Obesity blocks oligodendrocyte precursor cell differentiation and impedes repair after white matter stroke

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 precursor cells (OPCs), decreased myelin thickness with elevated g-ratios, and shorter paranodal axonal segments, indicating accelerated myelin turnover. Fate mapping of OPCs in PDGFRa-CreERT;Rpl22tm1.1Psam mice demonstrated that OPC differentiation rates are enhanced by obesity. Gene expression analyses using a novel oligodendrocyte staging assay demonstrated OPC differentiation is blocked by obesity in between the pre-myelinating and myelinating stage. 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-pi-positive mature oligodendrocytes in the lesion core. These data indicate that obesity disrupts normal white matter biology by blocking oligodendrocyte differentiation, leads to an exaggerated response of OPCs to white matter ischemia, and limits remyelination after stroke.