Generation of functional adipoids from human induced pluripotent stem cells

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.