Sex-dependent susceptibility to brain metabolic dysfunction and memory impairment in response to pre and postnatal high-fat diet

•Postweaning HFD-induced peripheral metabolic disorders in adult male rats more than females.•Maternal HFD-induced brain metabolic disorders affect immature male and female offspring equally.•Maternal HFD aggravated brain metabolic disorders and learning and memory impairments in adult male offspring with HFD more than females.•Maternal HFD exacerbated neuronal death and degeneration as a result of synergism with postweaning HFD in male and female offspring. The developing brain is sensitive to the impacts of early-life nutritional intake. This study investigates whether maternal high fat diet (HFD) causes glucose metabolism impairment, neuroinflammation, and memory impairment in immature and adult offspring, and whether it may be affected by postweaning diets in a sex-dependent manner in adult offspring. After weaning, female rats were fed HFD (55.9% fat) or normal chow diet (NCD; 10% fat) for 8 weeks before mating, during pregnancy, and lactation. On postnatal day 21 (PND21), the male and female offspring of both groups were split into two new groups, and NCD or HFD feeding was maintained until PND180. On PND21 and PND180, brain glucose metabolism, inflammation, and Alzheimer's pathology-related markers were by qPCR. In adult offspring, peripheral insulin resistance parameters, spatial memory performance, and brain glucose metabolism (18F-FDG-PET scan and protein levels of IDE and GLUT3) were assessed. Histological analysis was also performed on PND21 and adult offspring. On PND21, we found that maternal HFD affected transcript levels of glucose metabolism markers in both sexes. In adult offspring, more profoundly in males, postweaning HFD in combination with maternal HFD induced peripheral and brain metabolic disturbances, impaired memory performance and elevated inflammation, dementia risk markers, and neuronal loss. Our results suggest that maternal HFD affects brain glucose metabolism in the early ages of both sexes. Postweaning HFD sex-dependently causes brain metabolic dysfunction and memory impairment in later-life offspring; effects that can be worsened in combination with maternal HFD. [Display omitted]