Introduction

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 in vitro adipose organ-chip devices show superior cell function over conventional cell culture. However, none of these models represent disease states. Only when these in vitro 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.

Methods

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.

Results

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.

Conclusions

The adipose-chip exhibited key characteristics of IR and can serve as model to study diabetes and facilitate discovery of novel therapeutics.

中文翻译：

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迈向芯片上的抗胰岛素脂肪模型

介绍

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剂。脂肪细胞的胰岛素敏感性缺陷使身体容易产生可能导致糖尿病的胰岛素抵抗 (IR)。然而，介导脂肪细胞 IR 的机制仍然难以捉摸，这强调需要开发能够验证胰岛素信号通路并发现寻找新疗法的新机制的实验模型。目前，体外脂肪器官芯片装置显示出优于传统细胞培养的细胞功能。然而，这些模型都不代表疾病状态。只有当这些在体外模型可以代表健康和疾病状态，它们可用于开发治疗方法。在这里，我们建立了胰岛素抵抗脂肪细胞的器官芯片模型，以及胰岛素信号通路和脂质代谢方面的表征。

方法

我们在微流控芯片上将胰岛素抵抗分化、维持和诱导成原代脂肪细胞。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。

结果

我们通过减少 Akt 磷酸化、Glut4 表达、Glut4 易位和葡萄糖摄取来证实存在胰岛素抵抗。我们还通过减少脂肪酸摄取引起的脂质积累和甘油分泌升高证实了胰岛素信号传导中断的缺陷。正如之前的报告所暗示的，用罗格列酮进行的测试显示胰岛素敏感性和脂肪酸代谢有显着改善。

结论

脂肪芯片展示了 IR 的关键特征，可以作为研究糖尿病的模型并促进新疗法的发现。