Disruption of the striated muscle glycogen targeting subunit PPP1R3A of protein phosphatase 1 leads to increased weight gain, fat deposition, and development of insulin resistance.
Disruption of the PPP1R3A gene encoding the glycogen targeting subunit (G(M)/R(GL)) of protein phosphatase 1 (PP1) causes substantial lowering of the glycogen synthase activity and a 10-fold decrease in the glycogen levels in skeletal muscle. Homozygous G(M)(-/-) mice show increased weight gain after 3 months of age and become obese, weighing approximately 20% more than their wild-type (WT) littermates after 12 months of age. Glucose tolerance is impaired in 11-month-old G(M)(-/-) mice, and their skeletal muscle is insulin-resistant at > or =12 months of age. The massive abdominal and other fat depositions observed at this age are likely to be a consequence of impaired blood glucose utilization in skeletal muscle. PP1-G(M) activity, assayed after specific immunoadsorption, was absent from G(M)(-/-) mice and stimulated in the hind limb muscles of WT mice by intravenous infusion of insulin. PP1-R5/PTG, another glycogen targeted form of PP1, was not significantly stimulated by insulin in the skeletal muscle of WT mice but showed compensatory stimulation by insulin in G(M)(-/-) mice. Our results suggest that dysfunction of PP1-G(M) may contribute to the pathophysiology of human type 2 diabetes.
Delibegovic
Mirela
M
Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom.
Armstrong
Christopher G
CG
Dobbie
Lorraine
L
Watt
Peter W
PW
Smith
Andrew J H
AJ
Cohen
Patricia T W
PT
D000273:Adipose Tissue; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage; D007333:Insulin Resistance / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D054645:Protein Phosphatase 1; D015430:Weight Gain / Q000235:genetics*
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C491294:PPP1R3C protein, human; C104748:Ppp1r3c protein, mouse; D006003:Glycogen; D006006:Glycogen Synthase; C114205:PPP1R3A protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1