688 Obesity Induces Colonic and Mesenteric Fat Inflammation and Promotes Tumorigenesis in a Model of Murine Colon Cancer

Abstract

Background: Obesity is defined as a chronic low-level inflammatory condition characterized by high levels of circulating IL-6 and LPS and increases the risk of colon cancer development. Aim: We aimed to investigate the mechanism of obesity enhanced colon tumorigenesis in a murine model of diet-induced obesity. Method: Mice were fed either a control diet (10% calories from fat) or a high fat (HF) diet (60% calories from fat) and colonic tumors were induced by intraperitoneal injection of the genotoxic compound azoxymethane (AOM) followed by 2 rounds of oral dextran-sodium sulfate (DSS). Proximal and distal colon tissue was assessed for gene expression of inflammatory markers by qRT-PCR. The mesenteric fat was similarly assessed. The macrophage infiltrate in mesenteric fat was measured by immunohistochemistry staining for CD68. Bacterial translocation of live bacteria to the mesenteric lymph nodes (MLN) and spleen was determined using culture-dependent techniques. Results: Mice fed a HF diet for 10 weeks gained significantly more weight during the course of the experiment compared to mice fed a lean diet. They also had increased proximal colon gene expression of inflammatory mediators including tnfa, nos2 and il1b which was not observed distally. However, increased proximal gene expression did not lead to overt inflammation in the colon as determined by histological grading. Feeding a HF diet also resulted in mesenteric adipose tissue gene expression of tnfa and il1b and increased infiltration of CD68+ macrophages. Mice fed a HF diet and given AOM-DSS had an increased number of colonic tumors compared to control diet fed mice. However, there were few differences in inflammatory gene expression between the control diet or HF diet fed mice given AOM-DSS, and this observation extended to cytokine protein secretion from distal colon explant supernatants. The highest levels of live bacteria were recovered from the MLN of mice fed a HF diet and given AOM-DSS. Macrophages isolated from the mesenteric fat of mice fed a HF diet did not robustly respond to LPS stimulation, while those isolated from mice fed a HF diet and given AOM-DSS had increased baseline cytokine secretion that was further enhanced by LPS stimulation. Conclusion: Obesity increases tumor formation in a model of inflammation-induced colon cancer. Obesity itself induces inflammation of the colon and mesenteric fat. Mesenteric fat-associated macrophages from obese tumor bearing mice are primed to respond to LPS or translocated bacteria leading to an increase in local and systemic inflammation. We believe our results highlight the yet unknown role of mesenteric fat as a rheostat for intestinal and systemic inflammatory states.