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
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
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DOI：
10.2337/diabetes.52.3.596
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发表时间：
2003-03-01
期刊：
影响因子：
7.7
通讯作者：
Cohen, PTW
中科院分区：
文献类型：
--
作者：
Delibegovic, M;Armstrong, CG;Cohen, PTW
编码蛋白磷酸酶1 （PP1）糖原靶向亚基（G(M)/R-GL）的PPP1R3A基因的破坏导致糖原合成酶活性显著降低，骨骼肌糖原水平降低10倍。纯合子G(M)（-/-）小鼠在3个月后体重增加，变得肥胖。12个月后，体重比野生型（WT）幼崽多20%。11月龄G(M)（-/-）小鼠的葡萄糖耐量受损，其骨骼肌在大于或等于12月龄时出现胰岛素抵抗。在这个年龄观察到的大量腹部和其他脂肪沉积可能是骨骼肌中血糖利用受损的结果。经特异性免疫吸附测定，PP1-G(M)活性在G(M)（-/-）小鼠中不存在，而在WT小鼠后肢肌肉中通过静脉注射胰岛素刺激PP1-G(M)活性。PP1- r5 /PTG是PP1的另一种糖原靶向形式，胰岛素在WT小鼠骨骼肌中不显著刺激PP1- r5 /PTG，但在G(M)（-/-）小鼠中表现出代偿性刺激。我们的研究结果提示PP1-G(M)功能障碍可能参与了人类2型糖尿病的病理生理。
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.