YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity.

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.