Regulation of Satiety Quiescence by Neuropeptide Signaling in Caenorhabditis elegans

Abstract

Sleep and metabolism are interconnected homeostatic states; the sleep cycle can be entrained by the feeding cycle, and perturbation of the sleep often results in dysregulation in metabolism. However, the neuro-molecular mechanism by which metabolism regulates sleep is not fully understood. We investigated how metabolism and feeding regulate sleep using satiety quiescence behavior as a readout in Caenorhabditis elegans, which shares certain key aspects of postprandial sleep in mammals. From an RNA interference-based screen of two neuropeptide families, RFamide-related peptides (FLPs) and insulin-like peptides (INSs), we identified flp-11, known to regulate other types of sleep-like behaviors in C. elegans, as a gene that plays the most significant role in satiety quiescence. A mutation in flp-11 significantly reduces quiescence, whereas over-expression of the gene enhances it. A genetic analysis shows that FLP-11 acts upstream of the cGMP signaling but downstream of the TGFβ pathway, suggesting that TGFβ released from a pair of head sensory neurons (ASI) activates FLP-11 in an interneuron (RIS). Then, cGMP signaling acting in downstream of RIS neurons induces satiety quiescence. Among the 28 INSs genes screened, ins-1, known to play a significant role in starvation-associated behavior working in AIA is inhibitory to satiety quiescence. Our study suggests that specific combinations of neuropeptides are released, and their signals are integrated in order for an animal to gauge its metabolic state and to control satiety quiescence, a feeding-induced sleep-like state in C. elegans.

Mass Spectrometry–Driven Discovery of Neuropeptides Mediating Nictation Behavior of Nematodes

“…A second possibility is for all these neuropeptides to contribute to the execution of dauer behaviors and physiological functions, which is partially supported by our findings that flp-7 and flp-11 are involved in mediating nictation, a dauer-specific behavior. It is not known whether these neuropeptides are also more abundant when regulating their other known roles ( 68 , 81 , 82 , 83 , 84 ) or even whether there would be a general correlation between neuropeptide abundance and usage. It remains curious that almost all quantified neuropeptides are so plentiful, as it seems unlikely that dauers need all of them simultaneously.…”

Postprandial sleep in short-sleeping Mexican cavefish

“…In many species, sleep deprivation results in increased food intake, while prolonged periods of food deprivation lead to a reduction in metabolic rate and suppression of sleep (Keene et al 2010;Arble et al 2015;Stahl et al 2017;Regalado et al 2017;Goldstein et al 2018). Conversely, animals ranging from the nematode, C. elegans, to humans, increase sleep immediately following a meal, revealing an acute effect of dietary nutrients on sleep regulation (Stahl et al 1983;Murphy et al 2016;Makino et al 2021). Defining how evolution has shaped interactions between sleep, metabolic regulation, and feeding is critical to determine the functions of these traits.…”

A sleep-active neuron can promote survival while sleep behavior is disturbed

“…C. elegans has a small and invariant nervous system and sleep is controlled by relatively few neurons. RIS is a GABAergic and peptidergic interneuron that activates during sleep, and its ablation virtually abolishes sleep behavior during molting of developing larvae, in arrested larvae, and in adults following cellular stress [10][11][12][13][14][15][16][17][18][19][20][21]. Optogenetic manipulations showed that acute activation of RIS inhibits wakefulness activity such as feeding and locomotion [10,15], whereas inactivation of RIS inhibits sleep [12,18,22,23].…”