Biology subjects

Delpierre, P.

Publications and source records attributed to Delpierre, P..

2 recordsLinked to original sources

bioRxiv2026

Experimental and mathematical models reveal that AMPK modulates circadian clock gene expression and period through NAD+-dependent regulation of Bmal1

The circadian clock allows living systems to anticipate environmental daily variations by scheduling cellular mechanisms according to the time of the day. The reciprocal interplay between metabolism and circadian clock is essential for energy homeostasis, and the disruption of metabolic clock inputs contributes to dysfunction of clocks in peripheral tissues. However, the molecular mechanisms through which the feeding/fasting cycle entrains peripheral clocks remain incompletely understood. Here, we investigate experimentally and theoretically the role of AMP-dependent kinase (AMPK), a key fasting sensor, in metabolic regulation of the circadian clock. Using a luciferase reporter driven by the Bmal1 promoter to monitor molecular clock activity in human U2OS cells, and thanks to a signal processing method based on the Hilbert transform to retrieve the instantaneous phase and period of circadian signals, we show that pharmacological activation of AMPK by AICAR significantly elevates Bmal1 promoter activity and markedly lengthens the clock period in a dose-dependent manner. Conversely, the clock period is shortened by the pharmacological inhibition by SR18292 of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1-alpha). Importantly, the action of AICAR is abolished by FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, demonstrating that AMPK-dependent modulation of Bmal1 promoter activity requires NAD+ availability. These experimental results are recapitulated by numerical simulations of our previously published mathematical model, where PGC-1-alpha plays a key role in mediating AMPK activity to the clock. Moreover, the comparison of experimentally measured and theoretically predicted phase response curves, following AMPK activation at different circadian phases, provides an additional validation of the model. By integrating biological experiments with mathematical modeling, our results identify a key mechanism through which metabolic factors can entrain and regulate the circadian clock via NAD+-dependent AMPK-mediated regulation of Bmal1 promoter activity.

cell biology↗

bioRxiv2025

A minimal activator-inhibitor-repressor model to describe the hepatic circadian clock

Circadian clocks rely on gene regulation networks which generate periodic biochemical oscillations informing our cells about the time of the day. Mathematical modeling has been effective to describe the dynamics of the multiple intertwined feedback loops making up circadian clocks, however it is often delicate to adapt the complexity of the model to the question addressed and to the data available. Traditionally, two main modeling approaches have been followed, using either comprehensive models recapitulating most molecular actors involved, or minimal qualitative models highlighting the core mechanisms. However, analyzing the behavior of large models may be difficult, and small models often lack predictive power, questioning their relevance. Through a systematic reduction of a more complex model, we obtain a simple three-gene clock model, featuring the activator Bmal1, the repressor Reverb and the inhibitor Cry, that accurately describes the corresponding temporal expression profiles for the mouse hepatic clock. We characterize this model by carrying out a sensitivity analysis for its limit cycle, as well as by computing phase response curves for the different possible inputs. Predictions from the model are compatible with a number of synchronizing mechanisms from the literature. SIGNIFICANCELiving systems adapt to the day/night cycle thanks to cellular clocks, which track the time of the day and orchestrate physiological processes throughout the 24 hours. The dynamics of these clocks is complex, due to the interaction of intertwined feedback loops generating the biochemical oscillations and ensuring their synchronization. Mathematical modeling has proved useful to unravel this complexity, however there is usually a difficult choice to be made between comprehensive and minimal models, with opposite strengths and weaknesses. Here, we propose a simple activator-inhibitor-repressor model reproducing surprinsingly well experimental data from mouse livers, whose analysis casts light on the roles of the main actors of the mammalian circadian clock.

systems biology↗