Developmental sleep during lethargus is associated with metabolic homeostasis and heritable adaptive responses to...

Sleep is a fundamental physiological state essential for metabolic and neuronal homeostasis; however, its contribution to lipid and energy metabolism during development remains incompletely understood. Here, we used Caenorhabditis elegans to investigate the metabolic significance of Developmentally Timed Sleep (DTS). Lethargus-associated DTS was mechanically disrupted using 1 kHz piezoelectric buzzer-induced mechanical stimulation, followed by behavioural, physiological, metabolic and molecular analyses. DTS disruption was associated with reduced behavioural quiescence, altered sleep-associated gene expression, reduced survival and elevated oxidative stress. Notably, disruption during the L4-young adult lethargus window was associated with increased feeding and markedly enhanced lipid accumulation, accompanied by upregulation of the lipid metabolic regulators fat-6, nhr-64 and nhr-80. Despite increased lipid storage, levels of the triglyceride lipase ATGL were elevated, suggesting enhanced lipid mobilization concurrent with persistent lipid accumulation. This metabolic phenotype was accompanied by reduced mitochondrial activity, decreased intracellular ATP, downregulation of atp-3 and activation of AMPK-mediated energy sensing, suggesting energetic stress and potentially inefficient downstream utilization of mobilized lipids. DTS disruption was additionally associated with increased acy-1 and crh-1 expression and enhanced CREB phosphorylation, indicating altered cAMP-CREB-associated neuronal signalling. Furthermore, disruption of DTS in offspring of Salmonella Typhi-infected parents was associated with reduction in their ability to generate heritable adaptive resistance and altered daf-16, sgk-1 and skn-1 mRNA expression. Collectively, these findings suggest that developmental sleep may play a role in lipid storage, mobilization, mitochondrial bioenergetics and cellular energy sensing, with potential consequences for neuronal and adaptive stress responses.