Endocrine Abstracts (2012) 28 S5.3

Molecular control of glycogen storage in muscle

Kei Sakamoto

Nestlé Institute of Health Sciences, Lausanne, Switzerland.

Glycogen breakdown and synthesis plays a critical role in regulating energy metabolism and glucose homeostasis. Glycogen synthesis is considered to be of major importance for glucose homeostasis, as the conversion of glucose to glycogen is a major fate of glucose ingested in the body. Glycogen synthase (GS), a key enzyme in glycogen synthesis, is activated by the allosteric stimulator glucose-6-phosphate (G6P) and by dephosphorylation through inactivation of GS kinase-3 (GSK3) with insulin. The importance of the allosteric regulation of GS in vivo was unknown, mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors and also to the lack of a genetic handle on this process. We have solved this previously intractable problem by initially identifying a key amino acid residue required for activation of GS by G6P and then by generating a knock-in mouse model in which the normal form of the enzyme is replaced by a mutant that cannot bind G6P, but is still capable of being activated normally by dephosphorylation. We demonstrate that knock-in mice expressing the G6P-insensitive mutant display an ~80% reduced muscle glycogen synthesis by insulin and markedly reduced glycogen levels. In contrast, we found that, in knock-in mice expressing constitutively active mutants of GSK3 in which the PKB phosphorylation sites on GSK3a (Ser21) and GSK3b (Ser9) were substituted by Ala, insulin-stimulated glycogen synthesis in muscle was similar to that of wild-type. Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle glycogen accumulation.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: British Medical Research Council (Quinquennial renewal of the MRC Protein Phosphorylation Unit), Diabetes UK (07/0003529).

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