The proposed studies of diet-induced regulation of components of the epigenetic machinery that is involved in regulation of Pdx1 expression have a potential to provide novel drug targets for the maintenance of body weight in humans. Given that in addition to maintenance of blood glucose level, Pdx1 of mice is involved in islets regeneration and neogenesis, studies of caloric restriction-induced chromatin remodeling in the region of Pdx1 promoter will further our understanding of the equivalent processes in humans and, thus, will provide insights into pancreatic islets regeneration and neogenesis in humans.
impact statement issue
During the past 20 years there has been a dramatic increase of obesity in the United States. Obesity has become one of the major U.S. health issues and is implicated in etiology of cardiovascular diseases (CVD) and type 2 diabetes (T2D). According to the Centers for Disease Control and Prevention, CVD and T2D are the first and sixth major causes of death in the United States in 2005, respectively. As of 2006, about two-thirds of U.S. adults were overweight or obese, while one-third of U.S. adults were obese. In 2007, only Colorado had a prevalence of obesity less than 20 percent. Thirty states had prevalence equal to or greater than 25 percent; three of these states (Alabama, Mississippi, and Tennessee) had a prevalence of obesity equal to or greater than 30 percent.
Most studies show an increase in mortality rates associated with obesity. Individuals who are obese have a 10 to 50 percent increased risk of death from all causes, compared with healthy-weight individuals with body mass index (BMI) of 18.5 to 24.9. Most of the increased risks are due to cardiovascular causes. Obesity is associated with more than 112,000 excess deaths from CVD per year in the U.S. population relative to healthy-weight individuals, while overweight and obesity combined were associated with increased mortality from diabetes and kidney diseases (61,248 excess deaths). The health care consequences of these diseases costs taxpayers billions of dollars annually. A recent study estimated annual medical spending due to overweight and obesity, BMI over 25, to be as much as $92.6 billion dollars in 2002— 9.1 percent of U.S. health expenditures.
impact statement response
The preliminary study section includes our results of H3, H4 histones acetylation in Pdx1 promoter region in GPX1 OE islets and presented only for the methodological purposes. To study, H3 and H4 histones acetylation in proximal promoter region of Pdx1 islets (n=500 per sample) were isolated from four mice and cultured for 48 hours in RPMI 1640 medium with antibiotics before the assay. The histone cross-linking and chromatin immunoprecipitation (ChIP) were carried out by using a ChIP assay kit.
We have revealed that histone hyperacetylation occurs at the Pdx1 promoter. This is a novel epigenetic regulation mechanism of the gene in vivo. Our finding on the hyperacetylation of H3 and H4 histone at the proximal promoter of Pdx1 in the GPX1 OE mice reveals not only a novel, in vivo epigenetic, but also a potential transcriptional regulation for this key factor by antioxidant enzymes.
impact statement summary
Obesity has become a hallmark of modern industrialized societies. Because of its tremendous growth rate, obesity is defined as epidemic in almost all states. Obesity causes serious health problems, resulting in higher rates of morbidity and mortality. Although genetic predisposition has been recognized to play a role in the development of obesity, a rapid increase in the overweight and obese population suggests that epigenetic mechanisms must also be involved. Epigenetic mechanisms, such as promoter methylation, may cause a gene silencing, while histones acetylation causes chromatin remodeling and results in increased gene expression. We hypothesize that epigenetic mechanisms are also involved in regulating expression of genes that control blood glucose level, and thus, regulate body weight.
