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Lipolysis regulates major transcriptional programs in brown adipocytes
β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activ...
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/PMC9270495/ https://www.ncbi.nlm.nih.gov/pubmed/35803907 http://dx.doi.org/10.1038/s41467-022-31525-8 |
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author | Markussen, Lasse K. Rondini, Elizabeth A. Johansen, Olivia Sveidahl Madsen, Jesper G. S. Sustarsic, Elahu G. Marcher, Ann-Britt Hansen, Jacob B. Gerhart-Hines, Zachary Granneman, James G. Mandrup, Susanne |
author_facet | Markussen, Lasse K. Rondini, Elizabeth A. Johansen, Olivia Sveidahl Madsen, Jesper G. S. Sustarsic, Elahu G. Marcher, Ann-Britt Hansen, Jacob B. Gerhart-Hines, Zachary Granneman, James G. Mandrup, Susanne |
author_sort | Markussen, Lasse K. |
collection | PubMed |
description | β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in cultured brown adipocytes. Here we show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, however, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on transcription and function of cultured brown adipocytes. |
format | Online Article Text |
id | pubmed-9270495 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92704952022-07-10 Lipolysis regulates major transcriptional programs in brown adipocytes Markussen, Lasse K. Rondini, Elizabeth A. Johansen, Olivia Sveidahl Madsen, Jesper G. S. Sustarsic, Elahu G. Marcher, Ann-Britt Hansen, Jacob B. Gerhart-Hines, Zachary Granneman, James G. Mandrup, Susanne Nat Commun Article β-Adrenergic signaling is a core regulator of brown adipocyte function stimulating both lipolysis and transcription of thermogenic genes, thereby expanding the capacity for oxidative metabolism. We have used pharmacological inhibitors and a direct activator of lipolysis to acutely modulate the activity of lipases, thereby enabling us to uncover lipolysis-dependent signaling pathways downstream of β-adrenergic signaling in cultured brown adipocytes. Here we show that induction of lipolysis leads to acute induction of several gene programs and is required for transcriptional regulation by β-adrenergic signals. Using machine-learning algorithms to infer causal transcription factors, we show that PPARs are key mediators of lipolysis-induced activation of genes involved in lipid metabolism and thermogenesis. Importantly, however, lipolysis also activates the unfolded protein response and regulates the core circadian transcriptional machinery independently of PPARs. Our results demonstrate that lipolysis generates important metabolic signals that exert profound pleiotropic effects on transcription and function of cultured brown adipocytes. Nature Publishing Group UK 2022-07-08 /pmc/articles/PMC9270495/ /pubmed/35803907 http://dx.doi.org/10.1038/s41467-022-31525-8 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 Markussen, Lasse K. Rondini, Elizabeth A. Johansen, Olivia Sveidahl Madsen, Jesper G. S. Sustarsic, Elahu G. Marcher, Ann-Britt Hansen, Jacob B. Gerhart-Hines, Zachary Granneman, James G. Mandrup, Susanne Lipolysis regulates major transcriptional programs in brown adipocytes |
title | Lipolysis regulates major transcriptional programs in brown adipocytes |
title_full | Lipolysis regulates major transcriptional programs in brown adipocytes |
title_fullStr | Lipolysis regulates major transcriptional programs in brown adipocytes |
title_full_unstemmed | Lipolysis regulates major transcriptional programs in brown adipocytes |
title_short | Lipolysis regulates major transcriptional programs in brown adipocytes |
title_sort | lipolysis regulates major transcriptional programs in brown adipocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270495/ https://www.ncbi.nlm.nih.gov/pubmed/35803907 http://dx.doi.org/10.1038/s41467-022-31525-8 |
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