Mathematical analysis of circadian disruption and metabolic re-entrainment of hepatic gluconeogenesis: the intertwining entraining roles of light and feeding

Abstract

The circadian rhythms influence the metabolic activity from molecular level to tissue, organ, and host level. Disruption of the circadian rhythms manifests to the host's health as metabolic syndromes, including obesity, diabetes, and elevated plasma glucose, eventually leading to cardiovascular diseases. Therefore, it is imperative to understand the mechanism behind the relationship between circadian rhythms and metabolism. To start answering this question, we propose a semimechanistic mathematical model to study the effect of circadian disruption on hepatic gluconeogenesis in humans. Our model takes the light-dark cycle and feeding-fasting cycle as two environmental inputs that entrain the metabolic activity in the liver. The model was validated by comparison with data from mice and rat experimental studies. Formal sensitivity and uncertainty analyses were conducted to elaborate on the driving forces for hepatic gluconeogenesis. Furthermore, simulating the impact of Clock gene knockout suggests that modification to the local pathways tied most closely to the feeding-fasting rhythms may be the most efficient way to restore the disrupted glucose metabolism in liver.

Circular RNA circCHFR Facilitates the Proliferation and Migration of Vascular Smooth Muscle via miR-370/FOXO1/Cyclin D1 Pathway

“…FOXO1 is also known as forkhead within the rhabdomyosarcoma, as well as a transcription factor playing an important role in regulation of gluconeogenesis. 28,29 In VSMCs, FOXO1 has been powerfully proven to regulate vascular remodeling and diabetic cardiomyopathy. 30,31 In addition, FOXO1 functions a transcrip-tion factor to modulate the human cancers.…”

Circadian Misalignment and Metabolic Disorders: A Story of Twisted Clocks

“…These theoretical works thus allow the exploration of the fine-tuning of the genetic circadian clocks, which in turn may be responsible for subtle changes in clock-controlled processes. Models focusing on the circadian control of metabolism already exist [ 98 , 99 , 100 ]. The next step will be to incorporate both genetic details and clock-controlled processes into an integrated model.…”

At the Interface of Lifestyle, Behavior, and Circadian Rhythms: Metabolic Implications

“…Inconsistencies could arise from behaviors, life style choices, genetic makeup, and socioeconomic factors, accumulating convolution in studying long-term effects. However, current understanding suggests that behavioral changes (i.e., restricted feeding) can reverse chronodisruption (205, 209) due to genetic or behavioral causes, and broadening the understanding of mechanism behind circadian metabolism would be beneficial for chronotherapy and discussion in more biologically pertinent social clock.…”

“…Along those lines, a model that takes in the feeding/fasting rhythms through NAD + mediated SIRT1 activation and light/dark cycle through the HPA axis modeled with Goodwin oscillator predicted asymmetrical entrainment of clock genes to the two environmental cues was recently discussed in (204). The model was further developed to study the effect of zeitgeber phase mismatch on expression of gluconeogenic genes such as G6pc and Pck1 (205). This model reproduced the finding that genetic circadian disruption through Clock gene knockout results in altered level of gluconeogenic gene expression and predicted that certain phase relations between the two zeitgebers can recover the wild-type expression level in knockout cells.…”