Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling
Regulation of Insulin Receptor Pathway and Glucose Metabolism by CD36 Signaling
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DOI：
10.2337/db17-1226
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发表时间：
2018-07-01
期刊：
影响因子：
7.7
通讯作者：
Abumrad, Nada A.
中科院分区：
文献类型：
--
作者：
Samovski, Dmitri;Dhule, Pallavi;Abumrad, Nada A.
在能量摄入减少期间，骨骼肌通过快速抑制胰岛素刺激的葡萄糖利用来维持体内平衡。由于脂肪酸转运蛋白 CD36 的缺乏，观察到这种适应能力的丧失。类似的损失也是 CD36 功能失调的胰岛素抵抗状态的特征。为了阐明 CD36 与肌肉葡萄糖利用之间的联系，我们检查了 CD36 信号传导是否可能影响胰岛素作用。首先，我们发现骨骼肌特异性的 CD36 缺失会降低胰岛素信号和葡萄糖代谢基因的表达。它会减少肌肉神经酰胺，但会损害进餐期间的葡萄糖处理。其次，CD36 的消耗会抑制原代人肌管中的胰岛素信号传导，并且该机制被证明涉及 CD36 与胰岛素受体 (IR) 的功能性相互作用。 CD36 通过 Fyn 激酶促进 IR 的酪氨酸磷酸化，并增强 P85 和下游信号传导的 IR 募集。第三，用饱和脂肪酸预处理15分钟抑制CD36-Fyn增强IR磷酸化，而不饱和脂肪酸是中性或刺激性的。这些发现定义了对肌肉葡萄糖代谢和最佳胰岛素反应性重要的机制。全基因组分析和 RNA 测序数据表明了潜在的人类相关性，这些数据将基因决定的低肌肉 CD36 表达与 2 型糖尿病的发病率联系起来。
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin-resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization, we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes. It decreases muscle ceramides but impairs glucose disposal during a meal. Second, depletion of CD36 suppresses insulin signaling in primary-derived human myotubes, and the mechanism is shown to involve functional CD36 interaction with the insulin receptor (IR). CD36 promotes tyrosine phosphorylation of IR by the Fyn kinase and enhances IR recruitment of P85 and downstream signaling. Third, pretreatment for 15 min with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, whereas unsaturated fatty acids are neutral or stimulatory. These findings define mechanisms important for muscle glucose metabolism and optimal insulin responsiveness. Potential human relevance is suggested by genome-wide analysis and RNA sequencing data that associate genetically determined low muscle CD36 expression to incidence of type 2 diabetes.