Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55α Subunit of Phosphoinositide 3-Kinase.
Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55α Subunit of Phosphoinositide 3-Kinase.
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DOI：
10.3389/fphys.2018.00789
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发表时间：
2018
影响因子：
4
通讯作者：
McCurdy CE
中科院分区：
文献类型：
--
作者：
Martins VF;Tahvilian S;Kang JH;Svensson K;Hetrick B;Chick WS;Schenk S;McCurdy CE
PI3K （Phosphoinositide 3-kinase）信号通路在骨骼肌胰岛素刺激的葡萄糖摄取中起重要作用。而PI3K调节亚基（p85α, p55α， p50α或p85β）的单个或组合的全身和组织特异性敲除（KO）；增加胰岛素敏感性，没有研究检验增加个体调节亚基的表达是否会抑制体内胰岛素的作用。因此，本研究的目的是确定PI3K的p55α调控亚基的骨骼肌特异性过表达是否会损害骨骼肌胰岛素敏感性，或者通过限制热量来阻止其增强。方法：我们开发了一种新型的“floxed”小鼠，通过Cre-LoxP方法，允许他莫昔芬（TMX）诱导和骨骼肌特异性过表达PI3K的p55α亚基（称为“p55α- mox”）。从10周龄开始，p55α-mOX小鼠和它们的窝群同伴（被称为野生型[WT]）要么继续自由获取食物（ad lium； AL），要么转换为卡路里限制饮食（CR； AL摄入量的60%）20天。我们使用2-脱氧葡萄糖（2DOG）摄取法测量了离体比目鱼肌和指长伸肌的身体组成、全身能量消耗、口服葡萄糖耐量和离体骨骼肌胰岛素敏感性。结果：与WT小鼠相比，p55α- mox小鼠肌肉中p55α mRNA和蛋白的表达增加了约2倍。al喂养小鼠的能量消耗、总活动或食物摄入量在基因型之间没有差异。p55α- mox小鼠的体重、脂肪和瘦肉质量、组织质量、空腹血糖和胰岛素在AL组与WT组小鼠之间是相当的，CR组小鼠的空腹血糖和胰岛素也同样降低。有趣的是，过表达p55α并不影响口服葡萄糖耐量或骨骼肌胰岛素信号或敏感性，也不影响CR增强这些参数的能力。结论：骨骼肌特异性过表达p55α不影响骨骼肌胰岛素的作用，提示p85α和/或p50α可能是骨骼肌胰岛素信号传导和敏感性的更重要调节因子。
Introduction: The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole-body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85α, p55α, and p50α or p85β); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action in vivo. Therefore, the objective of this study was to determine whether skeletal muscle-specific overexpression of the p55α regulatory subunit of PI3K impairs skeletal muscle insulin sensitivity, or prevents its enhancement by caloric restriction. Methods: We developed a novel “floxed” mouse that, through the Cre-LoxP approach, allows for tamoxifen (TMX)-inducible and skeletal muscle-specific overexpression of the p55α subunit of PI3K (referred to as, ‘p55α-mOX’). Beginning at 10 weeks of age, p55α-mOX mice and their floxed littermates (referred to as wildtype [WT]) either continued with free access to food (ad libitum; AL), or were switched to a calorie restricted diet (CR; 60% of AL intake) for 20 days. We measured body composition, whole-body energy expenditure, oral glucose tolerance and ex vivo skeletal muscle insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake method. Results: p55α mRNA and protein expression was increased ∼2 fold in muscle from p55α-mOX versus WT mice. There were no differences in energy expenditure, total activity, or food intake of AL-fed mice between genotypes. Body weight, fat and lean mass, tissue weights, and fasting glucose and insulin were comparable between p55α-mOX and WT mice on AL, and were decreased equally by CR. Interestingly, overexpression of p55α did not impair oral glucose tolerance or skeletal muscle insulin signaling or sensitivity, nor did it impact the ability of CR to enhance these parameters. Conclusion: Skeletal muscle-specific overexpression of p55α does not impact skeletal muscle insulin action, suggesting that p85α and/or p50α may be more important regulators of skeletal muscle insulin signaling and sensitivity.
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影响因子：
8.1
作者：
Dent JR;Martins VF;Svensson K;LaBarge SA;Schlenk NC;Esparza MC;Buckner EH;Meyer GA;Hamilton DL;Schenk S;Philp A
通讯作者：
Philp A
通过p85α单体二聚体平衡对PI3K途径进行调节。
影响因子：
7.7
作者：
Cheung LW;Walkiewicz KW;Besong TM;Guo H;Hawke DH;Arold ST;Mills GB
通讯作者：
Mills GB
影响因子：
3.5
作者：
LEE, AD;HANSEN, PA;HOLLOSZY, JO
通讯作者：
HOLLOSZY, JO
影响因子：
15.9
作者：
Mauvais-Jarvis, F;Ueki, K;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
29
作者：
O'Neill, Brian T.;Kim, Jaetaek;Abel, E. Dale
通讯作者：
Abel, E. Dale