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Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice

Disruption of the circadian cycle is strongly associated with metabolic imbalance and reduced longevity in humans. Also, rodent models of circadian arrhythmia, such as the constitutive knockout of the clock gene Bmal1, leads to metabolic disturbances and early death. Although astrocyte clock regulat...

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Autores principales: Barca‐Mayo, Olga, Boender, Arjen J., Armirotti, Andrea, De Pietri Tonelli, Davide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496695/
https://www.ncbi.nlm.nih.gov/pubmed/31833591
http://dx.doi.org/10.1002/glia.23764
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author Barca‐Mayo, Olga
Boender, Arjen J.
Armirotti, Andrea
De Pietri Tonelli, Davide
author_facet Barca‐Mayo, Olga
Boender, Arjen J.
Armirotti, Andrea
De Pietri Tonelli, Davide
author_sort Barca‐Mayo, Olga
collection PubMed
description Disruption of the circadian cycle is strongly associated with metabolic imbalance and reduced longevity in humans. Also, rodent models of circadian arrhythmia, such as the constitutive knockout of the clock gene Bmal1, leads to metabolic disturbances and early death. Although astrocyte clock regulates molecular and behavioral circadian rhythms, its involvement in the regulation of energy balance and lifespan is unknown. Here, we show that astrocyte‐specific deletion of Bmal1 is sufficient to alter energy balance, glucose homeostasis, and reduce lifespan. Mutant animals displayed impaired hypothalamic molecular clock, age‐dependent astrogliosis, apoptosis of hypothalamic astrocytes, and increased glutamate and GABA levels. Importantly, modulation of GABAA‐receptor signaling completely restored glutamate levels, delayed the reactive gliosis as well as the metabolic phenotypes and expanded the lifespan of the mutants. Our results demonstrate that the astrocytic clock can influence many aspects of brain function and neurological disease and suggest astrocytes and GABAA receptor as pharmacological targets to prevent the metabolic dysfunctions and shortened lifespan associated with alterations of circadian rhythms.
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spelling pubmed-74966952020-09-25 Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice Barca‐Mayo, Olga Boender, Arjen J. Armirotti, Andrea De Pietri Tonelli, Davide Glia Research Articles Disruption of the circadian cycle is strongly associated with metabolic imbalance and reduced longevity in humans. Also, rodent models of circadian arrhythmia, such as the constitutive knockout of the clock gene Bmal1, leads to metabolic disturbances and early death. Although astrocyte clock regulates molecular and behavioral circadian rhythms, its involvement in the regulation of energy balance and lifespan is unknown. Here, we show that astrocyte‐specific deletion of Bmal1 is sufficient to alter energy balance, glucose homeostasis, and reduce lifespan. Mutant animals displayed impaired hypothalamic molecular clock, age‐dependent astrogliosis, apoptosis of hypothalamic astrocytes, and increased glutamate and GABA levels. Importantly, modulation of GABAA‐receptor signaling completely restored glutamate levels, delayed the reactive gliosis as well as the metabolic phenotypes and expanded the lifespan of the mutants. Our results demonstrate that the astrocytic clock can influence many aspects of brain function and neurological disease and suggest astrocytes and GABAA receptor as pharmacological targets to prevent the metabolic dysfunctions and shortened lifespan associated with alterations of circadian rhythms. John Wiley & Sons, Inc. 2019-12-13 2020-06 /pmc/articles/PMC7496695/ /pubmed/31833591 http://dx.doi.org/10.1002/glia.23764 Text en © 2019 The Authors. GLIA published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Barca‐Mayo, Olga
Boender, Arjen J.
Armirotti, Andrea
De Pietri Tonelli, Davide
Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice
title Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice
title_full Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice
title_fullStr Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice
title_full_unstemmed Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice
title_short Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice
title_sort deletion of astrocytic bmal1 results in metabolic imbalance and shorter lifespan in mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496695/
https://www.ncbi.nlm.nih.gov/pubmed/31833591
http://dx.doi.org/10.1002/glia.23764
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