Probing Insulin Sensitivity with Metabolically Competent Human Stem Cell-Derived White Adipose Tissue Microphysiological Systems
Lin Qi
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorPeter-James H. Zushin
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorChing-Fang Chang
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorYue Tung Lee
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorDiana L. Alba
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, 94143 USA
Diabetes Center, University of California, San Francisco, San Francisco, CA, 94143 USA
Search for more papers by this authorSuneil K. Koliwad
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, 94143 USA
Diabetes Center, University of California, San Francisco, San Francisco, CA, 94143 USA
Search for more papers by this authorCorresponding Author
Andreas Stahl
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
E-mail: [email protected]
Search for more papers by this authorLin Qi
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorPeter-James H. Zushin
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorChing-Fang Chang
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorYue Tung Lee
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
Search for more papers by this authorDiana L. Alba
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, 94143 USA
Diabetes Center, University of California, San Francisco, San Francisco, CA, 94143 USA
Search for more papers by this authorSuneil K. Koliwad
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA, 94143 USA
Diabetes Center, University of California, San Francisco, San Francisco, CA, 94143 USA
Search for more papers by this authorCorresponding Author
Andreas Stahl
Department of Nutritional Science and Toxicology, College of Natural Resources, University of California, Berkeley, Berkeley, CA, 94720 USA
E-mail: [email protected]
Search for more papers by this authorAbstract
Impaired white adipose tissue (WAT) function has been recognized as a critical early event in obesity-driven disorders, but high buoyancy, fragility, and heterogeneity of primary adipocytes have largely prevented their use in drug discovery efforts highlighting the need for human stem cell-based approaches. Here, human stem cells are utilized to derive metabolically functional 3D adipose tissue (iADIPO) in a microphysiological system (MPS). Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery. Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived. Through concomitant optimization of an iADIPO-MPS, it is abled to obtain WAT with more unilocular and significantly larger (≈40%) lipid droplets compared to iADIPO in 2D culture, increased insulin responsiveness of glucose uptake (≈2–3 fold), fatty acid uptake (≈3–6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models, allowing to identify both insulin sensitizers and desensitizers.
Conflict of Interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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