High-fat feeding has sex-dependent effects on the structure and biomechanical properties of cerebral parenchymal arterioles and cognitive function.

One-third of dementia cases could be prevented by correcting modifiable risk factors, including obesity caused by consuming a high-fat (HF) diet consumption. Dementia is associated with white matter injury, which is associated with impaired cerebral parenchymal arteriole (PA) function. Yet, the impact of HF feeding on PAs remains understudied. We tested the hypothesis that HF feeding would result in structural and biomechanical remodeling of the PAs from male and female rats. We also proposed that HF feeding would impair endothelium-dependent dilation and that these changes would be associated with cognitive decline and neuroinflammation. Three-week-old male and female Sprague-Dawley rats were fed a control or HF diet for 20-24 wk. HF feeding increased body weight and blood pressure in both sexes but caused hyperglycemia only in females. Pial artery blood flow was unchanged by HF feeding in both sexes. The PAs from HF-fed females exhibited inward remodeling; PAs from males were not remodeled but were less distensible. Endothelial function and myogenic tone generation in the PAs were not impacted by HF feeding in either sex. The changes observed in the males were associated with impaired spatial memory and reduced cerebral myelin basic protein expression. HF feeding increased the number of microglia in both sexes, but soma size was only increased in the males. These data suggest that HF feeding impairs cognitive function in males, which is associated with increased stiffness in PAs and increased microglial hypertrophy, whereas HF-fed females remain cognitively normal despite exhibiting significant PA remodeling. Female rats fed a high-fat diet exhibited inward remodeling of the cerebral parenchymal arterioles; this structural change did not impact cerebral blood flow or cognition. In males, parenchymal arterioles from high-fat fed rats were less distensible; this biomechanical change was associated with cognitive decline and neuroinflammation but not cerebral hypoperfusion. Endothelial function was not impacted by high-fat feeding in either sex. These studies suggest that the pathophysiology of obesity-associated dementia differs between the sexes.