Endothelial Notch signaling controls insulin transport in muscle
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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809271 |
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| author | Sana S Hasan Markus Jabs Jacqueline Taylor Lena Wiedmann Thomas Leibing Viola Nordström Giuseppina Federico Leticia P Roma Christopher Carlein Gretchen Wolff Bilgen Ekim‐Üstünel Maik Brune Iris Moll Fabian Tetzlaff Hermann‐Josef Gröne Thomas Fleming Cyrill Géraud Stephan Herzig Peter P Nawroth Andreas Fischer |
| author_facet | Sana S Hasan Markus Jabs Jacqueline Taylor Lena Wiedmann Thomas Leibing Viola Nordström Giuseppina Federico Leticia P Roma Christopher Carlein Gretchen Wolff Bilgen Ekim‐Üstünel Maik Brune Iris Moll Fabian Tetzlaff Hermann‐Josef Gröne Thomas Fleming Cyrill Géraud Stephan Herzig Peter P Nawroth Andreas Fischer |
| author_sort | Sana S Hasan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1ed45c1818f945c4851ba741b9225b1a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-1ed45c1818f945c4851ba741b9225b1a2025-08-24T11:44:08ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-03-0112411710.15252/emmm.201809271Endothelial Notch signaling controls insulin transport in muscleSana S Hasan0Markus Jabs1Jacqueline Taylor2Lena Wiedmann3Thomas Leibing4Viola Nordström5Giuseppina Federico6Leticia P Roma7Christopher Carlein8Gretchen Wolff9Bilgen Ekim‐Üstünel10Maik Brune11Iris Moll12Fabian Tetzlaff13Hermann‐Josef Gröne14Thomas Fleming15Cyrill Géraud16Stephan Herzig17Peter P Nawroth18Andreas Fischer19Division Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)Division Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)Division Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)Division Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg UniversityDivision of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ)Division of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ)Biophysics Department, Center for Human and Molecular Biology (ZHMB), Saarland UniversityBiophysics Department, Center for Human and Molecular Biology (ZHMB), Saarland UniversityInstitute for Diabetes and Cancer (IDC) and Joint Heidelberg‐IDC Translational Diabetes Program, Helmholtz Center MunichInstitute for Diabetes and Cancer (IDC) and Joint Heidelberg‐IDC Translational Diabetes Program, Helmholtz Center MunichDepartment of Medicine I and Clinical Chemistry, University Hospital of HeidelbergDivision Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)Division Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)Division of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ)Department of Medicine I and Clinical Chemistry, University Hospital of HeidelbergDepartment of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg UniversityInstitute for Diabetes and Cancer (IDC) and Joint Heidelberg‐IDC Translational Diabetes Program, Helmholtz Center MunichInstitute for Diabetes and Cancer (IDC) and Joint Heidelberg‐IDC Translational Diabetes Program, Helmholtz Center MunichDivision Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ)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.https://doi.org/10.15252/emmm.201809271caveolaeendothelial cellinsulin transportmuscleNotch signaling |
| spellingShingle | Sana S Hasan Markus Jabs Jacqueline Taylor Lena Wiedmann Thomas Leibing Viola Nordström Giuseppina Federico Leticia P Roma Christopher Carlein Gretchen Wolff Bilgen Ekim‐Üstünel Maik Brune Iris Moll Fabian Tetzlaff Hermann‐Josef Gröne Thomas Fleming Cyrill Géraud Stephan Herzig Peter P Nawroth Andreas Fischer Endothelial Notch signaling controls insulin transport in muscle EMBO Molecular Medicine caveolae endothelial cell insulin transport muscle Notch signaling |
| title | Endothelial Notch signaling controls insulin transport in muscle |
| title_full | Endothelial Notch signaling controls insulin transport in muscle |
| title_fullStr | Endothelial Notch signaling controls insulin transport in muscle |
| title_full_unstemmed | Endothelial Notch signaling controls insulin transport in muscle |
| title_short | Endothelial Notch signaling controls insulin transport in muscle |
| title_sort | endothelial notch signaling controls insulin transport in muscle |
| topic | caveolae endothelial cell insulin transport muscle Notch signaling |
| url | https://doi.org/10.15252/emmm.201809271 |
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