Abstract 448: Role Of Pcpe2 In Adipose Tissue Remodeling And Lipoprotein Metabolism

Abstract

Increased prevalence of obesity in the US continues to drive greater risk for developing type 2 diabetes and cardiovascular disease. Excessive caloric intake stresses adipocytes into storing lipid in an unhealthy manner, directing lipid into existing adipocytes, or adipocyte hypertrophy. Healthy adipose tissue expansion and remodeling occurs when adipose tissue precursor cells (PC) in the stromal vascular fraction (SVF) differentiate to create new pre-adipocytes which store lipid, called hyperplasia. Single cell sequencing of visceral adipose tissue (VAT) have identified two main types of PCs in the SVF, one called adipocyte precursor cells (APCs), while the other is a fibro-inflammatory progenitors (FIPs). APC are pre-adipocytes which given the proper signals, differentiate into mature adipocytes, while FIPs, can secrete cytokines inhibiting APC differentiation and initiating inflammation. Also influencing APC and FIP lineage in the SVF are the transforming growth factor beta (TGFb)-like signaling pathways which inhibit adipogenesis, while bone morphogenetic protein (BMP)-like signaling promotes adipogenesis. Little is known about how signaling through these pathways alters APCs and FIPs fate, especially during increased lipoprotein flux from high fat diet (HFD). Recently we discovered that both VAT PCs, APCs and FIPs express high levels of the extracellular matrix (ECM) protein, procollagen endopeptidase enhancer protein 2 (Pcpe2 ) whose expression decreases as APCs become committed adipocytes. We found that Pcpe2 is significantly up-regulated ~4-fold by TGFb1 suggesting that Pcpe2 plays a role in TGFb-like pathways in VAT PCs. Using PC-specific Pcpe2-hemagglutinin tagged (HA) overexpressor (ox) (PC-Pcpe oxHA ) and PC cell-specific Pcpe2 knockout (KO) (PC-Pcpe2 KO ) mice lines, studies show PC-Pcpe2 KO mice have reduced (~35-40%) body and VAT weight, while PC-Pcpe oxHA mice showed an increase (~40-45%) in body and VAT weight, characterized by hypertrophic adipocytes. In other studies we show APC rates of proliferation and differentiation are highly dependent on Pcpe2 expression. Overall, these studies reveal novel mechanistic insight into the mechanisms involved in dysfunctional fat storage.