DNA Repair Deficiency Associated with Obesity and the Meatbolic Syndrome

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The growing epidemic of human obesity is currently estimated to affect over 65 million adult Americans, with secondary consequences including but not limited to, decreased life span, non-alcohol-induced fatty liver disease, increased cardiovascular disease, increased incidence of stroke and type 2 diabetes. The majority of the total obese population (> 45 million Americans) has a combination of at least four of these disorders (obesity, insulin resistance, dyslipidemia, and hypertension), collectively known as the Metabolic Syndrome. The underlying causes of these diseases are not well established, but have been investigated using genetic models and/or exposure to conditions of exogenous stress. Although wild-type cells maintain overall energy homeostasis by minimizing cellular damage from exposure to reactive oxygen species (ROS), disease can be initiated by a variety of conditions that result in high levels of ROS. DMA is one of the major targets of ROS-induced damage, and the possible interrelationship between defective DNA repair and Metabolic Syndrome has not been explored in depth. However, we recently demonstrated that mice carrying a deletion of the DNA glycosylase NEIL1, develop symptoms consistent with Metabolic Syndrome: severe obesity, fatty liver, dyslipidemia, and insulin resistance. Disease is manifested primarily in male knockout mice and is observed in mice extensively backcrossed to C57BL/6 and heterozygotes. Our central hypothesis to understand the relationship between the loss of an enzyme that repairs oxidative-stressinduced DNA damage and the development of the Metabolic Syndrome is that in these animals, the threshold of DNA damage required to initiate events leading to Metabolic Syndrome is significantly reduced. Evidence supporting this model is that mitochondria! DNA contains significantly elevated levels of unrepaired damage and deletions. To discern the role that NEIL1 plays in cells, modulation of survival, mutagenesis and mitochondria! function will be evaluated. Additionally, due to its central role in maintaining mtDNA integrity, aims are designed to determine the identity and role of the mitochondrial- versus the nuclear-targeted forms of the enzyme. Since preliminary data show that some human polymorphic variants of NEIL1 are catalytically inactive, these variants will be characterized for their ability to initiate base excision repair and the ability to reverse the phenotype of the neiM -deficient mice.