Brown adipocytes (BAs) are a potential cell source for the treatment of metabolic disease, including type 2 diabetes. In this report, human pluripotent stem cells (hPSCs) are subject to directed differentiation through a paraxial mesoderm progenitor state that generates BAs at high efficiency. Molecular analysis identifies potential regulatory networks for BA development, giving insight into development along this lineage. hPSC-derived BAs undergo elevated rates of glycolysis, uncoupled respiration, and lipolysis that are responsive to changes in cyclic AMP (cAMP)-dependent signaling, consistent with metabolic activity in BA tissue depots. Transplanted human BAs engraft into the inter-scapular region of recipient mice and exhibit thermogenic activity. Recipient animals have elevated metabolic activity, respiratory exchange ratios, and whole-body energy expenditure. Finally, transplanted BAs reduce circulating glucose levels in hyperglycemic animals. These data provide a roadmap for brown adipocyte development and indicate that BAs generated from hPSCs have potential as a tool for therapeutic development.

棕色脂肪细胞（BAs）是治疗包括2型糖尿病在内的代谢疾病的潜在细胞来源。在此报告中，人类多能干细胞（hPSC）通过近轴中胚层祖细胞状态进行定向分化，该状态可高效生成BA。分子分析确定了BA发展的潜在监管网络，从而深入了解了该谱系的发展。源自hPSC的BA经历了较高的糖酵解，解偶联呼吸和脂解速率，这些速率响应于环状AMP（cAMP）依赖性信号传导的变化，与BA组织贮库中的代谢活性一致。移植的人BA移植到受体小鼠的肩cap骨间区域，并显示产热活性。收件人动物的代谢活动，呼吸交换率，和全身能量消耗。最后，移植的BAs降低了高血糖动物的循环葡萄糖水平。这些数据为褐色脂肪细胞的发展提供了路线图，并表明从hPSC产生的BA具有作为治疗发展工具的潜力。