Telomere-based Epigenetic Reprogramming of Adipocyte Progenitor Cells inInsulin Resistance

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7. Project Summary/Abstract The prevalence of type 2 diabetes and associated cardiovascular disease among U.S. Veterans is three-fold higher compared to the general population. This disparity has been attributed in part to the advanced age of the Veteran population. Currently, nearly half of the 30 million patients with type 2 diabetes in the United States are older than 60 years. Aging constitutes an important risk factor for type 2 diabetes and is associated with a decline in insulin sensitivity. One of the mechanisms implicated in organismal aging is the shortening of telomeres at the ends of chromosomes. These protective nucleoprotein complexes are maintained by telomerase and prevent replicative senescence during regenerative tissue remodeling. Although telomere shortening is associated with an increased risk for type 2 diabetes, a mechanistic relationship between age- induced telomere attrition and insulin resistance has never been shown. We have identified that physiological and genetic telomere attrition results in insulin resistance, impaired adipogenesis due to replicative senescence, and ectopic lipid deposition in muscle and liver. Telomere attrition alters the proliferative capacity of adipocyte progenitor cells and generates repressive chromatin modifications by reprogramming of the mammalian SWI/SNF (BAF) chromatin-remodeling complex. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that telomere attrition induces insulin resistance through chromatin silencing in adipocyte progenitor cells. In Specific Aim 1 we will determine whether alterations in telomere lengths of adipocyte progenitor cells influence adipose tissue regeneration and insulin resistance. In Specific Aim 2 we will utilize a combination of cellular and molecular approaches to determine whether epigenetic reprogramming by telomere attrition induces adipose tissue progenitor cell dysfunction. Ultimately, the results of these studies will not only characterize telomere attrition as a chromatin modifier of adipocyte progenitor cell dysfunction but also provide novel insights into the mechanistic basis for the association between aging and type 2 diabetes.