Abstract 239: Investigating The Roles Of Sr-b1 And Pcpe2 In Regulation Of Adipocyte Metabolic Homeostasis

Obesity is a universal epidemic and underlies comorbidities including type 2 diabetes and cardiovascular disease. Adipocytes store dietary metabolites within lipid droplets to avoid lipotoxicity and to provide energy to the body through metabolic processes such as lipid and glucose metabolism. Collaborative studies demonstrated that the extracellular matrix protein procollagen C-endopeptidase enhancer 2 (PCPE2) mediates the ability of scavenger receptor BI (SR-BI) to transport cholesterol into hepatocytes and adipocytes.It remains unknown if SR-BI and PCPE2 also play roles in other adipocyte metabolic processes and if their cooperative partnership is conserved. This knowledge gap prompted us to test the hypothesis that PCPE2 facilitates SR-BI’s ability to regulate metabolic processes in adipocytes. We validated a differentiated adipocyte model system using mesenchymal stem cells isolated from ears of wild-type (WT), SR-BI -/- , and PCPE2 - /- mice by demonstrating increased lipid droplet formation, mRNA expression of adipogenesis markers, and secretion of adiponectin over a 9-day post-differentiation period across genotypes. We used this model system to test the roles SR-BI and PCPE2in glucose and lipid metabolism. Compared to WT adipocytes, glucose uptake in SR-BI -/- and PCPE2 -/- adipocytes was decreased by 5.4% and 12.6%, respectively, despite increases in surface GLUT4 levels. We also observed that adipocytes lacking PCPE2 had an increased response to insulin through AKT signaling, which may be responsible for the increased surface expression of GLUT4. Loss of SR-BI or PCPE2 in adipocytes did not affect palmitic acid uptake, despite elevated mRNA expression of fatty acid transporters ( Cd36, Fabp4 ) compared to WT adipocytes. SR-BI -/- and PCPE2 -/- adipocytes showed an inverse response to insulin when measuring phosphorylation of fatty acid regulatory proteins (AMPK, ACC) compared to WT adipocytes, suggesting altered lipid metabolism in adipocytes lacking SR-BI or PCPE2. Together, our data suggest that, individually, SR-BI or PCPE2 is important for glucose uptake and fatty acid regulation, but not fatty acid uptake. Further investigations will determine whether a partnership is required for optimal metabolic function in adipocytes.