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Energy Restriction Reduces the Number of Advanced Aberrant Crypt Foci and Attenuates the Expression of Colonic Transforming Growth Factor ß and Cyclooxygenase Isoforms in Zucker Obese (fa/fa) Rats¹

Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, R3T 2N2 Canada

Several epidemiological studies have supported the concept that high energy intake, obesity, and/or hyperinsulinemia are risk factors for colon cancer. Previously, it was shown that Zucker obese rats are more sensitive to chemically induced colon cancer than their lean counterparts. The present study investigated whether moderate (20–25%) dietary energy restriction (ER) would attenuate colon carcinogenesis in the Zucker obese rat model. Six-week-old Zucker obese (fa/fa) rats and lean (Fa/Fa) rats received s.c. injections of azoxymethane at a dose of 10 mg/kg body weight once weekly for 2 weeks. A week later, obese rats (n = 16) were assigned to an ER diet (Ob-ER group), based on a low-fat AIN-93G semisynthetic diet. The remaining obese and lean rats (n = 16 rats/group) were fed the low-fat diet ad libitum (Ob group and Ln group, respectively). All rats were euthanized after 8 weeks, and their colons were assessed for aberrant crypt foci (ACF; n = 8/group) or for the expression of transforming growth factor (TGF)-ß and cyclooxygenase (COX) isoforms at the protein and mRNA transcript levels (n = 8/group). Ob rats had a higher number of advanced ACF (crypt multiplicity 7) than Ln rats. Dietary ER significantly reduced the appearance of advanced ACF in Ob-ER rats without significantly affecting the blood insulin level or body weights. TGF-ß and COX isoforms were differentially expressed in the colonic mucosae of Ob and Ln rats. Dietary ER significantly reduced TGF-ß1/ß2 and COX-1/2 protein expression in obese rats. This study is the first to demonstrate that moderate ER attenuated TGF-ß and COX protein expression and the carcinogenic process in Zucker obese rats. These findings provide insights leading to the proposal that the mechanism(s) underlying the early events of colon carcinogenesis in Zucker obese rats may extend beyond the role of excessive body weight and hyperinsulinemia per se.

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