VULNERABILITY OF LATERAL HYPOTHALAMIC NEUROTENSIN NEURONS IS ASSOCIATED WITH HYPERPHAGIA INDUCED BY A HIGH-FAT–HIGH-FRUCTOSE DIET IN APP/PS1 TRANSGENIC MICE

Hyperphagia has been observed in both Alzheimer's disease (AD) patients and AD animal models. Western diets, rich in carbohydrates and fats, are known to promote overeating and have been reported to exacerbate AD pathology in animal studies. However, it remains unclear whether Western diets interact with AD pathology to affect feeding behavior and the appetite control circuitry.
In this study, wild-type (WT) and APP/PS1 transgenic mice were fed either a normal chow diet (NCD) or a high-fat diet combined with high-fructose drinking water (HFHFrD). HFHFrD induced metabolic stress, cognitive dysfunction and altered feeding behavior in APP/PS1 mice without exacerbating senile plaque burden, suggesting that these symptoms preceded overt plaque exacerbation. Among the four groups, increased dark-phase caloric intake was observed exclusively in HFHFrD APP/PS1 mice that driven by prolonged feeding bout duration.
To identify diet- and genotype-sensitive nodes within the appetite-control circuitry, a fasting-refeeding paradigm was employed to synchronize feeding behaviors and assess neuronal activation using c-Fos immunostaining. Notably, neuronal activation of HFHFrD APP/PS1 mice attenuated in the lateral hypothalamus (LH) compared with that of HFHFrD WT mice. Specifically, the percentage of fasting-refeeding-activated neurotensin-expressing neurons in the LH (LH^Nts neurons) was reduced in APP/PS1 mice. Consistently, reduced number of Vglut2 puncta onto LH^Nts neurons of HFHFrD APP/PS1 mice suggests the excitatory input onto LH^Nts neurons may be reduced.
Together, the vulnerability of LH^Nts neurons may contribute to the hyperphagia observed in HFHFrD APP/PS1 mice, highlighting a link between HFHFrD and AD-related feeding dysregulation.