Data-driven identification of small molecules inducing Brown Adipocyte differentiation

Promoting the recruitment and function of human brown adipose tissue (BAT) holds significant promise for preventing and treating obesity and related metabolic complications. While identifying genes to enhance BAT recruitment and thermogenic activation is crucial, traditional upregulation methods often lack efficiency. Small molecules, however, can effectively facilitate this process through safe and rapid mechanisms. In our study, we employed the DECCODE method, an unbiased drug-induced transcriptomics approach, to identify small molecules that facilitated cell conversion. We began by establishing a transcriptomic profile of BAT cells as our target and then assessed small molecules from the LINCS collection for their similarity to this target, thus identifying a pool of candidates. Our validation in human thermogenic adipocytes revealed that three drugs—Saxagliptin, Tolvaptan, and Targinine—already approved for other uses significantly enhance BAT recruitment and activation in a human thermogenic adipocyte cellular model. Cell cultures from KOLF2 C1 human induced pluripotent stem (iPS) were differentiated according to a chemically-defined differentiation protocol specifically designed to generate human brown adipocytes (BAs) from PSCs. RNA-seq was performed on samples isolated on Day 50 (D50, three replicates) and Day 60 (D60, three replicates). The transcriptomic profile obtained for D60 was used as an input for the DECCODE method to identify small molecules that could facilitate the differentiation from mesodermal progenitors to mature BAs. The transcriptomic profile obtained for D50 was used to comparative purposes