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, C. G. Armstrong, L. Dobbie, P. W. Watt, A. J. H. Smith, P. T. W. Cohen

Research output: Contribution to journalArticle

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Abstract

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 similar to20% 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 greater than or equal to 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.

Original languageEnglish
Pages (from-to)596-604
Number of pages8
JournalDiabetes
Volume52
Issue number3
DOIs
Publication statusPublished - Mar 2003

Keywords

  • RABBIT SKELETAL-MUSCLE
  • REGULATORY SUBUNIT
  • 3'-UNTRANSLATED REGION
  • GLUCOSE-INTOLERANCE
  • CELLULAR-REGULATION
  • CATALYTIC SUBUNIT
  • 3T3-L1 ADIPOCYTES
  • SYNTHASE KINASE-3
  • PHOSPHORYLATION
  • POLYMORPHISM

Cite this

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. / Delibegovic, Mirela; Armstrong, C. G.; Dobbie, L.; Watt, P. W.; Smith, A. J. H.; Cohen, P. T. W.

In: Diabetes, Vol. 52, No. 3, 03.2003, p. 596-604.

Research output: Contribution to journalArticle

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abstract = "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 similar to20{\%} 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 greater than or equal to 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.",
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