Hippo-YAP/TAZ signaling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that transcriptional coregulators YAP and TAZ mediate the crosstalk between fat mass and leptin levels to maintain metabolic homeostasis. Activating YAP/TAZ in adipocytes by Lats1 and Lats2 deletion results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells. Surprisingly, Lats1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction, attributed to a paradoxical increase in circulating leptin levels. Mechanistically, YAP/TAZ-TEAD signaling upregulates leptin expression by directly binding an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is linked to, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ plays an essential role in coordinating adipose storage capacity and systemic energy balance through dual control of adipocyte plasticity and leptin gene transcription. SVF were isolated from the iWAT of 4-week-old Lats1fl/fl; Lats2fl/fl; Rosa-LSL-tdTomato (control, Con) and Adipoq-Cre; Lats1fl/fl; Lats2fl/fl; Rosa-LSL-tdTomato (AKO) mice. SVF cells were flow-sorted to exclude CD45 positive leukocytes. Singlets were selected based on gating. CD45-& tdT+ cells from AKO SVF and CD45-& tdT- cells from Con SVF were sorted for single-cell RNA-sequencing.脂肪组织兼具能量储存库与内分泌器官的双重功能，但其协调两项功能的分子机制仍有待阐明。本研究证实，转录共调节因子YAP与TAZ（YAP and TAZ）可介导脂肪量与瘦素水平间的串扰，以维持代谢稳态。通过敲除Lats1与Lats2（Lats1 and Lats2）激活脂肪细胞内的YAP/TAZ，可将成熟脂肪细胞转化为去脂样祖细胞，进而大幅降低机体脂肪总量。令人意外的是，Lats1/2敲除小鼠并未表现出脂肪营养不良相关的代谢功能障碍，这一悖论性现象源于循环瘦素水平的反常升高。机制研究显示，YAP/TAZ-TEAD信号通路（YAP/TAZ-TEAD signaling）可直接结合瘦素基因的上游增强子位点，从而上调瘦素的表达。本研究进一步发现，在禁食与复食过程中，YAP/TAZ的活性与瘦素调控密切相关，且是瘦素调控所必需的功能基础。上述结果表明，脂肪细胞Hippo-YAP/TAZ信号通路（adipocyte Hippo-YAP/TAZ）可通过双重调控脂肪细胞可塑性与瘦素基因转录，在协调脂肪储存能力与全身能量平衡中发挥核心作用。 本研究从4周龄的Lats1fl/fl; Lats2fl/fl; Rosa-LSL-tdTomato（对照组，Con）及Adipoq-Cre; Lats1fl/fl; Lats2fl/fl; Rosa-LSL-tdTomato（AKO）小鼠的腹股沟白色脂肪组织（inguinal white adipose tissue, iWAT）中分离基质血管组分（stromal vascular fraction, SVF）；对所得SVF细胞进行流式分选以剔除CD45阳性白细胞，并通过门控策略筛选单细胞；随后分别分选AKO组SVF中的CD45阴性且tdT阳性细胞，以及对照组SVF中的CD45阴性且tdT阴性细胞，用于单细胞RNA测序（single-cell RNA-sequencing）。