Activation of direct and indirect pathways of glycogen synthesis by hepatic overexpression of protein targeting to glycogen.
Glycogen-targeting subunits of protein phosphatase-1, such as protein targeting to glycogen (PTG), direct the phosphatase to the glycogen particle, where it stimulates glycogenesis. We have investigated the metabolic impact of overexpressing PTG in liver of normal rats. After administration of PTG cDNA in a recombinant adenovirus, animals were fasted or allowed to continue feeding for 24 hours. Liver glycogen was nearly completely depleted in fasted control animals, whereas glycogen levels in fasted or fed PTG-overexpressing animals were 70% higher than in fed controls. Nevertheless, transgenic animals regulated plasma glucose, triglycerides, FFAs, ketones, and insulin normally in the fasted and fed states. Fasted PTG-overexpressing animals receiving an oral bolus of [U-(13)C]glucose exhibited a large increase in hepatic glycogen content and a 70% increase in incorporation of [(13)C]glucose into glycogen. However, incorporation of labeled glucose accounted for only a small portion of the glycogen synthesized in PTG-overexpressing animals, consistent with our earlier finding that PTG promotes glycogen synthesis from gluconeogenic precursors. We conclude that hepatic PTG overexpression activates both direct and indirect pathways of glycogen synthesis. Because of its ability to enhance glucose storage without affecting other metabolic indicators, the glycogen-targeting subunit may prove valuable in controlling blood glucose levels in diabetes.
O'Doherty
R M
RM
Gifford Laboratories for Diabetes Research, Marjorie Touchstone Diabetes Center, Department of Biochemistry, Dallas, Texas, USA.
Jensen
P B
PB
Anderson
P
P
Jones
J G
JG
Berman
H K
HK
Kearney
D
D
Newgard
C B
CB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019422:Dietary Sucrose / Q000378:metabolism; D004734:Energy Metabolism; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005822:Genetic Vectors; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007659:Ketones / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D002352:Carrier Proteins; D019422:Dietary Sucrose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D007659:Ketones; D008112:Liver Glycogen; C491293:Ppp1r5 protein, rat; D011994:Recombinant Proteins; D014280:Triglycerides