High-throughput drug screening models of mature adipose tissues which replicate the physiology of patients' Body Mass Index (BMI).
High-throughput drug screening models of mature adipose tissues which replicate the physiology of patients' Body Mass Index (BMI).
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DOI：
10.1016/j.bioactmat.2021.05.020
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发表时间：
2022-01
影响因子：
18.9
通讯作者：
Matsusaki M
中科院分区：
文献类型：
--
作者：
Louis F;Sowa Y;Kitano S;Matsusaki M
肥胖是一种复杂且不完全了解的疾病，但目前的药物筛选策略大多依赖于不成熟的体外脂肪模型，无法正确概括它。为了解决这个问题，我们开发了一种统计验证的高通量筛选模型，通过种植患者的成熟脂肪细胞，包裹在生理性胶原微纤维中。这些脱落组织确保了脂肪细胞活性的维持，以及控制葡萄糖和脂肪酸摄取以及甘油释放的功能。因此，患者的BMI和胰岛素敏感性显示出强烈的负相关：健康的脂肪细胞与胰岛素诱导的葡萄糖摄取量最高相关，而体重不足和严重肥胖的脂肪细胞则证实了胰岛素抵抗。使用两种2型糖尿病治疗方法罗格列酮和褪黑素可以恢复胰岛素敏感性。最后，在模型中加入血管系统似乎更准确地概括了体内的生理学，特别是瘦素的分泌代谢。成熟的高通量筛查模型，了解肥胖的复杂性。与患者体重指数相关的成熟脂肪细胞活性和功能的维持。胰岛素敏感性多样性是可以复制和恢复的。再加上血管重建，更能体现患者的生理机能。
Obesity is a complex and incompletely understood disease, but current drug screening strategies mostly rely on immature in vitro adipose models which cannot recapitulate it properly. To address this issue, we developed a statistically validated high-throughput screening model by seeding human mature adipocytes from patients, encapsulated in physiological collagen microfibers. These drop tissues ensured the maintenance of adipocyte viability and functionality for controlling glucose and fatty acids uptake, as well as glycerol release. As such, patients’ BMI and insulin sensitivity displayed a strong inverse correlation: the healthy adipocytes were associated with the highest insulin-induced glucose uptake, while insulin resistance was confirmed in the underweight and severely obese adipocytes. Insulin sensitivity recovery was possible with two type 2 diabetes treatments, rosiglitazone and melatonin. Finally, the addition of blood vasculature to the model seemed to more accurately recapitulate the in vivo physiology, with particular respect to leptin secretion metabolism. Mature high-throughput screening model to understand the obesity complexity. Maintenance of mature adipocyte viability and functionality regarding patients' BMI. Insulin sensitivity diversity can be reproduced and recovered. Addition of blood vasculature recapitulates even more the patients' physiology.
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