Two differentiated brain systems micro-structurally associated with obesity Manfred G Kitzbichler 1 , Daniel Martins 2 , Richard AI Bethlehem 1 , Richard Dear 1 , Rafael Romero-Garcia 1,3 , Varun Warrier 1,4 , Jakob Seidlitz 5,6,7 , Ottavia Dipasquale 2 , Federico Turkheimer 2 , Mara Cercignani 8 , Edward T Bullmore 1† , Neil A Harrison 8† *For correspondence: HarrisonN4@cardiff.ac.uk (NAH) † These authors contributed equally to this work 1 Department of Psychiatry, University of Cambridge, UK; 2 King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK; 3 Department of Medical Physiology and Biophysics, Instituto de Biomedicina de Sevilla (IBiS) HUVR/CSIC Universidad de Sevilla/CIBERSAM, ISCIII, Sevilla, Spain; 4 Department of Psychology, University of Cambridge, UK; 5 Lifespan Brain Institute, The Children’s Hospital of Philadelphia and Penn Medicine, Philadelphia, PA, USA; 6 Department of Child and Adolescent Psychiatry and Behavioral Science, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 7 Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; 8 Cardiff University Brain Research Imaging Centre, Cardiff University, UK Abstract The relationship between obesity and brain structure is incompletely understood. Using diffusion-weighted MRI from ∼33,000 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-temporal- striatal 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, we estimated the genetic correlations between WHR and ISOVF (r g =0.026, P =0.36) and ICVF (r g =0.112, P< 9 × 10 -4 ). 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. Key words: NODDI - BMI - GWAS - WHR - UK Biobank Introduction Obesity has long been recognised as a preventable risk factor for cardiovascular and metabolic disorders such as heart disease and type-2 diabetes. More recently, it has also emerged as an important risk factor for neurodegenerative disorders, linked to both an increased risk of dementia and accelerated age-associated cognitive decline (Sellbom and Gunstad, 2012). Defined as the excessive accumulation of adipose tissue in the body (González-Muniesa et al., 2017), the 1 of 28 . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted November 27, 2022. ; https://doi.org/10.1101/2022.11.25.517981 doi: bioRxiv preprint