Regulation of Adipocyte Metabolic Homeostasis by SR‐BI and PCPE2

Obesity continues to be an epidemic in the United States, placing individuals at a higher risk of developing other comorbidities such as type 2 diabetes and cardiovascular disease. Adipocytes accumulate excess triglycerides and undergo hypertrophic expansion as a protective mechanism to avoid lipotoxicity. Adipocytes are also highly dynamic cells that perform many key metabolic processes including lipid and glucose metabolism. Recent collaborative studies demonstrated that SR‐BI function may require the extracellular matrix protein procollagen C‐endopeptidase enhancer 2 (PCPE2) to regulate cholesterol transport in hepatocytes and adipocytes. However, the roles of SR‐BI and PCPE2 in other adipocyte metabolic processes and whether they maintain their cooperative partnership for these functions remains unknown. This knowledge gap prompted our novel hypothesis that PCPE2 facilitates SR‐BI’s ability to regulate metabolic processes in adipocytes. To test our hypothesis, we have optimized an adipocyte model system where mesenchymal stem cells isolated from the outer ears of wild‐type (WT), SR‐BI knockout (SR‐BI‐/‐), and PCPE2‐/‐ mice are differentiated into adipocyte‐like cells. We validated our adipocyte model system by demonstrating increased Oil‐Red‐O staining, mRNA expression of adipogenesis markers, and adiponectin secretion over a 9‐day post‐differentiation period for all three genotypes. This model system was then used to test the roles of SR‐BI and PCPE2 on various metabolic functions, including glucose, fatty acid, and mitochondrial metabolism. Preliminary data suggest that loss of SR‐BI and PCPE2 impaired glucose uptake, despite observing elevated levels of GLUT4 at the cell surface. PCPE2‐/‐ adipocytes also showed increased response to insulin through AKT signaling, which may be responsible for the increased expression of GLUT4 at the cell surface. However, we observed that loss of SR‐BI or PCPE2 had no effect on transport of palmitic acid in adipocytes, despite there being elevated expression of fatty acid transporters (FABP4, CD36). Adipocytes lacking SR‐BI or PCPE2 showed an inverse response to insulin compared to WT adipocytes when measuring phosphorylation status of proteins responsible for mediating fatty acid synthesis (AMPK, ACC). These data suggest that although SR‐BI and PCPE2 do not appear to mediate uptake of palmitic acid, they may have altered lipid metabolism. Lastly, adipocytes lacking SR‐BI or PCPE2 exhibit changes in mitochondrial mass and morphology, but their role in maintaining healthy mitochondria remains inconclusive. Altogether, these data suggest that SR‐BI and PCPE2 appear to have independent roles in various steps of adipocyte metabolism, but their required partnership remains unclear.