Probing Insulin Sensitivity with Metabolically Competent Human Stem Cell-Derived White Adipose Tissue...

Area of Science:

• Biotechnology
• Metabolic Research
• Drug Discovery

Background:

• Impaired white adipose tissue (WAT) function is key in obesity-related disorders.
• Primary adipocytes are difficult to use in drug discovery due to fragility and heterogeneity.
• Human stem cell-based models are needed for effective WAT research.

Purpose of the Study:

• To derive metabolically functional 3D human adipose tissue (iADIPO) using human stem cells in a microphysiological system (MPS).
• To develop new differentiation conditions for hormonally responsive iADIPO suitable for type-2 diabetes drug discovery.
• To optimize the iADIPO-MPS for improved lipid droplet size and insulin responsiveness.

Main Methods:

• Utilized human stem cells to create 3D adipose tissue (iADIPO) in an MPS.
• Developed new differentiation protocols focusing on insulin sensitivity assays (glucose/fatty acid uptake, lipolysis suppression).
• Optimized the iADIPO-MPS to enhance lipid droplet characteristics and hormonal responsiveness.

Main Results:

• New differentiation conditions yielded hormonally responsive iADIPO.
• Optimized iADIPO-MPS produced larger lipid droplets (≈40%) compared to 2D cultures.
• Achieved increased insulin responsiveness for glucose (≈2-3 fold) and fatty acid uptake (≈3-6 fold), and ≈40% suppression of lipolysis.

Conclusions:

• The developed iADIPO-MPS offers a robust model for studying WAT function and insulin sensitivity.
• This model provides a dynamic range suitable for identifying insulin sensitizers and desensitizers in type-2 diabetes drug discovery.
• The approach addresses limitations of primary adipocytes and previous WAT models for drug screening.