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Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and activity

Arianna Fozzato, Lauryn E. New, Joanne C. Griffiths, Bianca Patel, Susan A. Deuchars, View ORCID ProfileBeatrice M. Filippi
doi: https://doi.org/10.1101/2023.01.04.522581
Arianna Fozzato
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, (UK)
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Lauryn E. New
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, (UK)
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Joanne C. Griffiths
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, (UK)
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Bianca Patel
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, (UK)
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Susan A. Deuchars
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, (UK)
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Beatrice M. Filippi
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, (UK)
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  • ORCID record for Beatrice M. Filippi
  • For correspondence: b.m.filippi@leeds.ac.uk
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Abstract

Objectives Brown adipose tissue (BAT) is a potent thermogenic organ, activated by the central nervous system (CNS) through direct noradrenergic sympathetic innervation. Dysregulation of signalling modules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT activity.

Methods Eight-week-old male Sprague Dawley rats received DVC stereotactic surgery to facilitate brain infusion for local administration of viruses that express mutated Drp1 genes. PET/CT scans were used to measure BAT glucose uptake using. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT.

Results We show that short-term HFD-feeding decreases the ability of BAT to uptake glucose and decreases catecholaminergic innervation of BAT, observed by altered intensities and pools of Tyrosine Hydroxylase (TH) labelling. HFD also increased the infiltration of enlarged white fat droplets in the BAT. We demonstrate that inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats can prevent the effects on BAT morphology and neural innervation, and increase BAT glucose uptake while lowering blood glucose and insulin levels. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduces BAT glucose uptake, TH and β3-adrenergic receptor levels.

Conclusions Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase energy expenditure and protect from developing obesity and diabetes.

Figure

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 04, 2023.
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Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and activity
Arianna Fozzato, Lauryn E. New, Joanne C. Griffiths, Bianca Patel, Susan A. Deuchars, Beatrice M. Filippi
bioRxiv 2023.01.04.522581; doi: https://doi.org/10.1101/2023.01.04.522581
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Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and activity
Arianna Fozzato, Lauryn E. New, Joanne C. Griffiths, Bianca Patel, Susan A. Deuchars, Beatrice M. Filippi
bioRxiv 2023.01.04.522581; doi: https://doi.org/10.1101/2023.01.04.522581

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