Defining mechanisms that regulate diet-induced wake impairments

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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.