title: Obesity-related promotion of aberrant crypt foci in DMH-treated obese Zucker rats correlates with dyslipidemia rather than hyperinsulinemia.
abstract: 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.
authors.affiliation: Department of Nutritional Physiology and Biochemistry, Max Rubner-Institute, Haid-und-Neu-Strasse 9, 76131 Karlsruhe, Germany.
authors.forename: Tatiana C L
authors.initials: TC
authors.lastname: Koch
authors.forename: Karlis
authors.initials: K
authors.lastname: Briviba
authors.forename: Bernhard
authors.initials: B
authors.lastname: Watzl
authors.forename: Achim
authors.initials: A
authors.lastname: Bub
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Barth
mesh_terms: 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
chemical_list: D019813:1,2-Dimethylhydrazine