title: Increased sensitivity of glycogen synthesis to phosphorylase-a and impaired expression of the glycogen-targeting protein R6 in hepatocytes from insulin-resistant Zucker fa/fa rats.
abstract: Hepatic insulin resistance in the leptin-receptor defective Zucker fa/fa rat is associated with impaired glycogen synthesis and increased activity of phosphorylase-a. We investigated the coupling between phosphorylase-a and glycogen synthesis in hepatocytes from fa/fa rats by modulating the concentration of phosphorylase-a. Treatment of hepatocytes from fa/fa rats and Fa/? controls with a selective phosphorylase inhibitor caused depletion of phosphorylase-a, activation of glycogen synthase and stimulation of glycogen synthesis. The flux-control coefficient of phosphorylase on glycogen synthesis was glucose dependent and at 10 mm glucose was higher in fa/fa than Fa/? hepatocytes. There was an inverse correlation between the activities of glycogen synthase and phosphorylase-a in both fa/fa and Fa/? hepatocytes. However, fa/fa hepatocytes had a higher activity of phosphorylase-a, for a corresponding activity of glycogen synthase. This defect was, in part, normalized by expression of the glycogen-targeting protein, PTG. Hepatocytes from fa/fa rats had normal expression of the glycogen-targeting proteins G(L) and PTG but markedly reduced expression of R6. Expression of R6 protein was increased in hepatocytes from Wistar rats after incubation with leptin and insulin. Diminished hepatic R6 expression in the leptin-receptor defective fa/fa rat may be a contributing factor to the elevated phosphorylase activity and/or its high control strength on glycogen synthesis.
authors.affiliation: School of Clinical Medical Sciences--Diabetes, University of Newcastle upon Tyne, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Arden
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hampson
authors.forename: Susan
authors.initials: S
authors.lastname: Aiston
authors.forename: Linda
authors.initials: L
authors.lastname: Härndahl
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Greenberg
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brady
authors.forename: Susan
authors.initials: S
authors.lastname: Freeman
authors.forename: Simon M
authors.initials: SM
authors.lastname: Poucher
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006003:Glycogen / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology*; D007328:Insulin / Q000737:chemistry; D007333:Insulin Resistance / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000737:chemistry; D008297:Male; D009765:Obesity / Q000201:enzymology / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D010762:Phosphorylase a / Q000737:chemistry* / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D054411:Receptors, Leptin
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; C491293:Ppp1r5 protein, rat; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D006003:Glycogen; D010762:Phosphorylase a; D010749:Phosphoprotein Phosphatases