Analysis of the generality and specificity of cell competition using an in vivo mouse model

Research Project

Project/Area Number	16K18978
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	General anatomy (including histology/embryology)
Research Institution	Osaka University
Principal Investigator	KAMURA Keiichiro 大阪大学, 生命機能研究科, 助教 (30604483)
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000) Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000) Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	YAP / TAZ / Hippoシグナル / 脂肪細胞 / 分化 / 肥満 / 発生 / 細胞競合
Outline of Final Research Achievements	Obesity is characterized by an expansion of white adipose tissue mass, which mainly consists of adipocytes. During the differentiation of adipocytes, PPARγ functions as a key transcriptional factor for adipogenesis, and is associated with its suppressive coregulator, TAZ. Previous studies have shown the importance of TAZ in adipogenesis using an in vitro model; however, the understanding of its role in adipogenesis in vivo remains limited. Here, we report a unique obese mouse model that is associated with TAZ downregulation, which arose from the overexpression of Yap, a Taz paralog. YAP activation facilitated Hippo signaling feedback, which induced a compensatory reduction in YAP, subsequently neutralizing its functional activity. This feedback also induced TAZ suppression and exclusion from the nucleus. In Yap transgenic mice, TAZ downregulation in adipose stem cells activated PPARγ, leading to their differentiation into mature adipocytes and consequently increased adipose tissue.
Academic Significance and Societal Importance of the Research Achievements	本研究では、Yap-Tgマウスが、TAZ抑制による脂肪細胞の分化促進の結果、肥満になることを示した。Yapの過剰発現によって誘導されたHippoシグナルのフィードバックは、脂肪幹細胞においてTAZ活性の減弱化を引き起こす。TAZの抑制によりPPARγが活性化することで、脂肪細胞の分化を促進し、最終的に脂肪組織の増大へとつながる。これらの結果により、in vivoにおいてTAZが脂肪細胞の分化に重要であることが明らかになると共に、肥満の治療への見識を得ることにもつながった。