Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes.
Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes.
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DOI：
10.1016/j.molmet.2015.06.009
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发表时间：
2015-09
影响因子：
8.1
通讯作者：
Leitinger N
中科院分区：
文献类型：
--
作者：
Adamson SE;Meher AK;Chiu YH;Sandilos JK;Oberholtzer NP;Walker NN;Hargett SR;Seaman SA;Peirce-Cottler SM;Isakson BE;McNamara CA;Keller SR;Harris TE;Bayliss DA;Leitinger N
脂肪细胞中的葡萄糖摄取缺陷会导致代谢稳态受损和胰岛素抵抗，这是 2 型糖尿病的标志。细胞外 ATP 衍生的核苷酸和核苷是脂肪细胞功能的重要调节剂，但脂肪细胞控制 ATP 释放的途径尚不清楚。在这里，我们研究了 Pannexin 1 (Panx1) 通道是否控制脂肪细胞的 ATP 释放并有助于代谢稳态。我们通过测量已知 Panx1 通道激活剂的 ATP 释放来评估培养的 3T3-L1 脂肪细胞和从鼠白色脂肪组织分离的脂肪细胞中的 Panx1 功能。在 Panx1 药理学抑制剂存在下，以及从我们实验室生成的野生型 (WT) 或脂肪细胞特异性 Panx1 敲除 (AdipPanx1 KO) 小鼠的白色脂肪组织中分离的脂肪细胞中，测量培养的 3T3-L1 脂肪细胞中的葡萄糖摄取。我们对喂食的 WT 和 AdipPanx1 KO 小鼠进行了体内葡萄糖摄取研究，并评估了喂食高脂肪饮食 12 周的 WT 和 AdipPanx1 KO 小鼠的胰岛素抵抗。通过在异源表达系统中进行电生理记录来评估 Panx1 通道功能对胰岛素的反应。最后，我们通过 qRT-PCR 测量了人内脏脂肪组织样本中的 Panx1 mRNA，并将表达水平与患者的血糖水平和 HOMA-IR 测量结果进行了比较。我们的数据表明，脂肪细胞表达功能性 Pannexin 1 (Panx1) 通道，可被激活以释放 ATP。对脂肪细胞中的 Panx1 进行药理学抑制或选择性基因删除可减少体外和体内胰岛素诱导的葡萄糖摄取，并加剧小鼠饮食诱导的胰岛素抵抗。此外，我们确定胰岛素是 Panx1 通道的新型激活剂。在肥胖人群中，脂肪组织中 Panx1 的表达增加，并与胰岛素抵抗程度相关。我们发现 Panx1 通道活性调节脂肪细胞中胰岛素刺激的葡萄糖摄取，从而有助于控制代谢稳态。脂肪细胞表达 Pannexin 1 通道，可被激活以释放 ATP。抑制 Pannexin 1 可减少脂肪细胞中胰岛素诱导的葡萄糖摄取。脂肪细胞 Pannexin 1 基因敲除小鼠对高脂肪饮食的胰岛素抵抗程度更高。我们将胰岛素确定为 Pannexin 1 通道的新型激活剂。人类脂肪组织中的 Pannexin 1 表达与胰岛素抵抗相关。
Defective glucose uptake in adipocytes leads to impaired metabolic homeostasis and insulin resistance, hallmarks of type 2 diabetes. Extracellular ATP-derived nucleotides and nucleosides are important regulators of adipocyte function, but the pathway for controlled ATP release from adipocytes is unknown. Here, we investigated whether Pannexin 1 (Panx1) channels control ATP release from adipocytes and contribute to metabolic homeostasis. We assessed Panx1 functionality in cultured 3T3-L1 adipocytes and in adipocytes isolated from murine white adipose tissue by measuring ATP release in response to known activators of Panx1 channels. Glucose uptake in cultured 3T3-L1 adipocytes was measured in the presence of Panx1 pharmacologic inhibitors and in adipocytes isolated from white adipose tissue from wildtype (WT) or adipocyte-specific Panx1 knockout (AdipPanx1 KO) mice generated in our laboratory. We performed in vivo glucose uptake studies in chow fed WT and AdipPanx1 KO mice and assessed insulin resistance in WT and AdipPanx1 KO mice fed a high fat diet for 12 weeks. Panx1 channel function was assessed in response to insulin by performing electrophysiologic recordings in a heterologous expression system. Finally, we measured Panx1 mRNA in human visceral adipose tissue samples by qRT-PCR and compared expression levels with glucose levels and HOMA-IR measurements in patients. Our data show that adipocytes express functional Pannexin 1 (Panx1) channels that can be activated to release ATP. Pharmacologic inhibition or selective genetic deletion of Panx1 from adipocytes decreased insulin-induced glucose uptake in vitro and in vivo and exacerbated diet-induced insulin resistance in mice. Further, we identify insulin as a novel activator of Panx1 channels. In obese humans Panx1 expression in adipose tissue is increased and correlates with the degree of insulin resistance. We show that Panx1 channel activity regulates insulin-stimulated glucose uptake in adipocytes and thus contributes to control of metabolic homeostasis. Adipocytes express Pannexin 1 channels that can be activated to release ATP. Inhibition of Pannexin 1 decreased insulin-induced glucose uptake in adipocytes. Adipocyte Pannexin 1 knockout mice are more insulin resistant on high fat diet. We identify insulin as a novel activator of Pannexin 1 channels. Pannexin 1 expression in human adipose tissue correlates with insulin resistance.