YAP/TAZ coordinate adipose plasticity and leptin dynamics to maintain metabolic homeostasis.

Adipose tissue serves dual roles as an energy reservoir and endocrine organ. We identify YAP/TAZ, Hippo pathway effectors, as key integrators of these functions. Mice with adipocyte-specific YAP/TAZ activation develop severe lipoatrophy yet maintain metabolic homeostasis through unexpectedly elevated leptin levels. Mechanistically, adipocyte YAP/TAZ operates through two transcriptional pathways: inhibiting PPARγ target genes via a YAP/TAZ-PPARγ axis, and directly upregulating leptin expression through YAP/TAZ-TEAD binding to a novel Lep enhancer. The physiological relevance of this mechanism is underscored by the finding that adipocyte YAP/TAZ activation correlates with and is required for regulating leptin expression during feeding-fasting cycles. These findings extend our understanding of the Hippo-YAP/TAZ pathway beyond its canonical role in organ size control, revealing a critical function in integrating adipose tissue plasticity with systemic energy homeostasis.