Regulation of the endothelial insulin and fatty acid transport

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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 VEGF-B inhibition had some beneficial functions in a mouse model of type 2 diabetes (Hagberg, Nature, 2012).Our unpublished preliminary data sets showed important functions of Notch signaling in endothelial cells for the control of insulin and fatty acid transport from blood to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.