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The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis
Misalignment of physiological circadian rhythms promotes obesity which is characterized by white adipose tissue (WAT) expansion. Differentiation of Adipose stem/progenitor cells (ASCs) contributes to WAT increase but the importance of the cellular clock in this process is incompletely understood. In...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9633602/ https://www.ncbi.nlm.nih.gov/pubmed/36329012 http://dx.doi.org/10.1038/s41420-022-01239-3 |
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author | Mandl, Markus Viertler, Hans P. Zopoglou, Maria Mitterberger-Vogt, Maria C. Gasser, Juliane Hatzmann, Florian M. Rauchenwald, Tina Zwierzina, Marit E. Mattesich, Monika Weiss, Alexander K. H. Mottes, Lorenza Brucker, Camille Waldegger, Petra Pierer, Gerhard Zwerschke, Werner |
author_facet | Mandl, Markus Viertler, Hans P. Zopoglou, Maria Mitterberger-Vogt, Maria C. Gasser, Juliane Hatzmann, Florian M. Rauchenwald, Tina Zwierzina, Marit E. Mattesich, Monika Weiss, Alexander K. H. Mottes, Lorenza Brucker, Camille Waldegger, Petra Pierer, Gerhard Zwerschke, Werner |
author_sort | Mandl, Markus |
collection | PubMed |
description | Misalignment of physiological circadian rhythms promotes obesity which is characterized by white adipose tissue (WAT) expansion. Differentiation of Adipose stem/progenitor cells (ASCs) contributes to WAT increase but the importance of the cellular clock in this process is incompletely understood. In the present study, we reveal the role of the circadian transcription factor Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) in human ASCs, isolated from subcutaneous (s)WAT samples of patients undergoing routine elective plastic abdominal surgery. We show that circadian synchronization by serum-shock or stimulation with adipogenic stimuli leads to a different expression pattern of ARNTL2 relative to its well-studied paralogue ARNTL1. We demonstrate that ARNTL2 mRNA is downregulated in ASCs upon weight-loss (WL) whereas ARNTL2 protein is rapidly induced in the course of adipogenic differentiation and highly abundant in adipocytes. ARNTL2 protein is maintained in ASCs cooperatively by mechanistic Target of Rapamycin (mTOR) and Mitogen-activated Protein Kinase (MAPK) signalling pathways while ARNTL2 functions as an inhibitor on both circuits, leading to a feedback mechanism. Consistently, ectopic overexpression of ARNTL2 repressed adipogenesis by facilitating the degradation of ARNTL1, inhibition of Kruppel-Like Factor 15 (KLF15) gene expression and down-regulation of the MAPK-CCAAT/enhancer-binding protein β (C/EBPβ) axis. Western blot analysis of sWAT samples from normal-weight, obese and WL donors revealed that ARNTL2 protein was solely elevated by WL compared to ARNTL1 which underscores unique functions of both transcription factors. In conclusion, our study reveals ARNTL2 to be a WL-regulated inhibitor of adipogenesis which might provide opportunities to develop strategies to ameliorate obesity. |
format | Online Article Text |
id | pubmed-9633602 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96336022022-11-05 The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis Mandl, Markus Viertler, Hans P. Zopoglou, Maria Mitterberger-Vogt, Maria C. Gasser, Juliane Hatzmann, Florian M. Rauchenwald, Tina Zwierzina, Marit E. Mattesich, Monika Weiss, Alexander K. H. Mottes, Lorenza Brucker, Camille Waldegger, Petra Pierer, Gerhard Zwerschke, Werner Cell Death Discov Article Misalignment of physiological circadian rhythms promotes obesity which is characterized by white adipose tissue (WAT) expansion. Differentiation of Adipose stem/progenitor cells (ASCs) contributes to WAT increase but the importance of the cellular clock in this process is incompletely understood. In the present study, we reveal the role of the circadian transcription factor Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) in human ASCs, isolated from subcutaneous (s)WAT samples of patients undergoing routine elective plastic abdominal surgery. We show that circadian synchronization by serum-shock or stimulation with adipogenic stimuli leads to a different expression pattern of ARNTL2 relative to its well-studied paralogue ARNTL1. We demonstrate that ARNTL2 mRNA is downregulated in ASCs upon weight-loss (WL) whereas ARNTL2 protein is rapidly induced in the course of adipogenic differentiation and highly abundant in adipocytes. ARNTL2 protein is maintained in ASCs cooperatively by mechanistic Target of Rapamycin (mTOR) and Mitogen-activated Protein Kinase (MAPK) signalling pathways while ARNTL2 functions as an inhibitor on both circuits, leading to a feedback mechanism. Consistently, ectopic overexpression of ARNTL2 repressed adipogenesis by facilitating the degradation of ARNTL1, inhibition of Kruppel-Like Factor 15 (KLF15) gene expression and down-regulation of the MAPK-CCAAT/enhancer-binding protein β (C/EBPβ) axis. Western blot analysis of sWAT samples from normal-weight, obese and WL donors revealed that ARNTL2 protein was solely elevated by WL compared to ARNTL1 which underscores unique functions of both transcription factors. In conclusion, our study reveals ARNTL2 to be a WL-regulated inhibitor of adipogenesis which might provide opportunities to develop strategies to ameliorate obesity. Nature Publishing Group UK 2022-11-03 /pmc/articles/PMC9633602/ /pubmed/36329012 http://dx.doi.org/10.1038/s41420-022-01239-3 Text en © The Author(s) 2022 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 Mandl, Markus Viertler, Hans P. Zopoglou, Maria Mitterberger-Vogt, Maria C. Gasser, Juliane Hatzmann, Florian M. Rauchenwald, Tina Zwierzina, Marit E. Mattesich, Monika Weiss, Alexander K. H. Mottes, Lorenza Brucker, Camille Waldegger, Petra Pierer, Gerhard Zwerschke, Werner The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
title | The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
title_full | The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
title_fullStr | The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
title_full_unstemmed | The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
title_short | The circadian transcription factor ARNTL2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
title_sort | circadian transcription factor arntl2 is regulated by weight-loss interventions in human white adipose tissue and inhibits adipogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9633602/ https://www.ncbi.nlm.nih.gov/pubmed/36329012 http://dx.doi.org/10.1038/s41420-022-01239-3 |
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