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.
