Sugar Metabolism in Development of Obesity Complications

Increased intake of high-fat diet (HFD) and sugar sweetened beverages contributes to the rise of obesity epidemic, which has devastating consequences on human health. As obesity affects enormous percent of our population, the life expectancy in the USA is expected to decrease for the first time in our history. Much of the initial research on obesity has focused on the effects of HFD, as a driver of poor metabolic outcomes. Over the last three decades we have learned that all-trans saturated fatty acids and cholesterol are particularly associated with poor health outcomes, while other fats, such as monounsaturated and polyunsaturated fatty acids, can promote health. As a product of this research, the intake of all-trans saturated fats has decreased on a population level, but unfortunately, this did not translate into decreased obesity epidemic. More recently, the contribution of sugar towards development of obesity epidemic has experienced a renewed interest. As a result of largely descriptive epidemiologic data, a number of countries and several US cities have instituted new sugar tax, as means of curbing obesity epidemic. Furthermore, FDA for the first time, mandates disclosure of sugar content on all food labels. Lastly, the majority of key drug companies are developing inhibitors of sugar metabolism as a treatment for obesity, fatty liver disease and insulin resistance. As an example, Pfizer has a ketohexokinase (KHK) inhibitor in phase 2A clinical studies and our collaborator Alnylam Pharmaceuticals is also vigorously pursuing this target. In spite of renewed interest in sugar as a driver of obesity associated metabolic complications, the mechanism by which it mediates these effects is largely unknown. Furthermore, it remains to be determined whether some sugar monosaccharides are more deleterious to health than the others. In order to study these important questions we supplemented mice with fructose- or glucose-sweetened water, both on normal chow or HFD. We directly compared fructose and glucose, as these monosaccharides are found in the most commonly consumed sweeteners, sucrose (table sugar) and high-fructose corn syrup. Furthermore, fructose and glucose have equal caloric density, excluding the possibility that the difference in caloric intake is mediating their unique metabolic effects. We found that fructose supplemented mice on HFD developed obesity, fatty liver disease and insulin resistance, whereas glucose supplemented mice remained sensitive to the action of insulin, in spite of accumulating similar amount of fat in the liver. These divergent effects are, in part, mediated by different type of fat deposition in the liver, as fructose promotes endogenous synthesis of free fatty acids, while glucose stimulates assembly of fatty acids into inert triglycerides. We also showed that human subjects with fatty liver disease have increased levels of KHK, the first enzyme of fructose metabolism and that liver-specific knockdown of KHK led to a decrease in liver lipid accumulation and improved insulin signaling in mice. In this application we propose to dissect pathways by which unique monosaccharides modify hepatic metabolism. We will investigate the effects of fructose and glucose supplementation on fatty acid synthesis and fatty acid oxidation pathways, the two major determinants of liver lipid accumulation. We will also study insulin signaling pathway, as insulin promotes fatty acid synthesis and decreases fat utilization. Lastly, using state of the art proteomic analysis we will identify novel pathways that are affected by fructose and glucose supplementation, as well as by KHK knockdown. In the second aim, we will study the effects of sugar on mitochondria, since these organelles regulate cellular energy homeostasis. More specifically, we will determine whether fructose-induced mitochondrial fragmentation is dependent on KHK activity. Moreover, we will determine the effects of sugars on ER stress, the pathway that can lead to mitochondria fragmentation and the effects of sugar on clearance of damaged mitochondria (mitophagy). Lastly we will study how sugar intake affects post-translational modifications of mitochondrial proteins and thus global metabolism. The studies proposed in this application will discover new pathways that are affected by sugar metabolism and increase our molecular understanding of how specific monosaccharides contribute to development of obesity and its complications. This research will also increase our understanding by which KHK knockdown abrogates poor outcomes associated with harmful fructose metabolism. Lastly we will provide valuable insights whether fructose or glucose component of caloric sweeteners is more harmful to health