METABOLIC AND COGNITIVE EFFECTS OF HIGH FAT DIET IN MALE AND FEMALE MICE

Abstract

Diabetes causes vascular dysfunction and is a major risk factor for vascular cognitive impairment including dementia (VCID). Diabetic women have increased risk of VCID compared to diabetic men. Data on the effects of prediabetes, which is 3 times more prevalent than diabetes, are lacking. Prediabetes can be modeled in mice via long-term administration of a high fat (HF) diet, which causes glucose intolerance. Therefore, we examined the effect of HF diet on cognitive function in middle-aged male and female mice. In addition, half of the mice were also subjected to unilateral carotid artery occlusion surgery, which causes chronic cerebral hypoperfusion and models VCID. We hypothesized that high fat diet/prediabetes would lead to more adverse metabolic and cognitive effects in middle-aged females compared to males in a mouse model of VCID. Middle-aged (8.5 month old) male and female C57BL/6J mice were placed on a HF or control diet for 6 months. At month 3, they received either VCID or sham surgery. Body weight and glucose tolerance were monitored. After 6 months on the diet, cognitive function was assessed through novel object recognition, object place recognition, and Morris water maze. Finally, blood flow was measured via laser speckle contrast imaging and brains were collected for histology. HF diet caused a greater increase in body weight and greater impairment in glucose tolerance in females than males after 3 months; however, there were no sex differences in glucose tolerance by the 6 month mark. Middle-aged mice showed impaired object recognition, regardless of sex, diet, or surgery. Spatial recognition was impaired by either HF diet, VCID surgery (or a combination of the two), regardless of sex. Spatial memory was impaired in VCID males, regardless of diet; however, in females, both HF diet and VCID (or a combination of the two) impairs spatial memory. These data indicate that chronic cerebral hypoperfusion impairs spatial recognition and spatial memory in both sexes. Further, similar to the effects of diabetes on VCID risk observed clinically, prediabetes also appears to increase cognitive deficits to a greater extent in aged females than males.