FA1 Induces Pro-Inflammatory and Anti-Adipogenic Pathways/Markers in Human Myotubes Established from Lean, Obese, and Type 2 Diabetic Subjects but Not Insulin Resistance.
FA1 Induces Pro-Inflammatory and Anti-Adipogenic Pathways/Markers in Human Myotubes Established from Lean, Obese, and Type 2 Diabetic Subjects but Not Insulin Resistance.
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FA1诱导通过瘦，肥胖和2型糖尿病患者建立的人肌管中的促炎和抗辅助途径/标记，但不胰岛素抵抗。
DOI：
10.3389/fendo.2013.00045
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发表时间：
2013
影响因子：
5.2
通讯作者：
Gaster M
中科院分区：
文献类型：
--
作者：
Abdallah BM;Beck-Nielsen H;Gaster M
目的：Delta like 1/fetal antigen 1（Dlk 1/FA 1）是由成年人和小鼠中的激素产生细胞分泌的蛋白质，已知其抑制脂肪生成。最近的研究表明Dlk 1/FA 1在诱导小鼠胰岛素抵抗中的作用。为了研究循环Dlk 1/FA 1在人类受试者中胰岛素抵抗和2型糖尿病中的参与，我们研究了慢性FA 1对从瘦、肥胖和2型糖尿病（T2 D）受试者建立的肌管中的中间代谢的影响。研究方法：从瘦和肥胖对照受试者以及肥胖T2 D受试者建立肌管培养物，并用补充有/没有棕榈酸酯（PA）的可溶性FA 1处理4天。脂质和葡萄糖代谢进行了研究与标记的前体，而基因的定量表达进行了分析，使用实时PCR。结果如下：与瘦肌管相比，糖尿病肌管表达显著降低的胰岛素刺激的葡萄糖代谢和显著降低的基础PA氧化。慢性FA 1暴露不影响肌管的中间代谢。葡萄糖和脂质代谢的胰岛素敏感性不受慢性FA 1暴露于瘦，肥胖和T2 D受试者建立的肌管的影响。相反，慢性FA 1暴露诱导促炎细胞因子表达（IL-6和CCL 2）与减少肌管中的脂肪形成标志物（ADD 1，AP 2，CD 36和PPARg 2）。与该观察结果一致，向培养的肌管中添加FA 1显示出显著抑制它们分化成脂肪细胞。结论：我们的研究结果排除了FA 1对从瘦，肥胖和T2 D受试者建立的培养肌管中葡萄糖和脂质代谢的直接影响。因此，FA 1诱导的IR的发病机制可能主要是通过FA 1诱导的促炎细胞因子的刺激介导的，促炎细胞因子反过来抑制人肌管中的脂肪生成。
Aims: Delta like 1/fetal antigen 1 (Dlk1/FA1) is a protein secreted by hormone producing cells in adult human and mice that is known to inhibit adipogenesis. Recent studies demonstrated the role of Dlk1/FA1 in inducing insulin resistance in mice. To investigate the involvement of circulating Dlk1/FA1 in insulin resistance and type 2 diabetes in human subjects, we studied the effects of chronic FA1 on the intermediary metabolism in myotubes established from lean, obese, and type 2 diabetic (T2D) subjects. Methods: Myotube cultures were established from lean and obese control subjects, and obese T2D subjects and treated with soluble FA1 for 4 days supplemented with/without palmitate (PA). Lipid- and glucose metabolism were studied with labeled precursors while quantitative expression of genes was analyzed using real-time PCR. Results: Diabetic myotubes express significantly reduced insulin stimulated glucose metabolism compared to lean myotubes and a significantly decreased basal PA oxidation. Chronic FA1 exposure did not affect the intermediary metabolism in myotubes. Insulin sensitivity of glucose and lipid metabolism was not affected by chronic FA1 exposure in myotubes established from lean, obese, and T2D subjects. Instead, chronic FA1 exposure induced pro-inflammatory cytokines expression (IL-6 and CCL2) in association with reducing adipogenic markers (ADD1, AP2, CD36, and PPARg2) in myotubes. Consistent with this observation, addition of FA1 to cultured myotubes was show to significantly inhibit their differentiation into adipocyte. Conclusion: Our results exclude direct effects of FA1 on glucose and lipid metabolism in cultured myotubes established from lean, obese, and T2D subjects. Therefore, the pathogenesis of FA1-induced IR might mainly be mediated via the FA1-induced stimulation of pro-inflammatory cytokines, which on turn inhibit adipogenesis in human myotubes.