Effects of high‐fat diet on nutrient metabolism and cognitive functions in young APPKI(NL‐G‐F/NL‐G‐F) mice

AIM: Type 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer’s disease (AD); however, the relationship between the 2 conditions is controversial. High‐fat diet (HFD) causes cognitive impairment with/without Aβ accumulation in middle‐aged or aged transgenic (Tg) and knock‐in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life has an impact on nutrient metabolism and neurological phenotypes in young AD mouse models is not known. In the present study, we examined the effects of HFD on young APPKI(NL‐G‐F/NL‐G‐F) mice, one of the novel KI‐AD mouse models. METHODS: The mice were categorized by diet into 2 experimental groups, normal diet (ND) and HFD. Four‐week‐old wild‐type (WT) and APPKI(NL‐G‐F/NL‐G‐F) mice were fed ND or HFD for 9 weeks. Both types of mice on ND and HFD were examined during young adulthood. RESULTS: HFD caused T2DM‐related metabolic disturbances in both young WT and APPKI(NL‐G‐F/NL‐G‐F) mice, whereas impaired thermoregulation and shortage of alternative energy sources specifically occurred in young APPKI(NL‐G‐F/NL‐G‐F) mice. However, HFD had no impact on the cognitive function, Aβ levels, and phosphorylation of hippocampal insulin receptor substrate 1 (IRS1) at all the 3 Ser sites in both types of mice. CONCLUSION: HFD is effective in causing metabolic disturbances in young WT and APPKI(NL‐G‐F/NL‐G‐F) mice but is ineffective in inducing neurological disorders in both types of mice, suggesting that the aging effects, along with long‐term HFD, facilitate neurological alterations.