Sleep Characteristics, Hypothalamic Signaling, and Metabolic Risk in Children - a Longitudinal Study - Project Summary/Abstract Sleep is a substantial yet understudied contributor to metabolic health, with measures of poor sleep associated with increased adiposity and metabolic risk markers in youth. Dysregulation of energy homeostasis, the body’s ability to actively maintain a steady internal state despite external disruptions, is a primary contributor to metabolic risk. The hypothalamus is a key brain region responsible for regulating major aspects of both energy and sleep homeostasis via neuroendocrine signaling. In compelling studies in rodents, inadequate sleep was shown to induce proinflammatory pathways, including hypothalamic inflammation, and led to impaired glucose tolerance. These animal studies also linked poor sleep to alterations in neuroendocrine signaling and a decrease in insulin sensitivity, suggesting that hypothalamic inflammation and impaired neuroendocrine signaling may represent an important mechanistic link between sleep and metabolic risk. While prior work shows associations between poor sleep and adiposity, insulin resistance, and glucose intolerance in youth, existing studies in children are limited because they are cross sectional in nature, have not examined prospective brain and metabolic trajectories, do not include objective naturalistic measures of sleep such as actigraphy, and lack rigorous measures of insulin resistance and glucose homeostasis1,10 . The work proposed here will address these limitations and will test for the first time in humans whether poor sleep is associated with longitudinal brain MRI markers of hypothalamic inflammation and impaired hypothalamic nutrient signaling as well as longitudinal increases in adiposity, insulin resistance, and/or glucose dysregulation in children. The overall objective of this study is to translate these important findings in animal models into studies in children. The central hypothesis is that poor sleep is associated with longitudinal impairments hypothalamic signaling, and increases in metabolic risk during childhood. Utilizing an animal to human translational approach, we will leverage the established BrainChild Cohort of 200 children (R01DK116858; MPI: Drs. Page & Xiang) ages 7-10 with measures of sleep (duration, quality, and timing variability), neuroimaging, and metabolic data measured longitudinally over 2 years to assess the following specific aims: the relationship between indices of sleep (measured with accelerometry) and: (1) MRI based markers of hypothalamic inflammation and hypothalamic nutrient signaling; (2) measures of adiposity, insulin resistance, and measures of glucose homeostasis from oral glucose tolerance tests (insulin sensitivity, beta cell function); (3) to explore the hypothalamic markers as a possible mechanism linking poor sleep to increases in metabolic risk in childhood. This proposal seeks to fill critical gaps in knowledge by studying children at an early age (7-10 years) and following them longitudinally to provide insights into the potential mechanisms and pathways linking poor sleep characteristics to obesity risk. This work could lead to clinical trials to test sleep modification as an important target for prevention of obesity and diabetes during childhood, a sensitive time period of development when interventions may have large and lasting benefits for long-term health. The outstanding inter-disciplinary mentorship team assembled in this proposal will provide rigorous training for a future career as independent investigator. Long-term training opportunities and goals include obtaining a competitive post-doctoral position on the topic of sleep modification during childhood, which could be a potential valuable tool towards obesity prevention.
