Hypothalamus Amyloid Levels Are Associated with Early Sex-Dependent Alterations in Peripheral Energy Homeostasis in...

We reported previously that diet-induced obesity exacerbates early-stage Alzheimer's disease (AD)-like pathology in TgF344-AD rats. Those findings also suggested that they may be prone to weight gain during early AD development, raising the possibility of early hypothalamic dysfunction. In this study, we investigate this by determining whether hypothalamic soluble amyloid-β₄₀ (Aβ₄₀) and amyloid-β₄₂ (Aβ₄₂) are detectable during early AD development in TgF344-AD rats and whether their presence is associated with alterations in energy homeostasis. Energy intake, body composition, whole body glucose clearance, body temperature rhythms, interscapular brown adipose tissue (iBAT) mass, and iBAT expression of the thermogenic uncoupling protein 1 (UCP1) were assessed. The results demonstrate that Aβ₄₀ and Aβ₄₂ are detectable in the hypothalamus during the early stages of AD development and that hypothalamic but not cortical Aβ₄₂ is associated with impaired glucose regulation in males and iBAT mass in females. Male TgF344-AD rats became heavier than wild-type (WT) littermates by 5 weeks of age, with a similar increase emerging later in females (~ 5 months). Female TgF344-AD rats consumed more chow and a high-fat high-sugar (HFHS) diet, gained more weight on that diet, and showed reduced UCP1, effects not seen in males. Both sexes exhibited elevated body temperatures. This increase was restricted to the dark phase in females, coinciding with excess caloric intake. Finally, HFHS feeding impaired glucose regulation in male but not female TgF344-AD rats. These findings suggest hypothalamic Aβ₄₂ may contribute to sex-specific disruptions in peripheral energy homeostasis that may be an early symptom of AD development.