Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ–TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo–YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

脂肪组织充当能量储存库和内分泌器官，但协调这些功能的机制仍然难以捉摸。在这里，我们证明转录共调节因子 YAP 和 TAZ 将脂肪量与瘦素水平解耦，并调节脂肪细胞可塑性以维持代谢稳态。通过删除上游调节因子Lats1和Lat2来激活脂肪细胞中的 YAP/TAZ 信号传导，通过将成熟脂肪细胞转化为脱脂祖细胞样细胞，导致脂肪量大幅减少，但不会因脂肪营养不良相关的代谢功能障碍而导致脂肪营养不良的增加循环瘦素水平。从机制上讲，我们证明 YAP/TAZ-TEAD 信号通过直接结合瘦素基因的上游增强子位点来上调瘦素表达。我们进一步表明，YAP/TAZ 活性与禁食和再进食期间的瘦素调节相关，并且在功能上是瘦素调节所必需的。这些结果表明，脂肪细胞 Hippo-YAP/TAZ 信号传导通过调节脂肪细胞可塑性和瘦素基因转录，构成了协调脂肪组织脂质储存能力和全身能量平衡的纽带。