The Fat‐Body Secreted Neuropeptide CCHa2 Signals Insulin‐Producing Cells in the Brain to Promote Sleep

Sleep is a fundamental behavior regulated by diverse environmental and physiological cues. While the central mechanisms underlying sleep regulation have been investigated in detail, far less is known about how nutrient signals from the periphery are communicated to the brain to modulate sleep. Here, we perform a targeted RNAi screen of genes enriched in the fat body and regulated by feeding state to identify genes that function in the fat body to regulate sleep in Drosophila. This analysis found that fat body-specific knockdown of CCHa2 significantly reduced sleep duration and sleep depth in fed flies, phenocopying sleep in starved flies. CCHa2-deficient flies exhibited reduced glycogen stores and diminished feeding drive. Analysis of single-cell transcriptomic atlases confirms that the CCHa2 receptor (CCHa2-R) is selectively expressed in insulin-producing cells (IPCs) of the fly brain. We find that knockdown of CCHa2-R in IPCs recapitulates the sleep loss phenotype of CCHa2 mutants, supporting a role in adipose-brain signaling. Further screening of genes identified in single cell atlases as being enriched in IPCs led to the identification of numerous genes that function in IPCs to regulate sleep, including modulators of wnt and insulin signaling. Together, these findings identify a fat body-IPC axis that is a critical modulator of sleep duration and intensity.