The Regulation of Gene Expression via Epigenetic Mechanisms during Onset of Obesity, Type 2 Diabetes

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 DESCRIPTION (provided by applicant): During the last a few decades, obesity and obesity related type 2 diabetes have become serious health problems worldwide. Obesity among both adults and children has significantly increased since 1990. During such a short period of time, genetic coding of human beings cannot be changed so significantly by evolution. Studies in chronic complex disorders such as obesity/type 2 diabetes are shifting the emphasis from genetic causative factors to epigenetic and environmental effects. Environmental factors including diets and lifestyles may play an important role in development of obesity/type 2 diabetes by influencing the epigenetic modifications to the human genome. It has been demonstrated recently that circulating fatty acids are associated with adiposity, insulin resistance, and muscle cell death. Now, the key question is what actual factors in adipocytes and muscle cells induced by fatty acids are mediating adiposity, insulin resistance, and muscle cell death. It is very likely each of the problems may be a result of regulation of more than one gene by fatty acids. Our preliminary data indicated that both saturated fatty acids and polyunsaturated fatty acids induced lipid accumulation in differentiated adipocytes while saturated fatty acids differentially affected adipocytes and muscles cells. The proposed project systematically addresses these questions using both adipocytes and muscle cells from the aspect of epigenetics. Aim 1 will identify the genes that are essential for lipid accumulation and insulin resistance in adipocytes. The genes that are essential for lipid accumulation should be the genes that are regulated by saturated fatty acids and unsaturated fatty acids in the same manner since both types of fatty acids cause significant lipid accumulation in differentiated adipocytes. The genes that are related with insulin resistance in differentiated adipocytes should be regulated by saturated fatty acids and polyunsaturated fatty acids in opposite manners since the two types of fatty acids have different effects on insulin resistance in differentiated adipocytes. Aim 2 will identify the genes essential for mediating cell death and insulin resistance in muscle cells. The genes that are mediating muscle cell death and insulin resistance should be regulated by saturated fatty acids and polyunsaturated fatty acids in opposite manners in muscle cells since these two types of fatty acids have different effects on muscle cell death and insulin resistance in muscle cells according to our preliminary data. Aim 3 will determine if epigenetic modifications are involved in mediating expression of genes identified in Aim 1&2. Studies in this Aim will be mainly focused on methylation and microRNAs. This project may directly lead to identification of potential drug targets. This project will also provide opportuniies for 2 graduate and 10 undergraduate Hispanic students to experience biomedical research.