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Towards an Insulin Resistant Adipose Model on a Chip

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Abstract

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.

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Acknowledgments

We acknowledge support from the Diabetes Research and Training Center (DRTC) at the University of Chicago. We gratefully acknowledge Dr. Nick Menhart and the Idea shop at Illinois Institute of Technology for technical assistance. We thank Dr. Gokhan Dalgin at University of Chicago for assistance with qPCR.

Funding

This work was supported by DRTC Grant P30 DK020595 and student scholarships from the Armor College of Engineering.

Conflict of interest

Authors Nida Tanataweethum, Franklin Zhong, Allyson Trang, Chaeeun Lee, Ronald N. Cohen, Abhinav Bhushan declare that they have no conflict of interest.

Ethical Approval

The studies were conducted with the approval and in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines. This article does not contain any studies with human participants performed by any of the authors.

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  1. Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, 60616, USA

    Nida Tanataweethum, Franklin Zhong, Allyson Trang, Chaeeun Lee & Abhinav Bhushan

  2. Section of Endocrinology, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA

    Ronald N. Cohen

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  1. Nida Tanataweethum
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Tanataweethum, N., Zhong, F., Trang, A. et al. Towards an Insulin Resistant Adipose Model on a Chip. Cel. Mol. Bioeng. 14, 89–99 (2021). https://doi.org/10.1007/s12195-020-00636-x

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