Autotaxin Is Regulated by Glucose and Insulin in Adipocytes
Autotaxin Is Regulated by Glucose and Insulin in Adipocytes
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DOI：
10.1210/en.2017-00035
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发表时间：
2017-04-01
期刊：
影响因子：
4.8
通讯作者：
Kienesberger, Petra C.
中科院分区：
文献类型：
--
作者：
D'Souza, Kenneth;Kane, Daniel A.;Kienesberger, Petra C.
自体趋化蛋白(ATX)是一种脂肪因子，可产生生物活性脂质--溶血磷脂酸。尽管最近的研究表明脂肪来源的ATX与包括肥胖和胰岛素抵抗在内的代谢紊乱有关，但ATX在脂肪细胞中的营养和激素调节仍不清楚。本研究探讨了葡萄糖和胰岛素对脂肪细胞中ATX的调节作用，以及ATX在脂肪细胞代谢中的作用。在高糖和高胰岛素浓度下诱导脂肪细胞胰岛素抵抗可增加ATX的分泌，而与胰岛素增敏剂罗格列酮共同孵育可阻止这一反应。此外，葡萄糖以时间和浓度依赖的方式独立地增加ATX信使RNA(MRNA)、蛋白质和活性。葡萄糖还显著上调了皮下脂肪组织外植体分泌的ATX活性。胰岛素引起了双相反应。急性胰岛素刺激以PI3Kinase依赖和mTORC1非依赖的方式增加ATX活性，而慢性胰岛素刺激则降低ATX的mRNA、蛋白和活性。为了研究ATX在3T3-L1脂肪细胞中的代谢作用，我们将细胞与ATX抑制剂PF-8380孵育24小时。而ATX抑制可增加过氧化物酶体增殖物激活受体-g及其下游靶点的表达，而胰岛素信号转导和线粒体呼吸不受影响。然而，ATX抑制增加了线粒体过氧化氢的产生。综上所述，这项研究表明，脂肪细胞的ATX分泌受到葡萄糖和胰岛素的不同调节。这项研究还表明，抑制自分泌/旁分泌ATX-溶血磷脂酸信号不会影响胰岛素信号或线粒体呼吸，但会增加脂肪细胞中活性氧的产生。
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response. Moreover, glucose independently increased ATX messenger RNA (mRNA), protein, and activity in a time- and concentration-dependent manner. Glucose also acutely upregulated secreted ATX activity in subcutaneous adipose tissue explants. Insulin elicited a biphasic response. Acute insulin stimulation increased ATX activity in a PI3Kinase-dependent and mTORC1-independent manner, whereas chronic insulin stimulation decreased ATX mRNA, protein, and activity. To examine the metabolic role of ATX in 3T3-L1 adipocytes, we incubated cells with the ATX inhibitor, PF-8380, for 24 hours. Whereas ATX inhibition increased the expression of peroxisome proliferator-activated receptor-g and its downstream targets, insulin signaling and mitochondrial respiration were unaffected. However, ATX inhibition enhanced mitochondrial H2O2 production. Taken together, this study suggests that ATX secretion from adipocytes is differentially regulated by glucose and insulin. This study also suggests that inhibition of autocrine/paracrine ATX-lysophosphatidic acid signaling does not influence insulin signaling or mitochondrial respiration, but increases reactive oxygen species production in adipocytes.