[초청강연] YAP/TAZ uncouples leptin expression from fat mass : revisiting the adipostat hypothesis

YAP/TAZ uncouples leptin expression from fat mass : revisiting the adipostat

hypothesis

Jae Myoung Suh

Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Daejeon,

Korea

Adipose tissue plays an essential role as an energy reservoir as well as an endocrine organ. The coordination of
these key functions is thus necessary to maintain metabolic health. For example, leptin production is tightly
linked to fat mass, but the underlying molecular mechanism is yet to be identified. Here, we show that the
transcriptional coregulators YAP and TAZ directly regulate leptin gene transcription through their interactions
with TEAD, the canonical target transcription factor of YAP/TAZ, and TEAD-binding elements within the Lep gene
enhancer. On the other hand, we show that Hippo-YAP/TAZ regulates adipose tissue storage capacity through
repression of PPARG. Together, we demonstrate that YAP/TAZ activation in mature adipocytes functions on two
distinct molecular axes: a YAP/TAZ-TEAD axis that increases systemic energy expenditure by increasing
circulating leptin levels and a YAP/TAZ-PPARG axis that decreases adipose tissue mass by repressing PPARG
target genes. Surprisingly, in mice with sustained activation of adipocyte YAP/TAZ results in an apparent
uncoupling of leptin gene expression from adipose tissue mass. Despite being fatless, or lipoatrophic, these mice
did not exhibit metabolic defects commonly associated with previous fatless mouse models. We show that the
paradoxical increase in leptin levels in our lipoatrophic mice compensates for their energy storage deficit by
increasing fat oxidation and energy expenditure. These findings position adipocyte YAP/TAZ at the nexus of
molecular crosstalk that links adipose storage capacity and systemic energy balance.