Obesity-related promotion of aberrant crypt foci in DMH-treated obese Zucker rats correlates with dyslipidemia rather than hyperinsulinemia
Koch, Tatiana C. L | Briviba, Karlis | Watzl, Bernhard | Bub, Achim | Barth, Stephan W
Background Obesity and energy restriction modulate the development of precancerous aberrant crypt foci (ACF) in animal models of colon cancer. Aim Investigation of the major obesity-associated determinants for ACF-development and underlying mechanisms leading to ACF-modulation, such as changes in DNA damage or colonocytes hyperproliferation. Methods Lean and obese Zucker rats fed ad libitum (a.l.) or obese pair fed (p.f.) were induced with 1,2-dimethylhydrazine (DMH) for colon cancer. Multiple regression analyses were performed to identify major metabolic factors correlated with ACF number and size (aberrant crypts/ACF). DNA damage is analyzed by the comet-assay, epithelial proliferation by immunohistochemistry. Results Aberrant crypt foci number was significantly elevated in Zucker obese a.l. (205.7 ± 65.4 vs. lean 9.5 ± 6.3, P < 0.05) and is reduced by pair feeding in Zucker obese rats (81.4 ± 28.5 vs. obese a.l., P < 0.05). Compared to lean the ACF size was higher in Zucker obese a.l. (2.1 ± 0.3 vs. lean 1.3 ± 0.2., P < 0.05) but is not reduced by pair feeding (1.7 ± 0.2; P > 0.05). While ACF number and size were modulated by genotype and/or pair feeding the DMH-induced DNA damage and hyperproliferation in colonocytes did not differ significantly between groups. Regression analysis showed that plasma parameters associated with lipid-metabolism (triglycerides, cholesterol, malondialdehyde) significantly correlated with the ACF number and size while parameters linked to carbohydrate-metabolism (glucose, insulin) were weaker determinants. Conclusion Obesity or pair feeding-associated modulation of ACF correlate with parameters related to lipid-metabolism but is not accompanied by changes in DNA damage and proliferation.
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