1. 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.
- Author
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Arden C, Green AR, Hampson LJ, Aiston S, Härndahl L, Greenberg CC, Brady MJ, Freeman S, Poucher SM, and Agius L
- Subjects
- Animals, Carrier Proteins antagonists & inhibitors, Carrier Proteins biosynthesis, Carrier Proteins physiology, Cells, Cultured, Diabetes Mellitus, Type 2 enzymology, Diabetes Mellitus, Type 2 genetics, Disease Models, Animal, Female, Glycogen metabolism, Glycogen physiology, Insulin chemistry, Intracellular Signaling Peptides and Proteins, Leptin chemistry, Male, Obesity enzymology, Obesity genetics, Phosphoprotein Phosphatases biosynthesis, Phosphoprotein Phosphatases metabolism, Phosphorylase a physiology, Protein Subunits metabolism, Rats, Rats, Wistar, Rats, Zucker, Receptors, Cell Surface deficiency, Receptors, Cell Surface genetics, Receptors, Cell Surface physiology, Receptors, Leptin, Glycogen biosynthesis, Hepatocytes enzymology, Insulin Resistance genetics, Phosphoprotein Phosphatases antagonists & inhibitors, Phosphorylase a chemistry, Protein Subunits antagonists & inhibitors, Protein Subunits biosynthesis
- 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.
- Published
- 2006
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