HGF Signaling in Adipose Tissue Growth and Metabolism

Project: Research project

Description

Obesity is a risk factor for the development of cardiovascular disease, diabetes, and cancer. The
emerging role of angiogenesis in regulating growth of adipose tissue is a subject of great interest and
investigation. We have reported that Hepatocyte Growth Factor (HGF), a pleiotropic factor with robust
angiogenic and mitogenic activity, is synthesized by both adipocytes and the stromal-vascular cells in adipose
tissue, and that adipocytes from obese subjects release significantly more HGF than adipocytes from lean
individuals. Most recently we have shown that silencing HGF expression in preadipocytes slows early
angiogenic events in an in vivo fat pad development model. Strong preliminary data in this application extend
these observations with the demonstration of a long-term impairment in fat pad development with stable
lentiviral silencing of HGF expression in preadipocytes. We also show that HGF promotes proliferation of
preadipocytes and protects these cells from apoptosis. The synthesis of HGF by preadipocytes and its
autocrine effects illustrate an important stem cell/pericyte property of the preadipocyte. Finally, we provide data
that preadipocytes function as pericytes to stabilize vascular structures in adipose tissue. Taken together, our
published and novel preliminary observations suggest a central role for HGF to promote adipose tissue
expansion via effects on both the vasculature and on preadipocytes. Therefore, the objective of this
application is to understand the mechanisms through which HGF regulates adipose tissue growth. Given that
HGF has both angiogenic and mitogenic properties, the central hypothesis of this application is that HGF
promotes vascular development and preadipocyte pericytic function, supporting growth of adipose
tissue. To test our hypothesis, we will elucidate the mechanism(s) through which HGF-induced angiogenesis
and neovascularization promote adipose tissue growth using RNA silencing and an in vivo fat pad
development model. We will also assess adipose tissue growth in a mouse model with targeted deletion of
HGF from adipose tissue. Further, we will investigate the pericytic properties of preadipocytes that permit these
cells to communicate with endothelial cells and stabilize vascular structures. The proposed work will pioneer a
new connection between adipose tissue HGF synthesis, angiogenesis and preadipocyte/pericyte function, and
it is our expectation that the completion of these studies will markedly advance our understanding of adipose
tissue growth.
StatusFinished
Effective start/end date9/20/098/31/12

Funding

  • National Institutes of Health: $346,500.00
  • National Institutes of Health: $346,500.00

Fingerprint

Hepatocyte Growth Factor
Adipose Tissue
Growth
Pericytes
Adipocytes
Blood Vessels
Stromal Cells
RNA Interference
Cardiovascular Diseases
Stem Cells
Endothelial Cells
Obesity
Fats
Apoptosis

ASJC

  • Medicine(all)