Obesity has risen dramatically over the last 30 years. In the U.S. alone, 60 million people are defined as clinically obese. Especially concerning is the nearly epidemic rate of childhood obesity. Obesity occurs through excessive adipogenesis (formation of adipocytes) or through increases in established adipocyte size. Environmental toxicants termed obesogens disrupt the endocrine system and can increase adipogenesis. Tributyltin (TBT), dichlorodiphenyl-dichloroethylene (DDE), bisphenol-A diglycidyl ether (BADGE), and tetrabromobisphenol-A (TBBPA), have been reported to increase obesity. The mechanism(s) by which xenobiotic obesogens function to disrupt the endocrine system and increase rates of obesity requires active investigation. Our work focuses on the surface glycoprotein, Thy1 (CD90). Thy1 is an glycophosphatidylinositol (GPI)-anchored membrane protein expressed on subsets of neurons, stem cells and other cell types. We discovered that fibroblasts are heterogeneous for expression of Thy1 and that only Thy1+ fibroblasts can differentiate into scar-forming myofibroblasts and only Thy1-/low fibroblasts can differentiate int adipocytes. In this R21 application, we hypothesize that there is a direct role for Thy1 in preventing adipogenesis. Our supporting data show that depletion of Thy1 increases adipogenesis while over- expression of Thy1 impairs adipogenesis. These data support the concept that Thy1 is more than a marker and that Thy1 can function to modify cell fate. We also discovered that Thy1 expression is reduced in both human and mouse multipotent stromal cells (MSCs) after exposure to TBBPA, BADGE and TBT. Importantly, one mechanism by which obesogens may function is to reprogram the epigenetic code of MSCs to alter physiology. The Thy1 locus contains multiple CpG islands that can be controlled epigenetically and may be key targets of obesogens. Developmental exposure to obesogens may reprogram Thy1 expression levels and modify physiology long after exposure. Therefore, we hypothesize that environmental obesogens alter Thy1 expression to increase adipogenesis and obesity. To investigate this hypothesis we have developed the following aims.
Aim 1 : Test the hypothesis that environmental obesogens diminish Thy1 expression and activity in multipotent stromal cells to increase adipogenesis.
Aim 2 : Test the hypothesis that developmental exposure to obesogens reduces Thy1 expression and increases adipogenesis and obesity in vivo. The results of these studies will show for the first time that Thy1 expression is reduced by environmental obesogens and this reduction is key to the mechanism whereby obesogens increase adipogenesis and obesity.
We discovered that a cell surface protein called Thy1 (CD90) controls the fate of multipotent stromal cells (MSCs). We hypothesize that environmental chemicals called obesogens reduce MSC expression of Thy1 and this increases adipogenesis and obesity. The goal of this project is to uncover how environmental obesogens regulate Thy1 and adipogenesis in MSCs in vitro and in vivo.
|Kuriyan, Ajay E; Woeller, Collynn F; O'Loughlin, Charles W et al. (2013) Orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype. Invest Ophthalmol Vis Sci 54:7370-7|