The role of Nf1 in sleep-dependent regulation of metabolic function - Project Summary
Neural regulation of sleep and metabolic homeostasis are critical to many aspects of human health. Despite
extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic
syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic state.
The genetic and functional basis of sleep is highly conserved from fruit flies to mammals. While the application
of genetic approaches in flies have been used to identify novel genes and neural circuit mechanisms regulating
sleep, the field has predominantly focused on sleep duration, rather than the physiological effects of sleep.
This proposal employs a novel assay for simultaneously measuring sleep and metabolic rate in single flies.
Preliminary data reveals that mutation of Neurofibromin 1 (Nf1), a gene that has been linked to sleep and
metabolic dysregulation in humans, abolishes sleep-dependent modulation of metabolic rate in flies. The
proposed experiments seek to identify the neurons required for sleep-metabolism interactions and determine
the effects of Nf1 on the activity of neural circuits regulating sleep and metabolic function. Further, genetic
experiments will be performed to identify the protein domains within NF1, and downstream signaling pathways,
that are required for sleep-metabolism interactions. The completion of this work will yield insights into the
cellular and neural circuit basis for the integration of sleep and metabolic rate, and establish flies as a model
for investigating these interactions. Given the robust conservation of sleep and metabolism between flies and
mammals, these results will provide a platform for investigation of how these processes are regulated, with the
potential to provide insight into the association between sleep loss and metabolism-related disease.
