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Metabolic regulators of sleep
Advisorvan der Linden, Alexander M.
Cell and Molecular Biology
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Sleep, while heavily researched still has no readily assignable function. Different theories have been proposed to explain the why and how of sleep but none appear to have defined its function universally, at least experimentally. Many of these theories unite around a common idea that sleep and metabolism are intrinsically connected. My dissertation is broken into three parts to explore the basic mechanisms underlying sleep and metabolic interactions. Chapter 1 describes our current understanding of metabolism in sleep as well as important regulators of cellular energy and their involvement in sleep, such as the AMP Activated Protein Kinase (AMPK) family members called Salt Inducible Kinases (SIKs). The nematode Caenorhabditis elegans expresses only one isoform of SIK known as KIN-29, and provides a powerful model system to understand the molecular and cellular mechanisms connecting sleep with energy homeostasis in an animal. In Chapter 2, I show that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of fat-energetic stores via the action of the class II histonede acytylase HDA-4, which in turn promotes sleep. Finally, in Chapter 3, I describe additional phenotypes, diet conditions and downstream targets of KIN-29/SIK acting in sensory neurons that mediate the regulation of fat metabolism, independent from sleep, using genetic and sensory-neuron specific expression profiling experiments.