Role of Pcpe2 in Adipose Tissue Remodeling and Lipoprotein Metabolism

Medical College Of Wisconsin, Milwaukee WI

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Abstract

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The increased prevalence of obesity in the US population continues to drive greater risk for developing type 2 diabetes and cardiovascular disease (CVD). Excessive caloric intake stresses adipocytes into storing lipid in an unhealthy manner, directing lipid into existing adipocytes, known as 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) has identified two main types of PCs in the SVF, adipocyte precursor cells (APCs), and fibroinflammatory adipocyte progenitors (FAPs). APC are pre-adipocytes which differentiate into mature adipocytes, while FAPs, secrete cytokines inhibiting APC differentiation. Also influencing APC and FAP lineage 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 the fate of APCs and FAPs especially during increased lipoprotein flux resulting from a high fat diet (HFD). Recently we discovered that both VAT PCs, APCs and FAPs express high levels of the extracellular matrix (ECM) protein, procollagen endopeptidase enhancer protein 2 (Pcpe2, gene name Pcolce2) whose expression decreases as APCs become committed adipocytes. We found that Pcpe2 is significantly upregulated (>2-4-fold by both TGFb1, and/or HFD feeding) suggesting that Pcpe2 may play a role in TGFb-like signaling pathways in VAT PCs. Based on our preliminary data we hypothesize that PC-Pcpe2 expression stimulates TGFb-like and/or suppressing BMP-like signaling pathways in VAT resulting in fibroinflammatory, hypertrophic adipose tissue and thus, unhealthy adipose expansion. To test our hypothesis, we will carry out two aims; Aim 1: Elucidate the mechanism by which Pcpe2’s regulates TGFb and BMP-like signaling using PC-specific Pcpe2-hemagglutinin tagged (HA) over-expressor (ox) (PC-PcpeoxHA) and PC cell-specific Pcpe2 knockout (KO) (PC-Pcpe2KO) mice lines and in Aim 2, investigate Pcpce2’s structure-function relationship based on its newly identified mucin-like O-linked glycoprotein linker domain.