Adipose Tissue is very versatile and essential for studies related to Obesity and Diabetes, however, the high buoyancy, fragility, and heterogeneity of primary adipocytes have largely prevented their use in drug discovery efforts, emphasizing the importance of human stem cell-based approaches.
Adipose Tissue Microphysiological systems can provide us with robust models for drug discovery as new differentiation conditions yielding hormonally responsive iADIPO are derived using three separate insulin sensitivity assays, namely glucose and fatty acid absorption and inhibition of lipolysis, as functional readouts.
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The authors state that “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 to create insulin-resistant WAT are 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 able 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.”.
Qi L, Zushin PH, Chang CF, Lee YT, Alba DL, Koliwad SK, Stahl A. Probing Insulin Sensitivity with Metabolically Competent Human Stem Cell-Derived White Adipose Tissue Microphysiological Systems. Small. 2021 Nov 10:e2103157. doi: 10.1002/smll.202103157. Epub ahead of print. PMID: 34761526.