311-OR: Role of Pcpe2 in Adipose Tissue Remodeling and Expansion

Prevalence of obesity in the US continues to drive greater risk for type 2 diabetes and cardiovascular disease. Excessive caloric intake stresses adipocytes into storing lipid in an unhealthy manner, directing lipid into existing adipocytes, or hypertrophy. Healthy adipose expansion 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 differentiate into mature adipocytes, while FIPs, secrete cytokines inhibiting APC differentiation. Influencing APC and FIP lineage are the transforming growth factor beta (TGFb)-like signaling which inhibit adipogenesis, while bone morphogenetic protein (BMP)-like signaling promotes adipogenesis. Little is known about how signaling 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 upregulated ~4-fold by both TGFb1, and HFD feeding suggesting that Pcpe2 plays a role in TGFb-like pathways in VAT PCs. Using PC-specific Pcpe2-hemagglutinin tagged (HA) over-expressor (ox) (PC-PcpeoxHA) and PC cell-specific Pcpe2 knockout (KO) (PC-Pcpe2KO) mice lines, show PC-Pcpe2KO mice have reduced (~35-40%) body and VAT weight, while PC-PcpeoxHA mice showed an increase (~40-45%) in body and VAT weight. 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. Disclosure M.G.Sorci-thomas: None. H.Xu: None. M.J.Thomas: None.