Defining mechanisms that regulate diet-induced wake impairments

描述(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。这本身就是另一个主要的公共卫生问题，因为这些认知障碍增加了事故的风险，降低了劳动力的生产率。此外，肥胖者的睡意在客观上和主观上都有增加的迹象，这可能是这些认知效应的基础。在动物模型中，嗜睡度增加是显著的，因为饮食诱导肥胖(DIO)小鼠每天多睡2个小时，代价是清醒。这些睡眠异常可通过体重正常化而逆转，但尚不清楚是否会启动 体重减轻(即急性能量负平衡)足以恢复这种觉醒障碍；如果是真的，开始健康的饮食或锻炼方案可能会极大地提高肥胖者的警觉性和清醒程度。因此，这项提案旨在定义饮食/能量平衡和/或肥胖导致觉醒障碍的机制和大脑区域。首先，DIO小鼠的能量平衡将通过急性饮食操作双向改变。其次，我们将研究PPAR-Gamma在调节DIO小鼠觉醒损伤中的作用，PPAR-Gamma通常促进正能量平衡。我们的初步研究表明，在DIO小鼠中，中枢抑制PPARg可以防止觉醒能力的下降。因此，这些研究将拓宽和加深我们对代谢对睡眠影响的理解，这可能为提高肥胖和非肥胖个体的警觉性和注意力提供新的策略。

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.