title: Hepatic overexpression of a constitutively active form of liver glycogen synthase improves glucose homeostasis.
abstract: In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state. Moreover, it markedly enhanced the clearance of blood glucose when fasted rats were challenged with a glucose load. Hepatic glycogen stores in rats overexpressing the activated mutant form of liver glycogen synthase were enhanced in the fed state and in response to an oral glucose load but showed a net decline during fasting. In order to test whether these effects were maintained during long term activation of liver glycogen synthase, we generated liver-specific transgenic mice expressing the constitutively active LGS form. These mice also showed an enhanced capacity to store glycogen in the fed state and an improved glucose tolerance when challenged with a glucose load. Thus, we conclude that the activation of liver glycogen synthase improves glucose tolerance in the fed state without compromising glycogenolysis in the postabsorptive state. On the basis of these findings, we propose that the activation of liver glycogen synthase may provide a potential strategy for improvement of glucose tolerance in the postprandial state.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Research in Biomedicine, University of Barcelona, Baldiri Reixac 10, E-08028 Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Ros
authors.forename: Delia
authors.initials: D
authors.lastname: Zafra
authors.forename: Jordi
authors.initials: J
authors.lastname: Valles-Ortega
authors.forename: Mar
authors.initials: M
authors.lastname: García-Rocha
authors.forename: Stephen
authors.initials: S
authors.lastname: Forrow
authors.forename: Jorge
authors.initials: J
authors.lastname: Domínguez
authors.forename: Joaquim
authors.initials: J
authors.lastname: Calbó
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Guinovart
mesh_terms: D000818:Animals; D001786:Blood Glucose; D015870:Gene Expression; D006006:Glycogen Synthase / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D008112:Liver Glycogen; D006006:Glycogen Synthase