Elucidating ACLP-dependent signaling pathways in the adipose tissue stromal-vascular niche

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PROJECT SUMMARY/ABSTRACT Obesity is a significant risk factor for cardiovascular disease, diabetes, fatty liver disease, and some cancers. In response to caloric excess, white adipose tissue (WAT) depots expand through hypertrophy and hyperplasia. Hypertrophy, the increase in size of preexisting white adipocytes, is associated with an unhealthy metabolic state, elevated inflammation, and insulin resistance. In contrast, WAT hyperplasia, the recruitment of the new fat cells from progenitors that reside in the adipose tissue stromal vascular (SV) niche, is associated with a more metabolically healthy state. Obesity also can induce the pathological accumulation of extracellular matrix (ECM) proteins in WAT, which is strongly associated with metabolic perturbations. The signaling pathways that regulate adipose tissue fibrosis are currently unknown; however, regulatory pathways that activate progenitor cells in the adipose tissue SV niche likely determine the balance between profibrotic and adipogenic cell fates. Because fibrosis is controlled by secreted factors that impinge on the SV niche, targeting this compartment, rather than the differentiated adipocyte itself, may represent a novel avenue for therapeutic intervention to treat obesity and metabolic complications. We discovered that the secreted protein aortic carboxypeptidase-like protein (ACLP) is activated in SV cells and it represses adipocyte differentiation, while stimulating a profibrotic cell fate. In addition, our preliminary findings connect ACLP signaling to the transforming growth factor β and platelet derived growth factor receptor pathways. We hypothesize that activation of ACLP signaling pathways in the SV niche blunts adipogenic hyperplasia and induces fibrosis, contributing to WAT dysfunction and metabolic disease. To test this hypothesis, in Aim 1 we will use novel ACLP recombinant proteins and high resolution proteomics/phosphoproteomics in studies of adipose tissue SV progenitor cells to delineate ACLP signaling cascades that repress adipogenic differentiation and stimulate ECM production. In Aim 2 we will identify the initiating mechanisms that lead to the expansion of profibrotic cells and ECM production in WAT using isolated blood vessels and WAT organ culture. In Aim 3 we will determine whether eliminating ACLP signaling in vivo in the adipose tissue SV niche enhances adipocyte hyperplasia and protects against diet induced metabolic disease. We will conditionally delete ACLP in the SV niche in mice subjected to a high and low fat diets. Measures of WAT fibrosis, whole body metabolism, and vascular remodeling will test whether eliminating ACLP-dependent signaling in the SV niche prevents WAT fibrosis and provides metabolic benefit. The anticipated outcome of these studies is the identification of signaling pathways that control a profibrotic/anti-adipogenic cell fate switch, which drives pathological WAT remodeling and a metabolically unhealthy state. We envision that blunting ACLP signaling by identifying actionable signaling targets in the SV niche will reduce pathological ECM accumulation as an intervention to inhibit obesity-induced diseases.