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.

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 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.

• Authors: Mirela Delibegovic, Christopher G Armstrong, Lorraine Dobbie, Peter W Watt, Andrew J H Smith, Patricia T W Cohen
• Journal: Diabetes (Diabetes) Vol. 52 Issue 3 Pg. 596-604 (Mar 2003) ISSN: 0012-1797 [Print] United States
• PMID: 12606498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Carrier Proteins
• Insulin
• Intracellular Signaling Peptides and Proteins
• PPP1R3C protein, human
• Ppp1r3c protein, mouse
• Glycogen
• Glycogen Synthase
• PPP1R3A protein, human
• Phosphoprotein Phosphatases
• Protein Phosphatase 1

Topics

• Adipose Tissue
• Animals
• Blood Glucose (metabolism)
• Body Composition (genetics)
• Carrier Proteins (metabolism)
• Glucose Intolerance (genetics)
• Glycogen (metabolism)
• Glycogen Synthase (metabolism)
• Insulin (administration & dosage)
• Insulin Resistance (genetics)
• Intracellular Signaling Peptides and Proteins
• Mice
• Mice, Knockout
• Muscle, Skeletal (drug effects, metabolism)
• Obesity (genetics)
• Phosphoprotein Phosphatases (deficiency, genetics, physiology)
• Protein Phosphatase 1
• Weight Gain (genetics)