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
- Mirela Delibegovic1,
- Christopher G. Armstrong1,
- Lorraine Dobbie2,
- Peter W. Watt1,
- Andrew J.H. Smith2 and
- Patricia T.W. Cohen1
- 1Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, United Kingdom
- 2GeneTargeting Laboratory, Centre for Genome Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom
Abstract
Disruption of the PPP1R3A gene encoding the glycogen targeting subunit (GM/RGL) 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 GM−/− mice show increased weight gain after 3 months of age and become obese, weighing ∼20% more than their wild-type (WT) littermates after 12 months of age. Glucose tolerance is impaired in 11-month-old GM−/− mice, and their skeletal muscle is insulin-resistant at ≥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-GM activity, assayed after specific immunoadsorption, was absent from GM−/− 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 GM−/− mice. Our results suggest that dysfunction of PP1-GM may contribute to the pathophysiology of human type 2 diabetes.
Footnotes
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Address correspondence and reprint requests to Professor Patricia T.W. Cohen, MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K. E-mail: p.t.w.cohen{at}dundee.ac.uk.
Received for publication 4 November 2002 and accepted in revised form 21 November 2002.
P.T.W.C. receives salary and research grants from the UK Medical Research Council. Some research support funds are derived from a consortium of five pharmaceutical companies: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novo Nordisk, and Pfizer. C.G.A. received salary during the course of this work from Diabetes UK. Since January 2002, he has been employed by Upstate Ltd (Dundee Discovery Services Division).
C.G.A.’s current affiliation is Upstate Ltd, Dundee Technology Park, Dundee, Scotland, United Kingdom. P.W.W.’s current affiliation is Sport & Exercise Science, University of Brighton, Eastbourne, England, United Kingdom.
2DOG, 2-deoxy-d-[1,2-3H]-glucose; G-6P, glucose-6-phosphate; GS, glycogen synthase; GSK-3, glycogen synthase kinase-3; PP1, protein phosphatase 1; WT, wild type.
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