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.
