TY - JOUR
T1 - Endothelial Notch signaling controls insulin transport in muscle
AU - Hasan, Sana S.
AU - Jabs, Markus
AU - Taylor, Jacqueline
AU - Wiedmann, Lena
AU - Leibing, Thomas
AU - Nordström, Viola
AU - Federico, Giuseppina
AU - Roma, Leticia P.
AU - Carlein, Christopher
AU - Wolff, Gretchen
AU - Ekim-Üstünel, Bilgen
AU - Brune, Maik
AU - Moll, Iris
AU - Tetzlaff, Fabian
AU - Gröne, Hermann Josef
AU - Fleming, Thomas
AU - Géraud, Cyrill
AU - Herzig, Stephan
AU - Nawroth, Peter P.
AU - Fischer, Andreas
N1 - Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2020/4/7
Y1 - 2020/4/7
N2 - 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.
AB - 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.
KW - Notch signaling
KW - caveolae
KW - endothelial cell
KW - insulin transport
KW - muscle
UR - http://www.scopus.com/inward/record.url?scp=85081980950&partnerID=8YFLogxK
U2 - 10.15252/emmm.201809271
DO - 10.15252/emmm.201809271
M3 - Article
C2 - 32187826
AN - SCOPUS:85081980950
SN - 1757-4676
VL - 12
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
M1 - e09271
ER -