The feeding and fasting cycles are strong behavioral signals that entrain biological rhythms of the periphery. The feeding rhythms synchronize the activities of the metabolic organs, such as liver, synergistically with the light/dark cycle primarily entraining the suprachiasmatic nucleus. The likely phase misalignment between the feeding rhythms and the light/dark cycles appears to induce circadian disruptions leading to multiple physiological abnormalities motivating the need to investigate the mechanisms behind joint light-feeding circadian entrainment of peripheral tissues. To address this question, we propose a semimechanistic mathematical model describing the circadian dynamics of peripheral clock genes in human hepatocyte under the control of metabolic and light rhythmic signals. The model takes the synergistically acting light/dark cycles and feeding rhythms as inputs and incorporates the activity of sirtuin 1, a cellular energy sensor and a metabolic enzyme activated by nicotinamide adenine dinucleotide. The clock gene dynamics was simulated under various light-feeding phase relations and intensities, to explore the feeding entrainment mechanism as well as the convolution of light and feeding signals in the periphery. Our model predicts that the peripheral clock genes in hepatocyte can be completely entrained to the feeding rhythms, independent of the light/dark cycle. Furthermore, it predicts that light-feeding phase relationship is a critical factor in robust circadian oscillations.
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.
The use of models in biology has become particularly relevant as it enables investigators to develop a mechanistic framework for understanding the operating principles of living systems as well as in quantitatively predicting their response to both pathological perturbations and pharmacological interventions. This application has resulted in a synergistic convergence of systems biology and pharmacokinetic-pharmacodynamic modeling techniques that has led to the emergence of quantitative systems pharmacology (QSP). In this review, we discuss how the foundational principles of chemical process systems engineering inform the progressive development of more physiologically-based systems biology models.
Disruption of circadian rhythms has been associated with metabolic syndromes, including obesity and diabetes. A variety of metabolic activities are under circadian modulation, as local and global clock gene knockouts result in glucose imbalance and increased risk of metabolic diseases. Insulin release from the pancreatic β cells exhibits daily variation, and recent studies have found that insulin secretion, not production, is under circadian modulation. As consideration of daily variation in insulin secretion is necessary to accurately describe glucose-stimulated insulin secretion, we describe a mathematical model that incorporates the circadian modulation via insulin granule trafficking. We use this model to understand the effect of oscillatory characteristics on insulin secretion at different times of the day. Furthermore, we integrate the dynamics of clock genes under the influence of competing environmental signals (light/dark cycle and feeding/fasting cycle) and demonstrate how circadian disruption and meal size distribution change the insulin secretion pattern over a 24-h day.
Oscillations are an important feature of cellular signaling that result from complex combinations of positive- and negative-feedback loops. The encoding and decoding mechanisms of oscillations based on amplitude and frequency have been extensively discussed in the literature in the context of intercellular and intracellular signaling. However, the fundamental questions of whether and how oscillatory signals offer any competitive advantages—and, if so, what—have not been fully answered. We investigated established oscillatory mechanisms and designed a study to analyze the oscillatory characteristics of signaling molecules and system output in an effort to answer these questions. Two classic oscillators, Goodwin and PER, were selected as the model systems, and corresponding no-feedback models were created for each oscillator to discover the advantage of oscillating signals. Through simulating the original oscillators and the matching no-feedback models, we show that oscillating systems have the capability to achieve better resource-to-output efficiency, and we identify oscillatory characteristics that lead to improved efficiency.
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