Abstract
Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active) and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile) cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into “whole-body” contextual models that mimic in vivo conditions.
Highlights
Glucose is the major metabolic fuel of mammals, with its maintenance at appropriate levels within the body being crucial for normal function, while dysregulation is associated with diseases such as diabetes mellitus, galactosemia and glycogen storage diseases [1]
In the absence of a suitable model for the present work, we developed a physiological model based on a central control glycogen circuitry by Hers et al [7] and Mutalik et al [24], with the whole body bioenergetics described in [25,26,27,28,29] as well as the feedback and feed forward control loops described in [30,31,32,33] for maintaining glucose homeostasis under different fed-fasting conditions
Negative feedback loops underpin the majority of the balances of nature, from predator-prey relationships to biochemical networks, and are clearly subjected to evolutionary pressures [52]
Summary
Glucose is the major metabolic fuel of mammals, with its maintenance at appropriate levels within the body being crucial for normal function, while dysregulation is associated with diseases such as diabetes mellitus, galactosemia and glycogen storage diseases [1]. Transitions between fed and fasted states require rapid shifting between the storage of excess glucose, in the form of glycogen, within the liver and muscle and the breakdown of these stores for delivery of glucose to other organs. Proper functioning of this system ensures that available nutrients are efficiently captured and stored during times of excess, while effectively managed and distributed during times of fasting. The liver is the central organ for regulation of glucose and glycogen and acts as the primary distributor of nutrients through the blood to other tissues. When in a fasted state, the liver breaks down glycogen stores, producing glucose for other tissues. Glucose regulation within the liver is performed by the glycogen circuit that controls both the storage of glucose as glycogen (glycogenesis) as well as its breakdown into glucose-6-phosphate from hepatic stores (glycogenolysis).
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