Over 1.6 billion adults worldwide are overweight, of which 400 million are obese. The World Health Organization predicts that 10% of the global population will be obese by 2015. In the US approximately 119 million people, roughly 2/3 of the population are obese. An astounding 400,000 deaths per year are attributed to obesity, and healthcare costs related directly and indirectly to obesity are estimated to be $117 billion per year. Needless to say, biomedical advancements in this field are essential to the future of mankind. Our goal is to assess the role of Estrogen Sulfotransferase in human adipogenesis. We have identified Estrogen Sulfotransferase (EST) as a possible regulator of adipocyte differentiation. We hypothesize that EST dually inhibits the Erk1/2 MAP kinase pathway and stimulates the PI3 kinase/Akt pathway in preadipocytes/adipocytes to positively regulate adipogenesis in humans. EST is a phase II drug metabolizing enzyme known to catalyze the sulfoconjugation of estrogens. EST is highly expressed in the white adipose tissue (WAT) of male mice, but the role of EST in the development and functions of adipose tissue remains largely unknown. Previous in vitro and in vivo studies with 3T3 -L1 preadipocytes/primary mouse pre- adipocytes and EST transgenic mice have shown that EST plays an important role as a negative regulator of adipogenesis in mice. Our current studies show that EST also plays a role in adipogenesis in male and female humans;however unlike mice, EST in human cells acts as a positive regulator of this process. We plan to test our hypothesis with four specific aims.
Aim one will test the extent of EST regulation over adipogenesis using shRNA transduction to knockdown EST and/or overexpress EST.
Aim two will test the mechanisms of EST regulation by using western blot analysis to assess changes in total and phosphorylated Erk 1 /2 (p-Erk) and Akt (p-Akt).
Aim 3 will test whether EST enzymatic activity is necessary for the effect on adipogenesis.
Aim 4 will test whether there is a correlation between EST expression and adiposity in humans, specifically if increased expression correlated with increased BMI. The outcome of this study will provide novel and significant data towards understanding adipogenesis in humans, and contribute to the development of new therapies to treat obesity.
This study is significant given the overall obesity profile of the world at the present time. Today, billions of people are overweight throughout the world, and many millions more are suffering from the side effects of obesity, such as heart disease and type II diabete[9-10]. This study will help to make headway in understanding the molecular and genetic mechanisms which underlie the development and regulation of adipose tissue and obesity in humans. Results from this study are expected to identify a novel adipogenic regulatory pathway, which may lead to the development of novel therapeutic strategies against obesity in humans.
| Ihunnah, Chibueze A; Wada, Taira; Philips, Brian J et al. (2014) Estrogen sulfotransferase/SULT1E1 promotes human adipogenesis. Mol Cell Biol 34:1682-94 |
