Regulation of the endothelial insulin and fatty acid transport

到目前为止，血管通常被认为是被动结构，在糖尿病等代谢性疾病的过程中受损。血管功能受损则会导致严重的并发症。然而，血管壁可以积极地促进全身代谢的控制。内皮在血液和组织之间提供器官特异性的选择性屏障。它阻止胰岛素、葡萄糖、脂肪酸和氨基酸的自由扩散，但提供跨细胞转运机制。虽然人们对这些机制有了很好的了解，但其管理方式仍然不明。最近，显示细胞因子VEGF-B（一种心脏血管生成因子）控制脂肪酸的内皮转运（Hagberg，Nature，2010）。VEGF-B抑制在2型糖尿病的小鼠模型中具有一些有益的功能（Hagberg，Nature，2012）我们未发表的初步数据集显示了Notch信号传导在内皮细胞中对于控制胰岛素和脂肪酸从血液到组织的转运的重要功能。在培养的内皮细胞和特定的小鼠模型中抑制Notch信号传导导致胰岛素向组织细胞的小窝蛋白依赖性转运增加。这增加了胰岛素敏感性并降低了血糖水平。然而，这种操作也降低了脂肪酶，脂肪酸转运蛋白和结合蛋白的表达水平或活性，导致血浆中三酰甘油浓度增加和肝脏中的积累。基于这些数据，我们假设Notch信号在内皮细胞显着有助于控制多少葡萄糖或脂肪酸提供给组织。这与目前对Notch信号传导控制代谢的理解非常吻合。肝细胞中的Notch信号传导平衡葡萄糖和脂肪酸氧化（Pajvani，Nature Med.2011; Pajvani，Nature Med.2013），而在脂肪细胞中，它控制分化成白色或棕色脂肪细胞（Bi，Nature，2014）。Notch信号传导如何机械地控制胰岛素的内皮转运; ii.）Notch如何控制脂肪酸跨内皮转运; iii.）Notch信号是如何在糖尿病条件下控制这些转运速率的。通过这个项目，我们将首次阐明内皮细胞中的Notch信号如何平衡葡萄糖和脂肪酸的供应，以及Notch信号的抑制如何影响小鼠模型中的1型和2型糖尿病。

Up to now blood vessels are often regarded as passive structures that get damaged in the course of metabolic diseases like diabetes mellitus. Impaired vascular function contributes then to severe complications. However, the blood vessel wall can actively contribute to the control of systemic metabolism. The endothelium provides an organ-specific, selective barrier between blood and tissue. It prevents free diffusion of insulin, glucose, fatty acids, and amino acids, but provides transcellular transport mechanisms. While those mechanisms are well understood, their regulation remains unidentified. Recently, it was shown the cytokine VEGF-B, a cardiac angiogenesis factor, controls endothelial transport of fatty acids (Hagberg, Nature, 2010). VEGF-B inhibition had some beneficial functions in a mouse model of type 2 diabetes (Hagberg, Nature, 2012).Our unpublished preliminary data sets showed important functions of Notch signaling in endothelial cells for the control of insulin and fatty acid transport from blood to tissue. Inhibition of Notch signaling in cultured endothelial cells and in a specific mouse model caused increased caveolin-dependent transport of insulin towards tissue cells. This increased insulin sensitivity and lowered blood glucose levels. However, this manipulation also lowered expression levels or activity of lipases, fatty acid transporters and binding proteins causing increased concentration of triacylglycerol in plasma and accumulation in liver.Based on these data we hypothesize that Notch signaling in the endothelium significantly contributes to the control how much glucose of fatty acids are provided to the tissue. This fits well to the current understanding of Notch signaling for the control of metabolism. Notch signaling in hepatocytes balances glucose and fatty acid oxidation (Pajvani, Nature Med. 2011; Pajvani, Nature Med. 2013), while in adipocytes it controls differentiation into white or brown fat cells (Bi, Nature, 2014).In this project we will clarify these questions: i.) How does Notch signaling mechanistically control endothelial transport of insulin; ii.) how does Notch control fatty acid transport across the endothelium; iii.) how does Notch signaling control these transport rates under diabetic conditions. With this project we will clarify for the first time how Notch signals in the endothelium balance the supply of glucose and fatty acid and how the inhibition of Notch signaling affects type 1 and type 2 diabetes in mouse models.