High‐fat/high‐carbohydrate diet increases glycogen accumulation in lung tissue in vivo

Abstract

Lung adenocarcinoma (LUAD) is the major histological subgroup of non‐small cell lung cancer (NSCLC) with an extremely high mortality rate even when diagnosed at an early stage. LUAD makes up around 40% of lung cancer cases and can quickly metastasize to other areas of the body. Glycogen is the short‐term storage of carbohydrates and can be easily mobilized in the body. Recently, other and our own data suggests glycogen can drive lung cancer progression, however, the mechanism of which glycogen accumulates in LUAD is poorly understood and potentially arises from a number of genetic and environmental factors. Although specific genetic variants driving aberrant LUAD glycogen accumulation have been identified, several studies have shown that caloric excess as well as specific nutrients in the diet can promote tumor growth. Further, LUAD patients with type II diabetes or high BMI have significantly poorer survival. Therefore, we hypothesized that a diet rich in fats and carbohydrates that mimics a Western diet increases glycogen accumulation in lung tissue and potentially drives LUAD tumor progression. To test our hypothesis that a Western diet alters glycogen metabolism independent of genetic drivers and tumor formation, we administered via oral gavage a Western diet comprised of corn oil and high fructose corn syrup (150 μl corn oil: 25% high‐fructose corn syrup solution) to wild‐type C57BL/6 mice at acute (1‐, 3‐, and 6‐hours) and chronic (two weeks) time points. At the end of each time point, mice were sacrificed and lung tissue was harvested. Using a combination of gas chromatography mass spectrometry (GCMS) and matrix‐assisted laser desorption ionization mass spectrometry imaging, we quantified central carbon metabolites and glycogen content in lung tissue resected from these mice. Mice administered H2O were used as a control. We found that the mice administered a Western diet for two weeks exhibited elevated levels of glycogen as well as metabolite pools within glycolysis and the TCA cycle in lung tissue compared to the control group. However, our acute studies revealed no change in lung glycogen up to 6‐hours after receiving the Western diet. Overall, these data highlight a link between diet and glycogen metabolism in the lung and suggest that intake of different dietary nutrients may play a role in glycogen accumulation in LUAD tumors and disease progression. Our results demonstrate that a high fat/high carbohydrate diet in wild‐type mice increases central carbon metabolism and glycogen accumulation in lung tissue after chronic exposure. Moving forward, we will examine the contribution of diet to glycogen metabolism in a mouse of LUAD and assess the effect of increased glycogen accumulation on tumor growth in vivo.