|Title||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.|
|Publication Type||Journal Article|
|Year of Publication||2003|
|Authors||Delibegovic M, Armstrong CG, Dobbie L, Watt PW, Smith AG, Cohen PTW|
|Date Published||2003 Mar|
|Keywords||Adipose Tissue, Animals, Blood Glucose, Body Composition, Carrier Proteins, Glucose Intolerance, Glycogen, Glycogen Synthase, Insulin, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Muscle, Skeletal, Obesity, Phosphoprotein Phosphatases, Protein Phosphatase 1, Weight Gain|
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.