TY - JOUR T1 - Obesity restricts oligodendrocyte maturation and impedes repair after white matter stroke JF - bioRxiv DO - 10.1101/283184 SP - 283184 AU - Guanxi Xiao AU - Jasmine Burguet AU - Riki Kawaguchi AU - Leif A. Havton AU - Jason D. Hinman Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/05/21/283184.abstract N2 - Obesity is a growing public health problem that increases rates of white matter atrophy and increases the likelihood of ischemic lesions within white matter. However, the cellular and molecular mechanisms that regulate these changes are unknown. We hypothesized that obesity may alter oligodendrocytes and myelin priming white matter for worsening injury and repair responses after ischemia. C57Bl/6 mice fed a high fat diet (60% kcal from fat) show increased numbers of oligodendrocyte progenitor cells (OPCs), decreased myelin thickness with elevated g-ratios, and shorter paranodal axonal segments, indicating compromised myelination in high fat diet mice. Fate mapping of OPCs in PDGFRα-CreERT;Rpl22tm1.1Psam mice demonstrated that OPC differentiation rates are enhanced by obesity. Gene expression analyses using a novel oligodendrocyte staging assay demonstrated that obesity restricts oligodendrocyte maturation in between the pre-myelinating and myelinating stages. Using a model of subcortical white matter stroke, the number of stroke-responsive OPCs in obese mice was increased after stroke. At early time points after ischemic white matter stroke, spatial mapping of stroke-responsive OPCs indicates that obesity leads to increased OPCs at the edge of ischemic white matter lesions. At later time points, obesity results in increased OPCs within the ischemic lesion while reducing the number of GST-π-positive mature oligodendrocytes in the lesion core. These data indicate that obesity disrupts normal white matter biology by impeding oligodendrocyte differentiation, leading to an exaggerated response of OPCs to white matter ischemia, and limited brain repair after stroke. ER -