227-OR: Disruption of Adipocyte YAP Improves Glucose Homeostasis in Mice and Decreases Adipose Tissue Fibrosis

Abstract

Adipose tissue is a dynamic metabolic organ that is essential for the regulation of whole-body glucose homeostasis. Dysfunctional adipose tissue hypertrophy with obesity is associated with glucose intolerance and insulin resistance underlying type 2 diabetes. Yes-associated protein 1 (YAP) is a transcription cofactor important in the Hippo signaling pathway. 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 increased weight and insulin resistance impact YAP protein levels. We found that YAP protein levels increase in adipose tissue in humans with type 2 diabetes and mouse models. 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 (YAP-KO) mice and placed them on either chow or high fat diet (HFD) for 12-14 weeks. On an HFD, adipose tissue YAP-KO mice show improved glucose tolerance compared to controls. Perigonadal fat pad weight was also decreased in knockout animals, with smaller adipocyte size. Adipose tissue fibrosis and gene expression associated with fibrosis was decreased in vivo and in 3T3-L1 cells treated with a YAP inhibitor. Together, these data indicate that YAP is increased in adipose tissue with weight gain and insulin resistance. Disruption of YAP in adipocytes improves glucose tolerance and adipose tissue fibrosis; suggesting that YAP plays an important role in adipose tissue and modulating glucose homeostasis under metabolic stress conditions. Disclosure D.Han: None. R.Aslam: None. T.Ojha: n/a. D.Yuen: Consultant; Fibrocor Therapeutics. C.T.Luk: None. Funding NSERC Discovery Grant (RGPIN-2018-05671) BBDC Gales Family Charitable Foundation Pilot and Feasibility GrantCanadian Institutes of Health Research Project Grant (PJT 168996)