Endocannabinoid signaling is a critical link between circadian desynchronization and metabolic dysfunction

Baca, B. A.; Denaroso, G. E.; Akli, S.; Pearson, G. L.; Wang, J.; Bowles, N. P.; Phillips, D.; Sorensen, W.; Hume, C.; Hill, M.; Karatsoreos, I. N.

doi:10.1101/2025.09.29.678590

bioRxiv · 10.1101/2025.09.29.678590

Endocannabinoid signaling is a critical link between circadian desynchronization and metabolic dysfunction

Baca, B. A.·Denaroso, G. E.·Akli, S.·Pearson, G. L.·Wang, J.·Bowles, N. P.·Phillips, D.·Sorensen, W.·Hume, C.·Hill, M.·Karatsoreos, I. N.

View original source ↗Export metadata ↓

Abstract

It is well documented that disruption of circadian rhythms can cause metabolic dysregulation, but the specific mechanisms involved remain unclear. Our findings demonstrate that the negative metabolic effects of environmental circadian desynchronization (ECD) are dependent upon the cannabinoid receptor 1 (CB1r). The endocannabinoid system has not previously been implicated in mediating the effects of circadian disruption. We showed that ECD induced a positive correlation between the levels of the endocannabinoids AEA and 2-AG in both plasma and liver. While global CB1r knockout protects against the metabolic effects of ECD, behavioral and physiological response to ECD was strikingly similar between WT and CB1r KO mice and could not account for their distinct metabolic outcomes. Using liver-specific CB1r KO mice, we further specified that the ECD-induced metabolic hormone disruption, but not weight gain, is mediated through liver CB1r signaling. Finally, we showed that ECD upregulated transcription of genes involved in oxidative phosphorylation in the liver of WT, but not liver-specific CB1r KO mice. In summary, ECD led to modular metabolic dysfunction through CB1r signaling in multiple tissues, with the liver playing a critical role.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Baca, B. A., Denaroso, G. E., Akli, S., Pearson, G. L., Wang, J., Bowles, N. P., Phillips, D., Sorensen, W., Hume, C., Hill, M., Karatsoreos, I. N.. 2025-10-01. Endocannabinoid signaling is a critical link between circadian desynchronization and metabolic dysfunction. https://doi.org/10.1101/2025.09.29.678590

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

28S-rsRNA facilitates PASMC proliferation through PKM2 β-hydroxybutyrylation

Ribosomal RNA-derived small RNAs (rsRNAs) are nucleic acid fragments originating from rRNA, the functions and roles of which in diseases remain incompletely understood. We identified 28S rsRNA-CTC_L20, an rsRNA whose expression is upregulated in hypoxic pulmonary artery smooth muscle cells (PASMCs) and in lung tissues of pulmonary hypertension (PH) models. In hypoxic cells, 28S rsRNA-CTC_L20 promotes PASMC proliferation, and its knockdown mitigates SuHx-induced pulmonary hypertension and vascular remodeling. Mechanistically, 28S rsRNA-CTC_L20 modulates {beta}-hydroxybutyrate (BHB) production by maintaining the stability of ketogenic enzyme mRNAs through its "CTGNNGG" motif. Elevated levels of BHB enhance the {beta}-hydroxybutyrylation modification at K166 of pyruvate kinase M2 (PKM2), increasing its activity and driving glycolysis to sustain proliferation. These results link ketone body metabolism to glycolysis in hypoxic cells and define an rsRNA-BHB-PKM2 {beta}-hydroxybutyrylation axis in PH. They also point to 28S rsRNA-CTC_L20 as a potential target for treating vascular remodeling.

physiology↗

bioRxiv2026

Selective activation of estrogen receptors modulates electrical activity and insulin secretion in human EndoC-βH1 cells

Estrogen receptors (ERs), ER and ER{beta} have important roles in the physiology of the endocrine pancreas in animal models, but the effects of ER activation on insulin-secreting human cells are still poorly understood. Here, we investigated the role of ER and ER{beta} as modulators of electrical activity and insulin secretion in the insulin-secreting human cell line EndoC-{beta}H1. Immunocytochemical analysis revealed a widespread cellular distribution of ER, while ER{beta} was predominantly localized outside the nucleus. We observed that both estradiol (E2) and the ER{beta} agonist diarylpropionitrile (DPN) led to a decrease in insulin secretion in the absence of stimulatory glucose concentrations, without affecting insulin content. Patch-clamp experiments revealed that a 48-hour treatment with either the ER agonist PPT or DPN resulted in depolarization of the resting membrane potential, increased action potential firing frequency, and altered the action potential waveform in EndoC-{beta}H1 cells. PPT increased voltage-dependent Ca2+ channel currents, while DPN reduced K+ and Na+ currents. These results suggest that activation of ER and ER{beta} modulates beta-cell electrical activity through distinct pathways involving ion channels. The effects of E2, PPT, and DPN were not caused by altered expression levels of ion channel genes after 48 hours of treatment. This suggests that these receptors act extranuclearly without affecting gene expression. Together, our findings demonstrate that selective activation of ER and ER{beta} modulates beta-cell excitability through distinct electrophysiological mechanisms and that E2 and DPN reduce basal insulin secretion in human EndoC-{beta}H1 cells. These results support ER and ER{beta} as potential targets for modulating human pancreatic beta-cell function.

physiology↗

bioRxiv2026

Body weight modifies the efficacy of lifespan-extending interventions in ad libitum-fed mice

Geroprotective interventions are often assessed by extension of lifespan in ad libitum-fed mice. Increased lifespan could therefore reflect rescue of adverse phenotypes of unhealthy controls. We analysed body weight and survival for 33,780 mice in the Interventions Testing Program (ITP) to test whether treatment effects varied with body weight. In males, each added standard deviation of attained adult weight made treatment 6% more favourable (HR 0.94), more apparent for interventions that lowered body weight (HR 0.90). Median lifespan increase rose from 6.2% in mice in the lightest quartile to 20.2% in the heaviest pre-dosing weight quartile among those experiments, mainly because control survival declined more steeply with weight than that of the intervention group. The effect of body weight was consistent across 13 of 14 compounds and reflected weight attained during adulthood rather than in early life. Weight-dependence of intervention effects was weak in ITP females, possibly because median survival of controls exceeded that of every sampled non-ITP female control group. Amelioration of weight-associated risk is therefore implicated as a major contributor to lifespan increases relative to heavy, short-lived controls. The geroprotective effects of these interventions may thus be less apparent in metabolically healthier mice or humans.

physiology↗