Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea.
Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
Cell Death Dis. 2022 Apr 27;13(4):407. doi: 10.1038/s41419-022-04847-0.
Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.
Wnt5a 是一种典型的非经典 Wnt，是肥胖人群和肥胖小鼠血清中升高的炎症因子。在本研究中，脂肪特异性敲除 Wnt5a（Wnt5a-FKO）可防止 HFD 诱导的雄性 C57BL/6J 小鼠血清 Wnt5a 水平升高，这表明脂肪细胞主要负责肥胖诱导的 Wnt5a 水平升高。与附睾白色脂肪组织（eWAT）相比，小鼠皮下白色脂肪组织（scWAT）对 HFD 的反应更为敏感，细胞大小增加和 Wnt5a 水平增加。此外，体外和体内脂肪细胞大小与 Wnt5a 水平呈正相关。在肥大脂肪细胞中，增大的脂滴增加了细胞硬度，并将细胞质中的 f-肌动蛋白应力纤维重新排列到皮质区域。在肥大脂肪细胞中，这些机械变化会引起 YAP（Yes 相关蛋白）和 TAZ（带有 PDZ 结合基序的转录共激活因子）的活性增加，抑制或敲低 YAP 和 TAZ 会降低 Wnt5a 的表达。ChIP（染色质免疫沉淀）分析显示，YAP 被 Wnt5a-1 基因启动子募集并增加 Wnt5a 的表达。这些结果表明，YAP 对肥大脂肪细胞中的机械应激做出反应，诱导 Wnt5a 的表达。当 8 周龄的 Wnt5a-FKO 小鼠喂食 HFD 20 周时，与 floxed 小鼠相比，脂肪量增加，尤其是在 scWAT 中，而食物摄入或活动没有明显变化。此外，无论饮食类型如何，Wnt5a-FKO 小鼠均表现出葡萄糖耐量受损。我们的研究结果表明，肥大/YAP/Wnt5a 信号构成了一个负反馈回路，可重新训练脂肪组织肥大。
