Two human brain systems micro-structurally associated with obesity

  1. Manfred G Kitzbichler
  2. Daniel Martins
  3. Richard AI Bethlehem
  4. Richard Dear
  5. Rafael Romero-Garcia
  6. Varun Warrier
  7. Jakob Seidlitz
  8. Ottavia Dipasquale
  9. Federico Turkheimer
  10. Mara Cercignani
  11. Edward T Bullmore
  12. Neil A Harrison  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. King's College London, United Kingdom
  3. University of Pennsylvania, United States
  4. Cardiff University, United Kingdom

Abstract

The relationship between obesity and human brain structure is incompletely understood. Using diffusion-weighted MRI from í30,000 UK Biobank participants we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal-temporalstriatal system associated with ISOVF and a medial temporal-occipital-striatal system associated with ICVF. The ISOVF~WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF~WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0:026, P = 0:36) and ICVF (rg = 0:112, P < 9 x 10*4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (p<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation.

Data availability

Data were provided by the UK Biobank (application IDs 20904 & 48943).Source code can be found on GitHub under https://github.com/ucam-department-of-psychiatry/UKB

The following previously published data sets were used

Article and author information

Author details

  1. Manfred G Kitzbichler

    Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4494-0753
  2. Daniel Martins

    Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0239-8206
  3. Richard AI Bethlehem

    Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0714-0685
  4. Richard Dear

    Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Rafael Romero-Garcia

    Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Varun Warrier

    Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Jakob Seidlitz

    Lifespan Brain Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ottavia Dipasquale

    Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Federico Turkheimer

    Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Mara Cercignani

    Brain Research Imaging Centre, Cardiff University, Cardiff, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4550-2456
  11. Edward T Bullmore

    Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Neil A Harrison

    Brain Research Imaging Centre, Cardiff University, Cardiff, United Kingdom
    For correspondence
    harrisonn4@cardiff.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9584-3769

Funding

Wellcome Trust (104025/Z/14/Z)

  • Manfred G Kitzbichler
  • Federico Turkheimer
  • Mara Cercignani
  • Neil A Harrison

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Susie Y Huang, Massachusetts General Hospital, United States

Version history

  1. Received: November 26, 2022
  2. Preprint posted: November 27, 2022 (view preprint)
  3. Accepted: October 5, 2023
  4. Accepted Manuscript published: October 20, 2023 (version 1)
  5. Version of Record published: November 30, 2023 (version 2)

Copyright

© 2023, Kitzbichler et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Manfred G Kitzbichler
  2. Daniel Martins
  3. Richard AI Bethlehem
  4. Richard Dear
  5. Rafael Romero-Garcia
  6. Varun Warrier
  7. Jakob Seidlitz
  8. Ottavia Dipasquale
  9. Federico Turkheimer
  10. Mara Cercignani
  11. Edward T Bullmore
  12. Neil A Harrison
(2023)
Two human brain systems micro-structurally associated with obesity
eLife 12:e85175.
https://doi.org/10.7554/eLife.85175

Share this article

https://doi.org/10.7554/eLife.85175

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