308-OR: Hippo-YAP/TAZ Signaling Coordinates Adipose Plasticity and Energy Balance by Uncoupling Leptin Expression from Fat Mass

Abstract

Adipose tissue regulates systemic energy homeostasis by acting as an energy reservoir and endocrine organ. Coordinated regulation of these functions is essential for metabolic health, but the underlying mechanisms are unknown. Here we show that the transcriptional coregulators YAP and TAZ mediate the crosstalk between adipose tissue mass and leptin levels to maintain systemic energy balance. The activation of adipocyte-specific YAP/TAZ via genetic ablation of the upstream regulators LATS1 and LATS2 resulted in a profound reduction in fat mass due to the conversion of mature adipocytes into delipidated cells with progenitor-like features. Rosiglitazone treatment normalized fat mass, indicating that PPARG inhibition is a major contributor to YAP/TAZ-induced lipoatrophy. Surprisingly, LATS1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction. This phenotype was attributed to a paradoxical increase in circulating leptin levels, which was found to offset the energy storage deficit by increasing fat oxidation and energy expenditure. Mechanistically, we identify a YAP/TAZ-TEAD axis that upregulates leptin expression by direct binding to an upstream enhancer site of the leptin gene. Finally, we show that YAP/TAZ activity is associated with leptin regulation during fasting and refeeding, indicating that YAP/TAZ links nutrient status in adipose tissue to systemic energy homeostasis. Taken together, we reveal that adipocyte Hippo-YAP/TAZ functions as a nexus for coordinating nutrient storage capacity and systemic energy balance by regulating adipocyte plasticity and leptin gene transcription. Disclosure S.Choi: None. K.Park: None. H.Shin: None. J.Suh: None.