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A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

Adélaïde A. Mohr, Alba M. Garcia-Serrano, João P.P. Vieira, Cecilia Skoug, Henrik Davidsson, View ORCID ProfileJoão M.N. Duarte
doi: https://doi.org/10.1101/2020.03.21.001149
Adélaïde A. Mohr
1Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
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Alba M. Garcia-Serrano
1Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
2Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
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João P.P. Vieira
1Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
2Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
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Cecilia Skoug
1Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
2Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
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Henrik Davidsson
1Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
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João M.N. Duarte
1Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
2Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
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  • ORCID record for João M.N. Duarte
  • For correspondence: joao.duarte@med.lu.se
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Abstract

The hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders. While mouse models have been extensively employed for understanding mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and high-sucrose diet (HFHSD) for 7 days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.

Footnotes

  • Abbreviations

    AgRP
    agouti-related peptide
    AMPK
    AMP-activated protein kinase
    ARC
    arcuate nucleus
    BOLD
    blood oxygen level-dependent
    CART
    cocaine and amphetamine regulated transcript
    CREB
    cAMP response element-binding protein
    DMN
    dorsomedial nucleus
    fMRI
    functional magnetic resonance imaging
    FOV
    field of view
    LH
    lateral hypothalamus
    MC4R
    melanocortin 4 receptor
    NPY
    neuropeptide Y
    POMC
    pro-opiomelanocortin
    PVN
    paraventricular nucleus
    T2D
    type 2 diabetes
    TE
    echo time
    TR
    repetition time
    VMN
    ventromedial nucleus
    VOI
    volume of interest.
  • Copyright 
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    Posted March 24, 2020.
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    A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet
    Adélaïde A. Mohr, Alba M. Garcia-Serrano, João P.P. Vieira, Cecilia Skoug, Henrik Davidsson, João M.N. Duarte
    bioRxiv 2020.03.21.001149; doi: https://doi.org/10.1101/2020.03.21.001149
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    A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet
    Adélaïde A. Mohr, Alba M. Garcia-Serrano, João P.P. Vieira, Cecilia Skoug, Henrik Davidsson, João M.N. Duarte
    bioRxiv 2020.03.21.001149; doi: https://doi.org/10.1101/2020.03.21.001149

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