Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome
Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome
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DOI：
10.1038/ijo.2016.129
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发表时间：
2016-11-01
影响因子：
4.9
通讯作者：
Grattoni, A.
中科院分区：
文献类型：
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作者：
Filgueira, C. S.;Nicolov, E.;Grattoni, A.
背景/目的：我们的目的是评估持续，低剂量和恒定的甲状腺受体β（TR β）选择性激动剂GC-1（sobetirome）从一种新的纳米通道膜装置（NMD）的药物输送管理。由于已知GC-1可加速代谢、实现体重减轻、改善胆固醇水平并具有抗糖尿病作用，因此通过我们的NMD稳定施用GC-1，该NMD由可植入纳米通道膜组成，作为常规每日施用的替代方案，其在临床环境中受到依从性问题的影响。饮食诱导的肥胖C57 BL/J6雄性小鼠喂食极高脂肪饮食（VHFD）并皮下接受NMD植入物。每组10只小鼠接受含有GC-1或磷酸盐缓冲盐水（对照）的胶囊。监测体重、瘦体重和脂肪量以及胆固醇、甘油三酯、胰岛素和葡萄糖24天。治疗后比较两组血浆促甲状腺激素（TSH）和甲状腺素水平。在白色脂肪组织（WAT）和棕色脂肪组织（BAT）中使用实时PCR检测一组产热标志物的mRNA水平。对脂肪组织、肝脏和对植入物的局部炎症反应进行组织学检查。结果：NMD释放的GC-1逆转了VHFD诱导的肥胖，并使血清胆固醇和甘油三酯正常化。在10天内观察到体重和脂肪量显著降低，而在7天内观察到血清胆固醇和葡萄糖水平降低。TSH的显著降低与TR β对GC-1的选择性一致。在NMD-GC-1处理的小鼠中，Ucp 1和产热基因PGC 1 α、Cidea、Dio 2和Cox 5 α的转录水平在WAT中显示出显著上调，但在BAT中降低。虽然NMD-GC-1治疗的小鼠表现出类似数量的胰岛，他们表现出显着增加β-cell area.CONCLUSIONS：我们的数据表明，NMD植入物实现稳定的GC-1管理，提供了一个有效的和严格控制的分子传递系统治疗肥胖症和代谢性疾病，从而解决遵守。
BACKGROUND/OBJECTIVES: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-beta (TR beta)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings.SUBJECTS/METHODS: Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and beta-cell area were assessed.RESULTS: GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TR beta selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1 alpha, Cidea, Dio2 and Cox5 alpha showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD-GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in beta-cell area.CONCLUSIONS: Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.