Abstract 4415: Intestinal tumorigenesis increased by obesity caused by leptin deficiency and/or high fat diet in ApcMin x Lepo
b mice involves blood glucose dysregulation
Authors: Ngo Ha Thi , Hetland Ragna Bogen , Steffensen Inger-Lise 
Published: August 2012

Abstract
Our objective was to study how obesity affects intestinal cancer in a double mutant mouse model obtained by intercrossing of C57BL/6J-ApcMin (multiple intestinal neoplasia)/+ and C57BL/6J-Lepob (obese)/+ mice. The Min mouse has a mutated tumor suppressor gene adenomatous polyposis coli (Apc), involved in both inherited and sporadic colorectal cancer. The obesity (ob) gene is coding for leptin, a hormone that regulates food intake and energy expenditure, leading to obesity if mutated. The offspring were given one s.c. injection of 25 mg/kg body weight (bw) of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or the vehicle 0.9% NaCl on day 3-6 after birth, and were given a 10 or 45 % fat diet from weaning to termination at 11 weeks. To test the hypothesis that obesity affects intestinal cancer via dysregulation of glucose, we measured blood glucose levels at weeks 6 and 11 and did a glucose tolerance test (GTT) at week 6. Colon and small intestine were fixed in formalin and stained with methylene blue. The number, diameter and localization of spontaneous (0.9% NaCl group) and PhIP-induced tumors were scored by transillumination in an inverse light microscope. Terminal bw was significantly higher in ob/ob mice compared with both ob/wt and wt/wt mice, and in mice on 45 vs on 10% fat diet. The incidence of small intestinal tumors was 100% in all mice of Min/+ background independent of treatment, diet or ob background. PhIP significantly increased the number of colonic and small intestinal tumors. The number of small intestinal tumors was significantly higher in ob/ob mice compared with ob/wt and wt/wt mice of both genders, and increased even further in mice on 45 vs 10% fat diet. The majority of the tumors were located in the distal half of the small intestine, but in ob/ob mice additional tumors were observed in the proximal part, again increased on 45 vs 10% fat diet. The incidence, number, size or localization of the few colonic tumors present was not affected by either ob genotype or diet. The blood sugar levels at both week 6 and 11 were significantly higher in ob/ob mice compared with ob/wt and wt/wt mice of both genders, and increased even further in mice on 45 vs 10% fat diet. The GTT test showed that ob/ob mice had a much slower decrease in blood glucose seen as higher area under the curve (AUC) after challenge than ob/wt and wt/wt mice. AUC was increased further in all ob genotypes by 45% fat. For all end points, ob/wt and wt/wt mice were essentially similar. Conclusions: Obesity induced by lack of leptin hormone significantly increased small intestinal tumorigenesis in Min/+ mice, which was increased further with a high fat diet. These obese mice also had significantly increased blood sugar levels and showed slower decrease after challenge in GTT, indicating a dysregulation of glucose as a possible cause of the increased intestinal tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4415. doi:1538-7445.AM2012-4415