1738-P: The Role of Adipocyte YAP in Glucose Homeostasis and Insulin Resistance In Vivo

Abstract

Adipose tissue is a dynamic metabolic organ that is essential for the regulation of whole-body glucose homeostasis. Adipose tissue hypertrophy with obesity is associated with glucose intolerance and insulin resistance underlying type 2 diabetes. Furthermore, studies suggest fibrosis formation is increased in adipose tissue of mice fed with a high-fat diet (HFD) and results in metabolically dysfunctional adipose tissue. Yes-associated protein 1 (YAP) is a transcription cofactor that promotes fibrosis in the lung, liver, and kidney. However, the role of YAP in adipose tissue and glucose homeostasis is unknown. To understand the role of YAP in vivo under metabolic stress conditions, we assessed how HFD impacts YAP protein levels. We have found that YAP protein levels increase in adipose tissue with weight gain. This suggests that YAP signaling may contribute to adipocyte dysfunction and insulin resistance under metabolic stress conditions. To further investigate the role of YAP in adipose tissue and glucose homeostasis in vivo, we developed adipose tissue-specific YAP knockout (adipose tissue YAP-KO) mice and placed them on both chow and HFD for 12 weeks. On an HFD, adipose tissue YAP-KO mice show improved glucose tolerance compared to controls. While blood glucose levels were lower, adipose tissue YAP-KO mice did not show improvements in insulin sensitivity. Together, these data indicate that YAP increases in adipose tissue with weight gain and disruption of YAP in adipocytes improves glucose tolerance; suggesting that adipocyte YAP plays an important role in modulating glucose homeostasis under metabolic stress conditions. Disclosure D. Han: None. R. Aslam: None. T. Ojha: None. D. Yuen: None. C.T. Luk: None.