A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.

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 f...

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Autores principales:	Ke Xu, Kevin T Morgan, Abby Todd Gehris, Timothy C Elston, Shawn M Gomez
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/03f02b4cbced4e46ada869f29d364880
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spelling	oai:doaj.org-article:03f02b4cbced4e46ada869f29d3648802021-11-18T05:51:44ZA whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.1553-734X1553-735810.1371/journal.pcbi.1002272https://doaj.org/article/03f02b4cbced4e46ada869f29d3648802011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22163177/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Timely, 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.Ke XuKevin T MorganAbby Todd GehrisTimothy C ElstonShawn M GomezPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 7, Iss 12, p e1002272 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Ke Xu Kevin T Morgan Abby Todd Gehris Timothy C Elston Shawn M Gomez A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
description	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.
format	article
author	Ke Xu Kevin T Morgan Abby Todd Gehris Timothy C Elston Shawn M Gomez
author_facet	Ke Xu Kevin T Morgan Abby Todd Gehris Timothy C Elston Shawn M Gomez
author_sort	Ke Xu
title	A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
title_short	A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
title_full	A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
title_fullStr	A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
title_full_unstemmed	A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
title_sort	whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/03f02b4cbced4e46ada869f29d364880
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A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.

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