The PhD Program for Neural Regenerative Medicine, College of Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes (NHRI), 250 Wuxing St. Taipei, Taiwan, 110.
Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Sci Rep. 2016 Nov 29;6:37659. doi: 10.1038/srep37659.
Many neurodegenerative diseases are accompanied by metabolic disorders. CCL5/RANTES, and its receptor CCR5 are known to contribute to neuronal function as well as to metabolic disorders such as type 2 diabetes mellitus, obesity, atherosclerosis and metabolic changes after HIV infection. Herein, we found that the lack of CCR5 or CCL5 in mice impaired regulation of energy metabolism in hypothalamus. Immunostaining and co-immunoprecipitation revealed the specific expression of CCR5, associated with insulin receptors, in the hypothalamic arcuate nucleus (ARC). Both ex vivo stimulation and in vitro tissue culture studies demonstrated that the activation of insulin, and PI3K-Akt pathways were impaired in CCR5 and CCL5 deficient hypothalamus. The inhibitory phosphorylation of insulin response substrate-1 at Ser302 (IRS-1) but not IRS-2, by insulin was markedly increased in CCR5 and CCL5 deficient animals. Elevating CCR5/CCL5 activity induced GLUT4 membrane translocation and reduced phospho-IRS-1 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, CCL5, abolished the de-phosphorylation of IRS-1 and insulin signal activation. In addition, intracerebroventricular delivery of CCL5 interrupted hypothalamic insulin signaling and elicited peripheral insulin responsiveness and glucose intolerance. Taken together, our data suggest that CCR5 regulates insulin signaling in hypothalamus which contributes to systemic insulin sensitivity and glucose metabolism.
许多神经退行性疾病伴随着代谢紊乱。趋化因子 CCL5/RANTES 及其受体 CCR5 不仅与神经元功能有关，还与代谢紊乱有关，如 2 型糖尿病、肥胖症、动脉粥样硬化和 HIV 感染后的代谢变化。在此，我们发现 CCR5 或 CCL5 的缺失会损害下丘脑的能量代谢调节。免疫染色和共免疫沉淀显示 CCR5 与胰岛素受体在下丘脑弓状核（ARC）中特异性表达。离体刺激和体外组织培养研究表明，胰岛素和 PI3K-Akt 途径的激活在 CCR5 和 CCL5 缺乏的下丘脑受到损害。胰岛素对胰岛素反应底物-1（IRS-1）Ser302 的抑制性磷酸化（IRS-1）而非 IRS-2 在 CCR5 和 CCL5 缺乏的动物中显著增加。提高 CCR5/CCL5 活性可诱导 GLUT4 膜易位，并通过 AMPKα-S6 激酶减少磷酸化 IRS-1。使用拮抗剂 CCL5 阻断 CCR5 可消除 IRS-1 的去磷酸化和胰岛素信号的激活。此外，CCL5 脑室给药可中断下丘脑的胰岛素信号传递，并引起外周胰岛素反应性和葡萄糖耐量下降。总之，我们的数据表明 CCR5 调节下丘脑的胰岛素信号转导，这有助于全身胰岛素敏感性和葡萄糖代谢。
