D'Souza Kenneth, Kane Daniel A, Touaibia Mohamed, Kershaw Erin E, Pulinilkunnil Thomas, Kienesberger Petra C
Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, Canada.
Department of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada.
Endocrinology. 2017 Apr 1;158(4):791-803. doi: 10.1210/en.2017-00035.
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-γ 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.
自分泌运动因子（ATX）是一种能产生生物活性脂质——溶血磷脂酸的脂肪因子。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，但脂肪细胞中ATX的营养和激素调节仍不清楚。本研究检测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。用高葡萄糖和胰岛素浓度诱导脂肪细胞产生胰岛素抵抗会增加ATX分泌，而与胰岛素增敏剂罗格列酮共同孵育可阻止这种反应。此外，葡萄糖以时间和浓度依赖性方式独立增加ATX信使核糖核酸（mRNA）、蛋白质和活性。葡萄糖还能急性上调皮下脂肪组织外植体中分泌的ATX活性。胰岛素引发双相反应。急性胰岛素刺激以PI3激酶依赖性和mTORC1非依赖性方式增加ATX活性，而慢性胰岛素刺激则降低ATX mRNA、蛋白质和活性。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。虽然抑制ATX可增加过氧化物酶体增殖物激活受体γ及其下游靶点的表达，但胰岛素信号传导和线粒体呼吸不受影响。然而，抑制ATX可增强线粒体过氧化氢的产生。综上所述，本研究表明脂肪细胞分泌的ATX受葡萄糖和胰岛素的差异调节。本研究还表明，抑制自分泌/旁分泌的ATX-溶血磷脂酸信号传导不会影响胰岛素信号传导或线粒体呼吸，但会增加脂肪细胞中活性氧的产生。
