Mechanisms of white adipose tissue progenitor differentiation and fibrosis
MetadataShow full item record
White adipose tissue (WAT) fibrosis is now recognized to contribute to obesity-associated metabolic dysfunction. In obesity, WAT expands through both adipocyte hypertrophy and hyperplasia and regulators that control these remodeling events are only partially understood. However these pathways are likely interconnected with those that regulate fibrosis, the excessive pericellular extracellular matrix (ECM) deposition that occurs in WAT in obesity. Thus it is postulated that WAT fibrosis may limit WAT expansion and further contribute to metabolic dysfunction. Several studies have indicated that WAT progenitors reside within the vascular niche and in other organs these cells respond to numerous proinflammatory and profibrotic mediators. Previous studies have identified that the secreted ECM protein, aortic carboxypeptidase-like protein (ACLP), is expressed in vascular smooth muscle cells and enhances lung myofibroblast differentiation. It is also recognized that in vitro, ACLP expression decreases with adipogenic differentiation however its role in this process is unknown. The goal of this research was to test the hypothesis that ACLP stimulates the differentiation of WAT progenitors into myofibroblasts and represses adipogenesis. Using in vitro adipogenesis assays, ACLP expression was found to be rapidly diminished with adipogenesis in mouse and human adipose progenitors and was not expressed by differentiated adipocytes. In gain of function studies, recombinant ACLP repressed adipogenesis and promoted myofibroblast differentiation in both mouse and human adipose progenitors. In loss of function studies utilizing chemical inhibitors, ACLP signaling in adipose progenitors was dependent on transforming growth factor β receptor activity. Analysis of fibrotic WAT revealed ACLP protein expression increased in the stromal-vascular fraction (SVF) and co-localized with pericellular ECM deposition. Analysis of mRNA expression in fibrotic WAT sub-populations revealed that immune cell depleted SVF was the primary source of ACLP. Additional studies investigated the cellular origin of WAT myofibroblasts, which used transgenic mice with fluorescent reporters for α smooth muscle actin and collagen I. Analysis of SVF demonstrated that multiple stromal-vascular cell types are capable of differentiating into both adipocytes and myofibroblasts. Taken together, these studies identified ACLP as a stromal derived mediator of adipose tissue progenitor differentiation and the accumulation of ACLP may limit adipocyte expansion in fibrotic WAT.