The role of YAP signaling in thermogenic adiposetissues

Abstract

One of major metabolic organs, brown adipose tissue (BAT), is responsible for energy expenditure through uncoupling protein 1 (UCP1) mediated non-shivering thermogenesis, which has been considered a promising pharmacological target to combat obesity. Recent report suggests that Gq-GPCRs are highly expressed in brown adipocytes (BAs) and activation of Gq signaling inhibits BAs differentiation through RhoA/ROCK. However, a major downstream signaling by Gq-coupled pathway to inhibit the function of BAs is poorly understood. Several elegant studies have demonstrated that Hippo pathway is closely regulated by GPCRs, especially, Gq-mediated signaling can stimulate YAP transcriptional activity promoting cancer cell proliferation and growth. In this study, I focused on the transcriptional co-activator YAP (yes-associated protein) as a potential downstream effector by Gq. Selectively activated Gq signaling in BAs represented increased YAP activation as a form of dephosphorylation, YAP nuclear localization, and YAP induced gene expression implicating the role of Gq-driven YAP in brown adipocytes. I further found that Gq-coupled receptor signaling regulates YAP activity in brown adipocytes via RhoA/ROCK signaling circuitry. Moreover, I investigated the role of YAP in adipocyte differentiation and functions using a genetic approach. Loss of YAP in thermogenic adipocytes promoted UCP1 expression and cellular oxygen consumption. Mice lacking YAP specifically in adipose tissues showed increased UCP1 expression and reduced adiposity in thermogenic adipose tissues against diet-induced obesity. Collectively, this study suggests the importance of Gq-mediated YAP signaling in thermogenic adipocytes and shows the role of YAP in thermogenic adipocytes, which inhibits thermogenic activity.