Abstract 3689: High fat diet induces the expression of IL-6 and MCP1 exclusively in the rostral portion of the parametrial fat pads in SKH-1 mice.

Sunlight-induced non-melanoma skin cancer is a major cancer in the United States. How obesity contributes to skin cancer, and the molecular changes induced by obesity that promote skin cancer development remain poorly understood. Our previous study showed that surgical removal of the parametrial fat pads from mice fed a high-fat diet inhibited UVB-induced skin carcinogenesis, but this was not observed in mice fed a low-fat chow diet (PNAS. 109: 9065-9070, 2012). These results indicate that dietary high fat caused the parametrial fat pads to secrete high levels of proinflammatory cytokines that may promote UVB-induced skin carcinogenesis. Female SKH-1 mice were fed a 60% kcal high fat diet for 6 months, and the mice were sacrificed at various time intervals. The parametrial fat pads were removed and dissected into rostral (the loose end proximal to the caudal zone) and caudal portion (attached to the uterus). Half of the fat were fixed in formalin for histopathology, and other half of the fat was homogenized, place into a hanging insert of a dual-chamber and incubated in minimal essential medium for 4 hours at 370C. Proteins that were released from the fat passed through the 0.4 μm pore in the insert to provide fat cell-derived medium that was collected and used for adipokine analysis by an antibody array. Our results showed that among the 38 adipokines measured, treatment of mice with a 60% kcal high fat diet time-dependently increased the level of IL-6 (0.5, 1.0, 10.3 and 27.8 fold) and MCP1 (0, 0, 1.5 and 21.2 fold) at 0.5, 1.5, 3 or 6 months of treatment, respectively. Several other adipokines (ICAM1, IGFBP6, Leptin, SerpinE1 and TIMP1) were also increased. Interestingly, the high fat diet-induced the expression of IL-6 and MCP1 almost exclusively in the rostral, but not in the caudal portion of the parametrial fat pads. IL-6 and MCP1 were not detected in control mice fed a low fat chow diet. In addition, the rostral fat from the mice fed the high fat diet had an increased number of dead adipocytes, macrophages, apoptotic cells, and mast cells when compared to the caudal fat. Surgical removal of the whole parametrial fat pads from mice fed the high fat diet resulted in a marked decrease in the levels of IL-6 and MCP1 in the compensatory fat that returned 6 months after the surgery when compared to that of the sham-operated control. In a separate study, we found that mice fed a 40% kcal high fat diet rich in omega-6 fatty acids for 3 months had a significant increase in IL-6 protein expression in the rostral portion of the parametrial fat pads compared to mice fed the same amount of calories from a high fat diet rich in omega-3 fatty acids. Our results suggest that the high fat diet-induced increases of IL-6 and MCP1 protein expression mainly in the rostral portion of the parametrial fat pads may help explain why removal of the parametrial fat pads from mice fed a high fat diet resulted in a decrease in UVB-induced skin carcinogenesis. Citation Format: Yourong Lou, Jamie J. Bernard, Qinyun Peng, Tao Li, Allan H. Conney, Yaoping Lu. High fat diet induces the expression of IL-6 and MCP1 exclusively in the rostral portion of the parametrial fat pads in SKH-1 mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3689. doi:10.1158/1538-7445.AM2013-3689