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Comments on Grubbs, J. J. et al. (2019) International Worm Meeting "A salt-induced kinase (SIK) is required for the metabolic regulation of sleep." (0)
Overview
Grubbs, J. J., Lopes, L. E., Raizen, D. M., & van der Linden, A. M. (2019). A salt-induced kinase (SIK) is required for the metabolic regulation of sleep presented in International Worm Meeting. Unpublished information; cite only with author permission.
Many lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unclear. C. elegans sleeps during development (developmentally timed sleep or DTS), during starvation, and following cellular stress (stress-induced sleep or SIS). We find that during DTS, when a cuticle is secreted, and during SIS, when cellular homeostasis is restored, ATP levels and body fat stores are reduced, suggesting that during sleep, energetic stores are allocated to non-neural tasks. Loss of kin-29, which encodes a homologue of a mammalian Salt-Inducible Kinase (SIK) that signal sleep pressure, results in low ATP levels despite high fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores by overexpressing the triglyceride lipase ATGL-1 corrects adiposity and sleep defects of kin-29 mutants. We performed pharmacological experiments that suggest that sleep is promoted by beta-oxidation of fatty acids. kin-29 sleep and energy homeostasis roles map to a small number of sensory neurons, including ASJ and ASK, that act upstream of fat regulation as well as of the central sleep-controlling neurons, ALA and RIS, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. A KIN-29 protein with serine 517 mutated to Alanine was unable to move to the nucleus during sleep and was defective for sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep. SIKs are therefore key nodes integrating sleep and energy homeostasis.
Affiliations:
- The Rockefeller University, New York City, NY
- Department of Biology, University of Nevada, Reno, NV
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania