Hinte, L. C.; Okamoto, R.; Jansen, S.; Spirig, S. E.; Tsiepa, S.; Shimobayashi, M.; Hall, M. N.

Human adipose tissue models are lacking although essential for metabolic research. Traditional primary cell cultures are poorly scalable and unsuitable for drug screening or modeling of genetic disease. Conventional two-dimensional adipocyte cultures cannot withstand the long-term treatment required to mimic chronic conditions such as obesity and insulin resistance. To overcome these limitations, we developed an accessible protocol to produce three-dimensional human induced pluripotent stem cell (hiPSC)-derived adipocyte microtissues, termed adipoids. hiPSC-derived adipoids display long-term stability and viability. Single-nucleus RNA sequencing revealed that adipoids contain mature adipocytes and adipocyte stem/progenitor cells, similar to human adipose tissue. Furthermore, hiPSC-derived adipoids contain unilocular adipocytes, exhibit stimulated lipolysis, and secrete adipokines. Thus, hiPSC-derived adipoids provide a functional, scalable and genetically tractable model to perform large-scale pharmacological screens and to investigate human metabolic disease.