Diet, Nutrient, and Environmentally Regulated Genes and Pathways in Obesity, Aging, and Cancer

Obesity has grown to epidemic proportions globally, with more than 1 billion adults overweight and 300 million of them considered clinically obese. Obesity has been shown to be a major contributor to chronic diseases, such as heart disease, diabetes, and cancer with the incidence of these diseases increasing with age. Yet, surprisingly still little is known about the genetic and molecular mechanisms involved in diseases that are correlated with increased lipid consumption. The role of aging in contributing to these diseases is also not well understood. The prevalence of obesity in the United States and the rest of the world has dramatically increased in a relatively short time period. Poor diets and diets high in fat, in combination with sedentary lifestyles are likely the primary causes of obesity in the western world. Therefore, investigating the effects of high fat dietary intake is an important step in understanding the factors that contribute to the increase in obesity and in turn the secondary diseases caused by it.

Obesity and aging have been established as a major contributor for developing heart disease, diabetes, and cancer. However, the genetics of the obesity-aging relationship is largely unknown and thus in need of investigation. Progress in obesity research is also hampered by the complexity in genetic/metabolic and environmental interactions. Therefore, it would be beneficial if one could study the central aspects of High Fat Diet (HFD)-induced obesity (ie. the molecular control of dietary fat accumulation) and aging (ie. the molecular pathways that control aging) in a simplified system. Drosophila has recently emerged as a powerful tool for discovering not only the conserved genetic network of metabolism as well as the central pathways regulating growth and aging. We aim to understand the genetic interplay of metabolism, growth, and aging by focusing on the nutrient sensing Insulin-TOR pathway as it relates to these diseases.

Areas of Research:

1. Role of Genes and Pathways in HFD Obesity and Heart Disease

An obstacle in the progress of the study of obesity is the complexity of mammalian genetics and their metabolic systems. Therefore, we are utilizing the genetic potential of Drosophila as a simplified model for the investigation of the central metabolic mechanisms of High Fat Diet-induced obesity and its relation to heart disease (in collaboration with Dr. Rolf Bodmer). By using Drosophila we are testing how genetic manipulation of novel lipid metabolic signaling pathways can modulate heart structure and function (Luong et al., 2006).

2. Role of Diet and Nutrition in Gut/Intestinal Stem Cell Function and Aging

We have preliminary data showing that increasing age significantly increases triglyceride accumulation and shows detrimental effects on Gut-Intestinal Stem Cell (ISC) structure and function in the Drosophila genetic model system. We are examining these date in light of the cancer-aging hypothesis which posits that aging is a trade-off due to cancer suppression. Drosophila is an established model to study aging, because the basic aging functions are evolutionarily conserved. Drosophila is also the simplest genetic model with a gut that has conserved structure and function. This makes Drosophila unique for studying the pathways that regulate aging and their effects on Gut-ISC function both intrinsically within the ISCs and within the niche (stroma) at the cellular level.

3. Novel Genes and Tissue Communication in Diabetes

Drosophila has recently emerged as a simplified model for studying lipid and glucose metabolism, which demonstrates that the basic metabolic functions are evolutionarily conserved (Luong et al., 2006). The thrifty gene hypothesis suggests that certain gene variants were selected during evolutionarily recent times of famine and that these genes are now contributing to the obesity and diabetes epidemic. We are using various genetic approaches to identify these factors. Drosophila is also the simplest genetic model with insulin-TOR signaling (Oldham and Hafen, 2003), thus making it ideal for identifying novel genetic components and studying their autonomous and non-autonomous contributions to insulin sensitivity in a Drosophila model of Type 2 Diabetes.