Tanataweethum Nida, Zhong Franklin, Trang Allyson, Lee Chaeeun, Cohen Ronald N, Bhushan Abhinav
Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616 USA.
Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, IL 60637 USA.
Cell Mol Bioeng. 2020 Jul 14;14(1):89-99. doi: 10.1007/s12195-020-00636-x. eCollection 2021 Feb.
Adipose tissue and adipocytes are primary regulators of insulin sensitivity and energy homeostasis. Defects in insulin sensitivity of the adipocytes predispose the body to insulin resistance (IR) that could lead to diabetes. However, the mechanisms mediating adipocyte IR remain elusive, which emphasizes the need to develop experimental models that can validate the insulin signaling pathways and discover new mechanisms in the search for novel therapeutics. Currently adipose organ-chip devices show superior cell function over conventional cell culture. However, none of these models represent disease states. Only when these models can represent both healthy and disease states, they can be useful for developing therapeutics. Here, we establish an organ-on-chip model of insulin-resistant adipocytes, as well as characterization in terms of insulin signaling pathway and lipid metabolism.
We differentiated, maintained, and induced insulin resistance into primary adipocytes in a microfluidic organ-on-chip. We then characterized IR by looking at the insulin signaling pathway and lipid metabolism, and validated by studying a diabetic drug, rosiglitazone.
We confirmed the presence of insulin resistance through reduction of Akt phosphorylation, Glut4 expression, Glut4 translocation and glucose uptake. We also confirmed defects of disrupted insulin signaling through reduction of lipid accumulation from fatty acid uptake and elevation of glycerol secretion. Testing with rosiglitazone showed a significant improvement in insulin sensitivity and fatty acid metabolism as suggested by previous reports.
The adipose-chip exhibited key characteristics of IR and can serve as model to study diabetes and facilitate discovery of novel therapeutics.
脂肪组织和脂肪细胞是胰岛素敏感性和能量稳态的主要调节因子。脂肪细胞胰岛素敏感性缺陷使机体易患胰岛素抵抗（IR），进而可能导致糖尿病。然而，介导脂肪细胞IR的机制仍不清楚，这凸显了开发能够验证胰岛素信号通路并在寻找新型疗法过程中发现新机制的实验模型的必要性。目前，脂肪器官芯片装置相较于传统细胞培养显示出卓越的细胞功能。然而，这些模型均未代表疾病状态。只有当这些模型能够同时代表健康和疾病状态时，它们才有助于开发治疗方法。在此，我们建立了胰岛素抵抗脂肪细胞的芯片器官模型，并对胰岛素信号通路和脂质代谢进行了表征。
我们在微流控芯片器官中对原代脂肪细胞进行分化、维持并诱导胰岛素抵抗。然后，我们通过观察胰岛素信号通路和脂质代谢来表征IR，并通过研究糖尿病药物罗格列酮进行验证。
我们通过降低Akt磷酸化、Glut4表达、Glut4转位和葡萄糖摄取证实了胰岛素抵抗的存在。我们还通过减少脂肪酸摄取导致的脂质积累和甘油分泌增加证实了胰岛素信号传导中断的缺陷。如先前报道所示，用罗格列酮进行测试显示胰岛素敏感性和脂肪酸代谢有显著改善。
脂肪芯片展现出IR的关键特征，可作为研究糖尿病的模型并有助于发现新型疗法。
