Overexpression of the adiponectin receptor AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity.
Overexpression of the adiponectin receptor AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity.
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大鼠骨骼肌中脂联素受体adipor1的过表达会扩增局部胰岛素敏感性。
DOI：
10.1210/en.2012-1368
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发表时间：
2012-11
期刊：
影响因子：
4.8
通讯作者：
Cleasby ME
中科院分区：
文献类型：
--
作者：
Patel SA;Hoehn KL;Lawrence RT;Sawbridge L;Talbot NA;Tomsig JL;Turner N;Cooney GJ;Whitehead JP;Kraegen EW;Cleasby ME
脂联素是一种脂肪因子，其血浆水平与胰岛素抵抗(IR)或肥胖程度呈负相关。它促进骨骼肌中葡萄糖的代谢和线粒体底物的氧化，其作用是通过与受体特别是脂联素受体1(AdipoR1)的结合而实现的。然而，脂联素敏感性的体内意义以及脂联素增敏肌肉胰岛素的分子机制尚未完全确定。我们采用体内电转移的方法，在大鼠单块肌肉中过表达AdipoR1，其中一些大鼠在饲料或高脂饲料(HFD)喂养6wk后，进行高胰岛素-正常血糖钳夹。在1wk后，在测试肌肉和对侧对照肌肉中研究对葡萄糖处置、信号和鞘磷脂代谢的影响。AdipoR1过表达(OE)增加了基础和胰岛素处理的大鼠肌肉中的葡萄糖摄取和糖原积累，也增加了高脂饲料喂养的大鼠的葡萄糖摄取和糖原积累，局部改善了肌肉IR。这些效应与胰岛素受体底物-1、AKT和糖原合成酶-3β的磷酸化增加有关。AdipoR1OE还导致p70S6激酶、AMP激活的蛋白激酶和乙酰辅酶A羧化酶的磷酸化增加，以及含有Pleckstrin同源结构域、磷酸酪氨酸结合结构域、亮氨酸拉链基序-1和脂联素的适配蛋白、过氧化体增殖物激活的受体-γ共激活因子-1α和解偶联蛋白-3的蛋白水平增加，这表明线粒体生物发生增加。虽然高脂饲料喂养和AdipoR1OE都不会引起鞘磷脂的普遍变化，但AdipoR1OE确实降低了神经鞘氨醇1-磷酸、神经酰胺18：1、神经酰胺20：2和二氢神经酰胺20：0的水平，以及神经酰胺合成酶丝氨酸棕榈酰转移酶和鞘磷脂Δ-4去饱和酶的基因水平，这些变化与胰岛素敏感性的增加有关。这些数据表明，局部脂联素敏感性的增强足以改善骨骼肌IR。
Adiponectin is an adipokine whose plasma levels are inversely related to degrees of insulin resistance (IR) or obesity. It enhances glucose disposal and mitochondrial substrate oxidation in skeletal muscle and its actions are mediated through binding to receptors, especially adiponectin receptor 1 (AdipoR1). However, the in vivo significance of adiponectin sensitivity and the molecular mechanisms of muscle insulin sensitization by adiponectin have not been fully established. We used in vivo electrotransfer to overexpress AdipoR1 in single muscles of rats, some of which were fed for 6 wk with chow or high-fat diet (HFD) and then subjected to hyperinsulinemic-euglycemic clamp. After 1 wk, the effects on glucose disposal, signaling, and sphingolipid metabolism were investigated in test vs. contralateral control muscles. AdipoR1 overexpression (OE) increased glucose uptake and glycogen accumulation in the basal and insulin-treated rat muscle and also in the HFD-fed rats, locally ameliorating muscle IR. These effects were associated with increased phosphorylation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3β. AdipoR1 OE also caused increased phosphorylation of p70S6 kinase, AMP-activated protein kinase, and acetyl-coA carboxylase as well as increased protein levels of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif-1 and adiponectin, peroxisome proliferator activated receptor-γ coactivator-1α, and uncoupling protein-3, indicative of increased mitochondrial biogenesis. Although neither HFD feeding nor AdipoR1 OE caused generalized changes in sphingolipids, AdipoR1 OE did reduce levels of sphingosine 1-phosphate, ceramide 18:1, ceramide 20:2, and dihydroceramide 20:0, plus mRNA levels of the ceramide synthetic enzymes serine palmitoyl transferase and sphingolipid Δ-4 desaturase, changes that are associated with increased insulin sensitivity. These data demonstrate that enhancement of local adiponectin sensitivity is sufficient to improve skeletal muscle IR.
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DOI：
10.1046/j.1365-201x.2003.01162.x
发表时间：
2003-08-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
Hegarty, BD;Furler, SM;Kraegen, EW
通讯作者：
Kraegen, EW
影响因子：
3.4
作者：
Dyck, David J.
通讯作者：
Dyck, David J.
影响因子：
--
作者：
Deepa, Sathyaseelan S.;Zhou, Lijun;Dong, Lily Q.
通讯作者：
Dong, Lily Q.
影响因子：
5.6
作者：
Blachnio-Zabielska, Agnieszka;Baranowski, Marcin;Gorski, Jan
通讯作者：
Gorski, Jan
影响因子：
82.9
作者：
Erion DM;Shulman GI
通讯作者：
Shulman GI