Obesity and related complications such as fatty liver disease and diabetes pose a growing threat to population health in the United States and around the world. A greater understanding of the dietary factors and cellular mechanisms that lead to the development of obesity is essential to devising preventive and therapeutic strategies to combat these metabolic diseases. Oxidative stress, such as that induced by consumption of high- fat diets, is thought to be a causal factor in the development of obesity. Oxidative stress induces damage to cellular components, including DNA, which, if left unrepaired, can lead to mutations and tumorigenesis. Oxidative DNA lesions are repaired by the base-excision repair pathway, which is initiated by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). OGG1 recognizes and excises the most commonly formed oxidative DNA lesion, 8-oxo-G. Interestingly, mice deficient in OGG1 have been recently reported to be susceptible to obesity and fatty liver, indicating an unexpected but critical role for this DNA repair enzyme in the development of metabolic disease. The overall goal of this project is to delineate the mechanisms that link oxidative DNA damage to obesity and metabolic syndrome and to identify dietary factors contributing to the development or prevention of DNA damage. Preliminary data have indicated that OGG1 deficient mice have increased hepatic lipid accumulation, along with markers of decreased fat oxidation in the liver. These mice also display impaired glucose tolerance and alterations in markers of mitochondrial morphology in skeletal muscle. The first two aims of this project will therefore address the mechanistic role of DNA damage in altering hepatic lipid oxidation and skeletal muscle mitochondrial dynamics.
These aims will be completed with the aid of novel cellular and transgenic models of obesity resulting from a defect in DNA repair deficiency and established methods to measure DNA damage, fat oxidation, mitochondrial morphology and respiration, and insulin signaling. The completion of these aims will further our understanding of oxidative stress-induced damage in the initiation and progression of fatty liver disease, as well as impaired insulin sensitivity, which can ultimately lead to the development of diabetes. With the knowledge gained from these studies, the third aim will broaden the investigation to delineate the role of dietary fatty acids of varying degrees of desaturation in the induction of DNA damage in metabolically active tissues, including liver, heart, muscle, and adipose tissue. Additionally, the third aim will utilize a newly developed transgenic mouse model overexpressing mitochondrial OGG1 to determine the role of dietary fat exposure and mitochondrial DNA repair in altering mitochondrial function and cell viability. This critical aim will address significant gaps in our understanding of the interplay between diet, DNA damage, and metabolic disease. The knowledge gained from the completion of this final aim will also guide future research focused on developing novel targeted therapeutics to combat metabolic dysfunction by modulating pathways of DNA damage recognition and repair.

Public Health Relevance

One of the greatest threats to public health is the increasing prevalence of adult and pediatric obesity, which brings with it a host of secondary conditions, including fatty liver disease and diabetes. In order to develop preventive strategies and novel therapeutics, it is of significant interest to understand the cellular changes that mediate the development of these diseases. Using novel models of obesity, this project will bridge key gaps in our understanding of the molecular mechanisms that link dietary factors such as fats to the induction of damage to DNA and the consequent development of obesity and related diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Career Transition Award (K99)
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Digestive Diseases and Nutrition C Subcommittee (DDK)
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Laughlin, Maren R
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Oregon Health and Science University
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United States
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