bims-ciryme 2025-12-14 papers

Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2520674122

The inferred functional connectome underlying circadian synchronization in the mouse suprachiasmatic nucleus.

K L Nikhil, Bharat Singhal, Daniel Granados-Fuentes, Jr-Shin Li, István Z Kiss, Erik D Herzog.

Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the suprachiasmatic nucleus (SCN). Although anatomical, molecular, and genetic approaches have revealed diverse SCN cell types, how network-level wiring enables their synchronization remains unclear. To overcome the challenges of inferring functional connectivity from fixed tissue, we developed Mutual Information & Transfer Entropy (MITE), an information-theoretic framework to infer directed cell-cell connections with high fidelity from long-term live-cell imaging. Recording and analyzing 3,290 h of clock gene expression from 8,261 SCN neurons across 17 mice, we uncovered a highly conserved, sparse SCN network organized into two asymmetrically coupled modules: dorsal and ventral. Connectivity analyses revealed five functional SCN cell types independent of neurochemical identity. Notably, only ~30% of vasoactive intestinal peptide neurons exhibited Hub-like connectivity, classifying them as Generators and Broadcasters of synchrony signals. Other spatially stereotyped cell types consistently identified as Bridges, Receivers, or Sinks. Simulations based on MITE-inferred connectomes recapitulated emergent SCN dynamics, including recovery from desynchrony and the daily dorsal-to-ventral phase wave of gene expression. Together, these results demonstrate that MITE enables precise mapping of cellular network topology, revealing the circuit logic and key cell types that mediate circadian synchrony across space and time in the mammalian SCN.

Keywords: circadian; connectome; information theory; suprachiasmatic nucleus; vasoactive intestinal peptide

DOI: https://doi.org/10.1073/pnas.2520674122

Nat Commun. 2025 Dec 11. 16(1): 11106

Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.

Konstantinos Makris, Vlera Fonda, Fania Feby Ramadhani, Lina Fadel, Morgane Davezac, Bertrand Payet, Ioannis K Deligiannis, Liwei Zhang, Teresa Horn, Laura Heimerl, Céline Jouffe, Marjolein Heddes, Celia P Martinez-Jimenez, Fabiana Quagliarini, N Henriette Uhlenhaut.

Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day-night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate mediators for its benefits. Here we show that in the liver, the glucocorticoid receptor (GR) is required for the metabolic response to caloric restriction. Hepatocyte-specific GR mutant males fail to mount this response, indicating that increased glucocorticoid amplitude is necessary for the adaptation. Using multiomics, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling GR to activate diet-specific gene expression programs. Our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.

DOI: https://doi.org/10.1038/s41467-025-67228-z

Cell Rep. 2025 Dec 10. pii: S2211-1247(25)01438-X. [Epub ahead of print]44(12): 116666

DEC1 regulates human β cell functional maturation and circadian rhythm.

Sam Preza, Bliss Zheng, Zihan Gao, Akshaya Biju, Mai Liu, Zhihui Cheng, Matthew Choi, Juan R Alvarez-Dominguez.

Stem cell-derived islet (SC-islet) organoids offer hope for cell replacement therapy in diabetes, but their immature function remains a challenge. Mature islet function requires the β cell circadian clock, yet how the clock regulates maturation is unclear. Here, we show that a circadian transcription factor specific to maturing SC-β cells, DEC1, regulates insulin responsiveness to glucose. SC-islet organoids form normally from DEC1-ablated human pluripotent stem cells, but their insulin release capacity and glucose threshold fail to increase during in vitro culture and upon transplant. This deficit reflects the downregulation of maturity-linked effectors of glucose utilization and insulin exocytosis, blunting glycolytic and oxidative metabolism, and is rescued by increasing metabolic flux. Moreover, DEC1 is needed to boost SC-islet maturity by synchronizing circadian glucose-responsive insulin secretion rhythms and clock machinery. Thus, DEC1 links circadian rhythms to human β cell maturation, highlighting the essential role of circadian control in generating fully functional SC-islet organoids.

Keywords: 3D organoids; CP: developmental biology; CP: metabolism; SC-β cell maturation; cell replacement therapy; circadian clock; glucose-stimulated insulin secretion; metabolic synchronization; β-cell energetics

DOI: https://doi.org/10.1016/j.celrep.2025.116666