Obesity-related promotion of aberrant crypt foci in DMH-treated obese Zucker rats correlates with dyslipidemia rather than hyperinsulinemia.
BACKGROUND
Obesity and energy restriction modulate the development of precancerous aberrant crypt foci (ACF) in animal models of colon cancer.


OBJECTIVE
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.


CONCLUSIONS
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.
Koch
Tatiana C L
TC
Department of Nutritional Physiology and Biochemistry, Max Rubner-Institute, Haid-und-Neu-Strasse 9, 76131 Karlsruhe, Germany.
Briviba
Karlis
K
Watzl
Bernhard
B
Bub
Achim
A
Barth
Stephan W
SW
D019813:1,2-Dimethylhydrazine / Q000633:toxicity; D000818:Animals; D031204:Caloric Restriction; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D020552:Comet Assay; D004249:DNA Damage; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000473:pathology*; D005260:Female; D006946:Hyperinsulinism / Q000473:pathology*; D007150:Immunohistochemistry; D009765:Obesity / Q000097:blood / Q000473:pathology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker
D019813:1,2-Dimethylhydrazine