Ataxin-2 in the hypothalamus at the crossroads between metabolism and clock genes

in Journal of Molecular Endocrinology
Authors:
Sara Carmo-SilvaCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
MIA – Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal

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Marisa Ferreira-MarquesCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

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Clévio NóbregaCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
ABC-RI, Algarve Biomedical Center Research Institute, Faro, Portugal
Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Faro, Portugal

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Mariana BotelhoCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

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Daniela CostaCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

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Célia A AveleiraCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
MIA – Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal

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Stefan M PulstDepartment of Neurology, University of Utah, Salt Lake City, Utah, USA

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Luís Pereira de AlmeidaCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

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Claudia CavadasCNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

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Correspondence should be addressed to C Cavadas: ccavadas@uc.pt
DOI:
https://doi.org/10.1530/JME-21-0272
Volume/Issue:
Volume 70: Issue 1
Article Type:
Research Article
Article ID:
e210272
Online Publication Date:
07 Dec 2022
Copyright:
© Society for Endocrinology 2022
Restricted access

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ATXN2 gene, encoding for ataxin-2, is located in a trait locus for obesity. Atxn2 knockout (KO) mice are obese and insulin resistant; however, the cause for this phenotype is still unknown. Moreover, several findings suggest ataxin-2 as a metabolic regulator, but the role of this protein in the hypothalamus was never studied before. The aim of this work was to understand if ataxin-2 modulation in the hypothalamus could play a role in metabolic regulation. Ataxin-2 was overexpressed/re-established in the hypothalamus of C57Bl6/Atxn2 KO mice fed either a chow or a high-fat diet (HFD). This delivery was achieved through stereotaxic injection of lentiviral vectors encoding for ataxin-2. We show, for the first time, that HFD decreases ataxin-2 levels in mouse hypothalamus and liver. Specific hypothalamic ataxin-2 overexpression prevents HFD-induced obesity and insulin resistance. Ataxin-2 re-establishment in Atxn2 KO mice improved metabolic dysfunction without changing body weight. Furthermore, we observed altered clock gene expression in Atxn2 KO that might be causative of metabolic dysfunction. Interestingly, ataxin-2 hypothalamic re-establishment rescued these circadian alterations. Thus, ataxin-2 in the hypothalamus is a determinant for weight, insulin sensitivity and clock gene expression. Ataxin-2’s potential role in the circadian clock, through the regulation of clock genes, might be a relevant mechanism to regulate metabolism. Overall, this work shows hypothalamic ataxin-2 as a new player in metabolism regulation, which might contribute to the development of new strategies for metabolic disorders.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© Society for Endocrinology 2022
Article ID:
e210272
Article Type:
Research Article
Received Date:
30 Jul 2022
Accepted Date:
14 Sep 2022
Print Publication Date:
01 Jan 2023
Online Publication Date:
07 Dec 2022
Keywords:
ataxin-2; hypothalamus; obesity; inflammation; clock genes

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