Reduced Oligodendrocyte Density and Axonal Caliber Associated With Mitochondrial Alterations in the White Matter of Chronically‐Starved Mice

OBJECTIVE: Anorexia nervosa (AN) is a severe eating disorder associated with extreme weight loss, hyperactivity, and amenorrhea. Neuroimaging studies revealed brain atrophy and disruption of white matter integrity in the corpus callosum (CC) of patients with AN. However, the underlying pathophysiological mechanisms remain unclear. Emerging evidence indicates that starvation induces changes in mitochondrial metabolism and dynamics. We hypothesize that disturbances in white matter integrity arise from modifications in oligodendrocytes, associated with changes in the morphology of myelinated fibers and mitochondrial structure. METHOD: The starvation-induced hyperactivity (SIH) model was used, in which mice received a restricted daily amount of food in combination with free access to a running wheel. A body weight loss of 25% was maintained over 2 weeks, followed by a 3-week refeeding phase. Oligodendrocyte density and staining intensity of oligodendrocyte lineage transcription factor 2 (OLIG2) in the CC were analyzed using immunohistochemical staining. Morphometric investigation of myelinated fibers and mitochondria was conducted by transmission electron microscopy (TEM) analysis. RESULTS: Starvation led to decreased oligodendrocyte density and reduced anti-OLIG2 staining intensity in the CC, which was reversible following refeeding. Additionally, starvation induced a decrease in axonal caliber and an increase in mitochondrial density in the white matter, accompanied by a reduction of mitochondrial area. DISCUSSION: The findings suggest that oligodendroglial and axonal alterations, alongside disrupted mitochondrial dynamics, impair structural integrity in the white matter and contribute to the pathophysiology of AN.