Endothelial Notch signaling controls insulin transport in muscle.

Sana S Hasan ,Peter P Nawroth ,Gretchen Wolff ,Stephan Herzig ,Iris Moll ,Markus Jabs ,Lena Wiedmann ,Viola Nordström ,Jacqueline Taylor ,Thomas Fleming ,Giuseppina Federico ,Hermann Josef Gröne ,Thomas Leibing ,Bilgen Ekim-Üstünel ,Fabian Tetzlaff ,Letícia Prates Roma ,Maik Brune ,Christopher Carlein ,Cyrill Géraud ,Andreas Fischer

doi:10.15252/emmm.201809271

Abstract

The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. Endothelial cells (ECs), through expression of a repertoire of angiocrine molecules, regulate metabolic demands in an organ‐specific manner. Insulin flux across the endothelium to muscle cells is a rate‐limiting process influencing insulin‐mediated lowering of blood glucose. Here, we demonstrate that Notch signaling in ECs regulates insulin transport to muscle. Notch signaling activity was higher in ECs isolated from obese mice compared to non‐obese. Sustained Notch signaling in ECs lowered insulin sensitivity and increased blood glucose levels. On the contrary, EC‐specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high‐fat diet‐induced insulin resistance model. This was associated with increased transcription of Cav1, Cav2, and Cavin1, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may therefore represent a therapeutic target for diabetes.

Highlights

The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport
We utilized diet-induced obesity (DIO) mouse models where C57BL/6J male mice were put on high-fat diet (HFD, 60% fat), high-fat-and-sucrose diet (HFS, 60% fat and 42 g/l sucrose in drinking water ad libitum), and a matching control diet (CD, 10% fat) for a period of 26 weeks starting at 4 weeks of age
This study demonstrates an eminent function of the endothelium for the control of systemic glucose homeostasis

Summary

Introduction

The role of the endothelium is not just limited to acting as an inert barrier for facilitating blood transport. EC-specific inhibition of Notch signaling increased insulin sensitivity and improved glucose tolerance and glucose uptake in muscle in a high-fat diet-induced insulin resistance model. This was associated with increased transcription of Cav, Cav, and Cavin, higher number of caveolae in ECs, and insulin uptake rates, as well as increased microvessel density. These data imply that Notch signaling in the endothelium actively controls insulin sensitivity and glucose homeostasis and may represent a therapeutic target for diabetes. We speculated that Notch signaling in ECs could be involved in the control of systemic glucose metabolism

Results

Discussion