Files
Abstract
Activation of human thermogenic adipocytes is a promising approach to treat obesity and diabetes. Previous studies have identified brown and beige adipocytes as two major types of thermogenic adipocytes with significant contribution to energy expenditure and glucose homeostasis. However, developmental and therapeutic feature of brown and beige adipocytes are still not well understood in human context owing to the difficulty of accessing these cells. Here we report a novel method of generating brown and beige adipocytes from human pluripotent stem cells and adipose-derived stem cells in a chemically-define, serum-free system with high efficiency. Generated brown and beige adipocytes express mature thermogenic adipocytes markers and exhibit uncoupled mitochondrial respiration in vitro. Transplant of generated thermogenic adipocytes also increase whole-body energy expenditure and oxygen consumption. Diabetic mouse received thermogenic adipocytes transplant also showed ameliorated hyperglycemia. To further understand the developmental feature of thermogenic adipocytes, transcriptomic profiling of the differentiation process was performed, and putative stage-wise genetic regulatory networks were proposed. Moreover, through modeling the lineage bifurcation between brown adipocytes and skeletal myocytes, a pool of previously underappreciated dermomyotomal progenitor cells capable of deriving brown adipocytes and skeletal myocytes at high efficiency were identified. Finally, we developed a high-throughput drug screening platform and identified compounds capable of activating beige adipocytes. These findings together reveal the utilities of our work in therapeutic development and understanding developmental mechanism of human thermogenic adipocytes.