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Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity

Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In t...

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Autores principales: Wang, Xiao-Lan, Kooijman, Sander, Gao, Yuanqing, Tzeplaeff, Laura, Cosquer, Brigitte, Milanova, Irina, Wolff, Samantha E. C., Korpel, Nikita, Champy, Marie-France, Petit-Demoulière, Benoit, Goncalves Da Cruz, Isabelle, Sorg-Guss, Tania, Rensen, Patrick C. N., Cassel, Jean-Christophe, Kalsbeek, Andries, Boutillier, Anne-Laurence, Yi, Chun-Xia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760060/
https://www.ncbi.nlm.nih.gov/pubmed/34050326
http://dx.doi.org/10.1038/s41380-021-01169-z
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author Wang, Xiao-Lan
Kooijman, Sander
Gao, Yuanqing
Tzeplaeff, Laura
Cosquer, Brigitte
Milanova, Irina
Wolff, Samantha E. C.
Korpel, Nikita
Champy, Marie-France
Petit-Demoulière, Benoit
Goncalves Da Cruz, Isabelle
Sorg-Guss, Tania
Rensen, Patrick C. N.
Cassel, Jean-Christophe
Kalsbeek, Andries
Boutillier, Anne-Laurence
Yi, Chun-Xia
author_facet Wang, Xiao-Lan
Kooijman, Sander
Gao, Yuanqing
Tzeplaeff, Laura
Cosquer, Brigitte
Milanova, Irina
Wolff, Samantha E. C.
Korpel, Nikita
Champy, Marie-France
Petit-Demoulière, Benoit
Goncalves Da Cruz, Isabelle
Sorg-Guss, Tania
Rensen, Patrick C. N.
Cassel, Jean-Christophe
Kalsbeek, Andries
Boutillier, Anne-Laurence
Yi, Chun-Xia
author_sort Wang, Xiao-Lan
collection PubMed
description Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.
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spelling pubmed-87600602022-01-26 Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity Wang, Xiao-Lan Kooijman, Sander Gao, Yuanqing Tzeplaeff, Laura Cosquer, Brigitte Milanova, Irina Wolff, Samantha E. C. Korpel, Nikita Champy, Marie-France Petit-Demoulière, Benoit Goncalves Da Cruz, Isabelle Sorg-Guss, Tania Rensen, Patrick C. N. Cassel, Jean-Christophe Kalsbeek, Andries Boutillier, Anne-Laurence Yi, Chun-Xia Mol Psychiatry Article Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease. Nature Publishing Group UK 2021-05-28 2021 /pmc/articles/PMC8760060/ /pubmed/34050326 http://dx.doi.org/10.1038/s41380-021-01169-z Text en © The Author(s) 2021 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
Wang, Xiao-Lan
Kooijman, Sander
Gao, Yuanqing
Tzeplaeff, Laura
Cosquer, Brigitte
Milanova, Irina
Wolff, Samantha E. C.
Korpel, Nikita
Champy, Marie-France
Petit-Demoulière, Benoit
Goncalves Da Cruz, Isabelle
Sorg-Guss, Tania
Rensen, Patrick C. N.
Cassel, Jean-Christophe
Kalsbeek, Andries
Boutillier, Anne-Laurence
Yi, Chun-Xia
Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
title Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
title_full Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
title_fullStr Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
title_full_unstemmed Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
title_short Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
title_sort microglia-specific knock-down of bmal1 improves memory and protects mice from high fat diet-induced obesity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760060/
https://www.ncbi.nlm.nih.gov/pubmed/34050326
http://dx.doi.org/10.1038/s41380-021-01169-z
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