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Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice

The current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are...

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Autores principales: Efthymiou, Vissarion, Ding, Lianggong, Balaz, Miroslav, Sun, Wenfei, Balazova, Lucia, Straub, Leon G., Dong, Hua, Simon, Eric, Ghosh, Adhideb, Perdikari, Aliki, Keller, Svenja, Ghoshdastider, Umesh, Horvath, Carla, Moser, Caroline, Hamilton, Bradford, Neubauer, Heike, Wolfrum, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344962/
https://www.ncbi.nlm.nih.gov/pubmed/37443109
http://dx.doi.org/10.1038/s41467-023-39715-8
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author Efthymiou, Vissarion
Ding, Lianggong
Balaz, Miroslav
Sun, Wenfei
Balazova, Lucia
Straub, Leon G.
Dong, Hua
Simon, Eric
Ghosh, Adhideb
Perdikari, Aliki
Keller, Svenja
Ghoshdastider, Umesh
Horvath, Carla
Moser, Caroline
Hamilton, Bradford
Neubauer, Heike
Wolfrum, Christian
author_facet Efthymiou, Vissarion
Ding, Lianggong
Balaz, Miroslav
Sun, Wenfei
Balazova, Lucia
Straub, Leon G.
Dong, Hua
Simon, Eric
Ghosh, Adhideb
Perdikari, Aliki
Keller, Svenja
Ghoshdastider, Umesh
Horvath, Carla
Moser, Caroline
Hamilton, Bradford
Neubauer, Heike
Wolfrum, Christian
author_sort Efthymiou, Vissarion
collection PubMed
description The current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are currently available. Here, we identify AXL receptor tyrosine kinase as a regulator of adipose function. Pharmacological and genetic inhibition of AXL enhance thermogenic capacity of brown and white adipocytes, in vitro and in vivo. Mechanistically, these effects are mediated through inhibition of PI3K/AKT/PDE signaling pathway, resulting in induction of nuclear FOXO1 localization and increased intracellular cAMP levels via PDE3/4 inhibition and subsequent stimulation of the PKA-ATF2 pathway. In line with this, both constitutive Axl deletion as well as inducible adipocyte-specific Axl deletion protect animals from diet-induced obesity concomitant with increases in energy expenditure. Based on these data, we propose AXL receptor as a target for the treatment of obesity.
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spelling pubmed-103449622023-07-15 Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice Efthymiou, Vissarion Ding, Lianggong Balaz, Miroslav Sun, Wenfei Balazova, Lucia Straub, Leon G. Dong, Hua Simon, Eric Ghosh, Adhideb Perdikari, Aliki Keller, Svenja Ghoshdastider, Umesh Horvath, Carla Moser, Caroline Hamilton, Bradford Neubauer, Heike Wolfrum, Christian Nat Commun Article The current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are currently available. Here, we identify AXL receptor tyrosine kinase as a regulator of adipose function. Pharmacological and genetic inhibition of AXL enhance thermogenic capacity of brown and white adipocytes, in vitro and in vivo. Mechanistically, these effects are mediated through inhibition of PI3K/AKT/PDE signaling pathway, resulting in induction of nuclear FOXO1 localization and increased intracellular cAMP levels via PDE3/4 inhibition and subsequent stimulation of the PKA-ATF2 pathway. In line with this, both constitutive Axl deletion as well as inducible adipocyte-specific Axl deletion protect animals from diet-induced obesity concomitant with increases in energy expenditure. Based on these data, we propose AXL receptor as a target for the treatment of obesity. Nature Publishing Group UK 2023-07-13 /pmc/articles/PMC10344962/ /pubmed/37443109 http://dx.doi.org/10.1038/s41467-023-39715-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Efthymiou, Vissarion
Ding, Lianggong
Balaz, Miroslav
Sun, Wenfei
Balazova, Lucia
Straub, Leon G.
Dong, Hua
Simon, Eric
Ghosh, Adhideb
Perdikari, Aliki
Keller, Svenja
Ghoshdastider, Umesh
Horvath, Carla
Moser, Caroline
Hamilton, Bradford
Neubauer, Heike
Wolfrum, Christian
Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
title Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
title_full Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
title_fullStr Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
title_full_unstemmed Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
title_short Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
title_sort inhibition of axl receptor tyrosine kinase enhances brown adipose tissue functionality in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344962/
https://www.ncbi.nlm.nih.gov/pubmed/37443109
http://dx.doi.org/10.1038/s41467-023-39715-8
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