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 Delibegovic, Christopher G. Armstrong, Lorraine Dobbie, Peter W. Watt, Andrew J. H. Smith, Tricia Cohen

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    58 Citations (Scopus)

    Abstract

    NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE ABSTRACT IN THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. 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. Diabetes 52: 596–604, 2003
    Original languageEnglish
    Pages (from-to)596-604
    Number of pages9
    JournalDiabetes
    Volume52
    Issue number3
    DOIs
    Publication statusPublished - Mar 2003

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