Azoxymethane alters the plasma metabolome to a greater extent in mice fed a high fat diet compared to an AIN-93 diet

Authors: Zeng, Huawei; UMAR, SHAHID - University Of Kansas; LIU, ZHENHUA - University Of Massachusetts; Bukowski, Michael

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/2/2021
Publication Date: 7/9/2021
Citation: Zeng, H., Umar, S., Liu, Z., Bukowski, M.R. 2021. Azoxymethane alters the plasma metabolome to a greater extent in mice fed a high fat diet compared to an AIN-93 diet. International Journal of Molecular Sciences. https://doi.org/10.3390/metabo11070448.
DOI: https://doi.org/10.3390/metabo11070448

Interpretive Summary: Colon cancer is a major public health issue in the US, with approximately 140,000 new cases and 50,000 deaths per year. Obesity has emerged as one of the leading environmental risk factors for colon cancer development as supported by epidemiological studies as well as controlled experimental animal studies. Our recent studies have shown that accumulation of excess body fat is associated with inflammation and formation of pre-cancer lesions in the colon. However, little is known about the underlying metabolic basis. In this study, we demonstrate that, compared to normal fat intake, high fat intake alters the profiling of (circulatory) metabolic molecules to a greater extent during colon cancer development in a mouse model of colon cancer. These data provide novel insights into obesity-related cancer risk and will be useful for scientists who are interested in the prevention of obesity-related colon cancer.

Technical Abstract: Objective: Consumption of a high fat diet (HFD) links obesity to colon cancer in humans. Consistent with this observation, our data show that a HFD (45% energy fat versus 16% energy fat in AIN-93 diet, AIN) promotes azoxymethane (AOM) induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. We hypothesize that AOM treatment results in different plasma metabolomic responses in an AOM mouse colon cancer model fed with a HFD compared to the AIN. Methods: Four-week-old male C57BL/6 mice were fed the AIN or HFD with or without AOM treatment for 16 weeks. At the end of this study, untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Results: Untargeted metabolomic profiling showed that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN only, AIN+AOM; HFD only, HFD+AOM). Sparse partial least squares discriminant analysis showed a separation between the HFD and HFD+AOM groups but not AIN and AIN+AOM groups. Major metabolites responsible for this separation were beta-sitosterol, dihydrocholesterol, alpha-tocopherol, methylphosphate, citric acid, cholesterol, isocitric acid, myristic acid, arachidonic acid, and nicotinamide. In addition, the concentrations of dihydrocholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway and enrichment analyses indicated that diets and AOM-induced colonic ACF modulated 5 metabolic pathways: (a) citrate cycle, (b) arginine biosynthesis, (c) aminoacyl-tRNA biosynthesis, (d) alanine, aspartate and glutamate metabolism, and (e) glyoxylate and dicarboxylate metabolism. Conclusions: Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels, and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN.