Inflammation and the development of metabolic deficits in sleep insufficiency and

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Chronic insufficient sleep and over nutrition are both associated with the incidence of cardiovascular and metabolic diseases. Substantial evidence supports a contribution of low-grade inflammation in the hypothalamus and peripheral metabolic tissues to the emergence of cardio metabolic pathologies in diet- induced obesity. However, the mechanisms underlying the development of metabolic deficits elicited by poor sleep are less understood. Epidemiological and empirical studies provide correlative evidence supporting a role for peripheral inflammation in the development of metabolic deficits induced by poor sleep, but a causal relationship has yet to be established. Moreover, it is unknown whether insufficient sleep elicits neuroinflammation in brain regions that regulate energy homeostasis, as is observed in over nutrition. To elucidate mechanisms of metabolic dysfunction resulting from poor sleep and over nutrition, the proposed project will test the hypothesis that inflammation contributes to metabolic deficits observed in these conditions by addressing two specific aims. Specific Aim 1 will determine the extent to which sleep disruption and over nutrition elicit inflammatory responses in the brain and periphery. To this end, sleep will be moderately disrupted and over nutrition will be induced with a high-fat diet in mice. Site-specific analyses o inflammatory mediators in metabolically relevant tissues, including brain regions that regulate energy balance, will be conducted following these manipulations. Specific Aim 2 will determine the extent to which anti-inflammatory actions preserve metabolic function in individuals subjected to sleep disruption and over nutrition. To address this aim, insulin sensitivity will be assessed following sleep disruption or high-fat diet exposure in genetic knockout mice that lack specific pro-inflammatory cytokine signaling. Pharmacological intervention will be employed as a complementary approach; insulin sensitivity will be assessed in genetically intact mice treated with anti-inflammatory agents throughout the period of exposure to sleep disruption or high-fat diet. Together, these aims will establish neural and peripheral targets of inflammation following sleep disruption and over nutrition, and will directly test the hypothesis that inflammation induced by these factors leads to metabolic dysfunction. The findings from the proposed aims will greatly contribute to our understanding of the pathogenesis of cardio metabolic diseases associated with poor sleep and over nutrition, and will help inform practices and policies that address these prevalent public health concerns.