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

Author:

Carmo-Silva Sara123ORCID,Ferreira-Marques Marisa124,Nóbrega Clévio156,Botelho Mariana1,Costa Daniela124,Aveleira Célia A123,Pulst Stefan M7,Pereira de Almeida Luís124,Cavadas Claudia124ORCID

Affiliation:

1. CNC-UC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

2. CIBB – Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal

3. MIA – Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal

4. Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

5. ABC-RI, Algarve Biomedical Center Research Institute, Faro, Portugal

6. Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Faro, Portugal

7. Department of Neurology, University of Utah, Salt Lake City, Utah, USA

Abstract

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.

Publisher

Bioscientifica

Subject

Endocrinology,Molecular Biology

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