Fructose Metabolism Effects on the Liver: Unraveling the Role of Defective Intestinal GNG in Individuals with Obesity

ABSTRACT The alarming rise in the rates of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) persists despite efforts to address contributing factors and promote dietary changes. One major challenge has been the inconsistency in dietary guidelines, especially regarding the role of fructose. While population studies have linked excessive fructose consumption to conditions like type 2 diabetes and NAFLD, questions linger about the precise impact of fructose and whether its effects vary between individuals with and without obesity. The mechanisms underlying these associations remain unclear, particularly in humans. For instance, studies using tracers have shown that fructose consumption is linked to increased rates of fatty acid synthesis (de novo lipogenesis (DNL)), but this effect appears to depend on factors such as the amount of fructose and how it is consumed. In this grant, we will test the hypothesis that within a defined range of fructose intake, the ability to convert fructose to glucose (via gluconeogenesis, GNG) in the small intestine plays a protective role for the liver, shielding it from the deleterious effects of fructose. Additionally, we will investigate whether this protective effect of the intestine is impaired in individuals with obesity, potentially making them more vulnerable to fructose consumption. To address these questions, we will conduct four one-day dietary studies in adults with and without obesity. Our study is based on the idea that uncontrolled flux of fructose to the liver, resulting from fructose consumption, is a key factor in the dysregulation of lipid and carbohydrate metabolism. We will employ a feeding approach using well-defined liquid meals and a combination of stable isotopes (non-radioactive tracers), administered orally and intravenously in trace amounts. This approach will enable us to simultaneously measure the fluxes in intestinal GNG, hepatic GNG, and DNL pathways in response to both low and high fructose intake. We will also explore whether these fluxes differ between individuals with obesity and lean controls. By concurrently assessing these pathways, our proposal has the potential to advance our understanding of postprandial fructose metabolism and offer critical mechanistic insights to support evidence-based dietary recommendations, particularly concerning more targeted limitations in fructose consumption.