The ability of adipose tissue to handle fluctuations in nutrient availability, by dynamically expanding and contracting, is critical for survival. However, dysregulation of this process can lead to lipodystrophy, obesity and dysregulated energy homeostasis. Various factors influence adipocyte plasticity, including anatomical location, neighboring immune cells, the vasculature and the surrounding extracellular matrix (ECM). While matrix metalloproteinases (MMPs) have been postulated to participate in the remodeling of the ECM, most attention has focused on the type I collagen-rich stromal/interstitial ECM. However, mature adipocytes are surrounded by a specialized form of ECM, termed the basement membrane, that mechanically regulates cell shape. Without modifying basement membrane assembly or remodeling, changes in adipocyte shape and storage capacity would not be possible. Nevertheless, the role of the basement membrane in regulating fat metabolism and function are almost uniformly overlooked. This proposal will seek to document the dynamic changes in MT1-MMP-mediated basement membrane remodeling in both physiological and pathological states while identifying the regulatory pathways involved in this process.
Aim 1 will provide a characterization of basement membrane remodeling and corresponding alterations in adipose inflammation, glucose/insulin homeostasis transcriptional events.
Aim 2 will elucidate the mechanism underlying MT1-MMP regulation by exploring its trafficking to the plasma membrane by insulin.
Aim 3 will determine the physiological consequence of impaired adipose plasticity in states of obesity by investigating adipose-specific conditional KO mice of MT1-MMP. The experiments outlined in this proposal are designed to explore and expand insights into the role and regulation of the basement membrane in adipose tissue. The work proposed here lays the groundwork for future studies into how the basement membrane is modified in adipose tissue, and has potential to help develop therapeutic targets in the fight against obesity.
Obesity and Type 2 diabetes have reached epidemic proportions. We will investigate the molecular mechanisms involved in the plasticity of adipose tissue, focused on the regulation of the basement membrane by the metalloprotease MT1-MMP.
