HGF Signaling in Adipose Tissue Growth and Metabolism

Indiana University Indianapolis, Indianapolis IN

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Abstract

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.