Abstract
Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an 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. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. 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.
Highlights
Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans [1,2].The global obesity epidemic has, in part, been attributed to the adoption of Western lifestyle practices, including increased consumption of high-energy diets [1–3]
Consumption of a HFD can lead to the accumulation of excess body fat that is associated with adipose tissue dysfunction and a chronic state of low-grade inflammation known to promote tumor development [5,6]
We recently reported that in a mouse model, a HFD promotes colonic aberrant crypt foci (ACF, putative preneoplastic lesions) formation accompanied by increased systemic levels of proinflammatory cytokines [7]
Summary
Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans [1,2]. The global obesity epidemic has, in part, been attributed to the adoption of Western lifestyle practices, including increased consumption of high-energy diets [1–3]. Consumption of a HFD can lead to the accumulation of excess body fat that is associated with adipose tissue dysfunction and a chronic state of low-grade inflammation known to promote tumor development [5,6]. There are few mechanistic studies on early colonic tumorigenesis concerning the underlying metabolic regulation in the context of HFDinduced obesity. We posit that determining plasma metabolomic responses may lead to a greater understanding of the metabolic regulation concerning a HFD and colonic ACF formation. Untargeted metabolite profiling (e.g., metabolomics) is an effective approach that aids in determining these underlying biochemical changes [10].
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