Defining mechanisms that regulate diet-induced wake impairments

描述（由申请人提供）：在美国，肥胖已经影响了超过三分之一的成年人和近五分之一的儿童。除了与各种健康问题有关外，肥胖还可能对认知功能产生负面影响，特别是警觉性和警觉性。这本身就是另一个重大的公共卫生问题，因为这些认知障碍增加了发生事故的风险，降低了劳动力的生产力。此外，肥胖个体在客观和主观上都表现出嗜睡的增加，这可能是这些认知影响的基础。在动物模型中，嗜睡的增加是很明显的，因为饮食诱导的肥胖（DIO）小鼠每天多睡2小时，而清醒时间却减少了。这些睡眠异常会随着体重的正常化而逆转，但尚不清楚是否开始

DESCRIPTION (provided by applicant): Obesity already affects over one-third of adults and nearly one-fifth of children in the United States. In addition to its association with various healh issues, obesity may negatively affect cognitive functioning, specifically vigilance and alertness. This in itself is another major public health concern, since these cognitive impairments heighten the risk for accidents and reduce productivity in the workforce. Further, obese individuals evidence both objective and subjective increases in sleepiness, which may underlie these cognitive effects. Increased sleepiness is prominent in animal models, as diet-induced obese (DIO) mice spend 2 hours more sleeping per day at the expense of wakefulness. These sleep abnormalities are reversed by normalization of body weight, but it is unclear whether initiation of weight loss (i.e. acute negative energy balance) is sufficient to restore this wake impairment; if true, beginning a healthy diet or exercise regimen may dramatically improve alertness and wakefulness in obese individuals. Therefore, this proposal will aim to define mechanisms and brain regions underlying wake impairments induced by diet/energy balance and/or obesity. First, energy balance will be bi- directionally modified by acute dietary manipulations in DIO mice. Second, we will examine the role of PPAR- gamma, which generally promotes positive energy balance, in mediating wake impairments in DIO mice. Our preliminary studies show that central PPARg inhibition in DIO mice prevents decreases in wakefulness. Thus, these studies will broaden and deepen our understanding of metabolic influences on sleep, which may provide novel strategies to improve alertness and attention in both obese and non-obese individuals.