CHROMATIN REMODELING AND ADIPONECTIN GENE EXPRESSION: REGULATION BY OBESITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, more than 44 million Americans are considered obese by body mass index (BMI), reflecting an increase of 74 percent since 1991. During the same time frame, diabetes increased by 61 percent, reflecting the strong correlation between obesity and the development of diabetes. Today an estimated 17 million people have diabetes in the United States, according to the study by the Centers for Disease Control and Prevention. Obesity is associated with diabetes, cardiovascular diseases, and many other health problems. Recent studies indicate that adipose tissue is not simply a tissue for energy storage, but also serves an important endocrine function. There are several hormones that are synthesized and secreted from adipose tissue and regulate energy metabolism of other organs or system, such as food intake and insulin sensitivity. Adiponectin is an adipose-derived hormone that plays a critical role in maintaining energy and glucose metabolism. Diminished adiponectin gene expression and low blood concentrations have been well documented in both obesity and type 2 diabetes. However, the molecular mechanisms that regulate adiponectin expression and the causative mechanisms that impair adiponectin gene expression in obesity and type 2 diabetes remain poorly understood. Our preliminary data demonstrate novel adipocyte-specific regulatory elements (enhancer) in the first intron of the human adiponectin gene, and that the transcription factor C/EBP¿ is required for regulating adiponectin expression. Furthermore, it has been demonstrated that C/EBP¿ recruits SWI/SNF chromatin-remodeling complexes into target genes and is involved in the adipogenic process. We propose to investigate the role of chromatin remodeling in controlling adiponectin gene expression during adipocyte differentiation, and also to explore the molecular mechanisms that cause down-regulation of adiponectin expression in obesity. This study will provide novel insight into the regulation of adiponectin synthesis and ultimately may lead to a new therapy for obesity related diabetes and cardiovascular disease. Importantly, these studies will provide compelling preliminary data supporting an NIH R01 application. This COBRE project will also provide a unique opportunity for me to collaborate with other PIs to translate my research into obesity-associated cardiovascular disease.