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到损害。血管功能受损会导致严重的并发症。然而，血管壁可以积极地促进全身新陈代谢的控制。内皮细胞在血液和组织之间提供了一种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。虽然这些机制已经很好地理解了，但它们的监管仍然不清楚。最近，有研究表明，细胞因子血管内皮生长因子-B，一种心脏血管生成因子，控制脂肪酸的内皮运输(Hagberg，自然，2010)。抑制血管内皮生长因子-B在2型糖尿病小鼠模型中有一些有益的功能(Hagberg，Natural，2012)。我们未发表的初步数据集显示，内皮细胞中的Notch信号在控制胰岛素和脂肪酸从血液到组织的运输方面具有重要作用。在培养的内皮细胞和特定的小鼠模型中，抑制Notch信号导致依赖小窝蛋白的胰岛素向组织细胞的转运增加。这增加了胰岛素敏感性，降低了血糖水平。然而，这种操作也降低了脂肪酶、脂肪酸转运体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积累。基于这些数据，我们假设内皮中的Notch信号显著有助于控制向组织提供多少脂肪酸的葡萄糖。这很好地符合目前对Notch信号控制新陈代谢的理解。肝细胞中的Notch信号平衡葡萄糖和脂肪酸氧化(Pajvani，自然医学。2011年；帕伊瓦尼，自然医学。而在脂肪细胞中，它控制着向白色或棕色脂肪细胞的分化(Bi.Nature，2014)。在这个项目中，我们将澄清这些问题：i)Notch信号如何机械地控制胰岛素的内皮运输；Notch如何控制脂肪酸在血管内皮细胞的运输；在糖尿病的情况下，Notch信号如何控制这些传输速率。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 VEGF-B inhibition had some beneficial functions in a mouse model of type 2 diabetes (Hagberg, Nature, 2012).Our unpublished preliminary data sets showed important functions of Notch signaling in endothelial cells for the control of insulin and fatty acid transport from blood to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.