Telomere Attrition in Adipose Tissue Senescence and Insulin Resistance

Type 2 diabetes and associated cardiovascular diseases are emerging as the most important health problems of the 21st century. An estimated half of the individuals with type 2 diabetes in the United States is above 60 years of age, with the highest prevalence found in those above 80 years of age, a number expected to increase to 40 million by 2050. Although it is well established that aging is associated with the development of insulin resistance and constitutes an independent risk factor for type 2 diabetes, the mechanisms underlying this relationship rernain unknown. Organismal aging has been linked to telomere attrition and is accelerated in diseases associated with mutations in the telomerase gene a. Telomerase stabilizes telomeres at the end of chromosomes to serve as protective capping and to prevent cellular senescence. Interestingly, recent epidemiological studies have indicated that patients with type 2 diabetes display shorter telomeres. These findings have gained considerable relevance as they suggest that telomere attrition may not merely affect lifespan but potentially causally contribute to age-related diseases including type 2 diabetes. However, although much attention has focused on the role of telomerase in aging, the relative contribution of telomere attrition to insulin resistance remains to be defined. In our preliminary studies we provide evidence for a previously unrecognized causal role of telomere attrition in the pathogenesis of insulin resistance. Using a murine model of telomerase deficiency, we demonstrate that telomere shortening results in insulin resistance. Loss of telomere length decreases fat mass, induces adipose tissue senescence, and activates inflammatory pathways, which ultimately alters insulin signaling. Based on these findings, the central hypothesis of this application is that telomere attrition results in insulin resistance by altering adipogenesis. To test this hypothesis, we propose the following three Specific Aims. Specific Aim 1: To determine the effect of progressive telomere attrition on insulin resistance and obesity. Based on our observation that modest telomere shortening results in insulin resistance and decreased fat mass, we propose to characterize tissue glucose homeostasis, diet-induced obesity, and energy balance in mice with long and critically short telomeres. Specific Aim 2: To determine whether prevention of telomere shortening in aging mice or in adipose tissue of telomerase-deficient mice attenuates insulin resistance. We will test the hypothesis that overexpression of telomerase during physiological aging or reconstitution of telomere length in adipose tissue of mice with progressive telomere attrition preserves insulin sensitivity. Specific Aim 3: To determine the mechanisms underlying adipose tissue senescence in mice with telomere exhaustion. Considering our finding that telomere shortening induces adipose tissue senescence and insulin resistance, we propose to determine the significance of telomere attrition for adipogenesis and characterize the epigenetic mechanism underlying adipose tissue senescence.