏表达。这些发现引导我们 假设心脏中的Wg-SNA Tf轴以系统的方式调节脂质稳态。这 假设将在目标1中得到验证。基于我们之前对苍蝇血淋巴(血液)的蛋白质组学分析，我们 进一步发现一种含有硫酯的可溶性蛋白2(Tep2)，这是一种以前分泌的蛋白质 未知参与脂质代谢，通过SNA信号在心脏上调，并分泌到 发行量。我们进一步的初步数据显示，Tep2突变改变了全身的血脂水平，而且两者都 SNA Tf和Tep2调控脂肪体中的转化生长因子信号，其中转化生长因子被认为与脂质有关 新陈代谢。因此，我们假设Tep2从心脏分泌到循环是一种功能 Wg-SNA轴通过调节脂肪体内转化生长因子途径调节系统脂平衡。这 假说将在目标2中得到验证。此外，我们发现高脂饮食(HFD)会导致心脏 Wg和SNA转录因子的表达。根据我们的初步观察，SNA转录因子的激活减少 全身性血脂水平，我们假设心脏WgSNA Tf-Tep2轴对高脂血症的诱导具有保护作用 肥胖。这一假设将在目标3中得到检验。总之，这一提议将揭示对心脏的新见解 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 治疗人类肥胖症及其并发症。

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.