Data-driven identification of small molecules inducing brown adipocyte activation and differentiation

Abstract

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 are often inefficient. Small molecules, however, can facilitate this process through safe, rapid mechanisms. In our study, we employed the Drug Enhanced Cell Conversion using Differential Expression (DECCODE) method, an unbiased drug-induced transcriptomics approach, to identify small molecules that facilitate cell conversion. We began by establishing a transcriptomic profile of human pluripotent stem cell (PSC)-derived BAT cells as our target, then assessed small molecules from the Library of Integrated Network-based Cellular Signatures (LINCS) collection for similarity to this target, identifying a candidate pool. Experimental validation in human thermogenic adipocytes showed that two drugs already approved for other indications, Saxagliptin and Tolvaptan, significantly enhance thermogenic activation. Our approach offers a practical, resource-efficient way to identify small molecules with repurposing potential. While thorough experimental validation remains essential, this in silico framework is versatile and could be broadly applied across various cellular lineages.