Energy restriction modulates the development of advanced preneoplastic lesions depending on the level of fat in the diet

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Abstract
Our objective was to investigate the ability of preneoplastic colonic lesions at different stages of development to respond to the growth‐retarding effects of energy restriction (ER). Male Fischer 344 rats were given three injections of azoxymethane (15 mg/kg sc) and fed a high‐fat corn oil diet for 16 weeks. This duration allowed aberrant crypt foci (ACF) to develop and acquire different growth states. ACF growth was assessed by enumerating the number of crypts per focus. At Week 16, 10 animals were killed and their colons were enumerated for ACF (baseline). The remaining animals were then allocated to four dietary groups: high‐fat (23% wt/wt), low‐fat (5% wt/wt), high‐fat energy‐restricted (HFER), or low‐fat energy‐restricted (LFER). After the animals were fed the experimental diets for six weeks, ER decreased the total number of ACF regardless of the level of fat. At Week 12, the LFER diet retarded the appearance of advanced ACF, but this was not the case for the HFER diet. Consequently, the level of fat was identified as the significant variable in affecting the number of ACF with different crypt multiplicity. The animals fed the LFER diet had the fewest tumors and microadenomas per rat. The HFER diet was ineffective in modulating tumor outcome. To our knowledge, these findings are the first to suggest that ER modulated the development of advanced ACF and colonic tumors depending on the level of fat in the diet.