Role of PPAR³ in the imunometabolic effects of adipose tissue and macrophages, in induced colon tumor model.

Abstract

Introduction: Cancer is the second leading cause of death worldwide, according to WHO. Colorectal cancer is responsible for approximately 34,000 new cases diagnosed each year in Brazil. Colorectal cancers are tumors that affect the large intestine (colon) and rectum. A lower incidence of colorectal cancer is associated with diets rich in fruits and vegetables, or foods that are sources of fiber. The fructo-oligosaccharides (FOS) fibers are fermented by the intestinal flora leading to increased production of butyrate, a short chain fatty acid that has been shown to play a role in inhibiting the development of tumor cells in the intestine. Tributyrin (TB), a prodrug butyrate, has anti-tumorigenic action by inhibiting the growth and proliferation of tumor cells in animal models induced carcinogenesis in colon and generate some anti-inflammatory effects. Furthermore, animal models of colon cancer induced by azoxymethane (AOM) and dextran sultato sodium (DSS) show the maintenance of an inflammatory state during tumorigenesis. The PPARg is considered a new therapeutic target because of its beneficial effects on inflammatory bowel diseases and against tumor cells, is highly expressed in white adipose tissue.Objective: Therefore, the objective of this project is to verify the effects of a diet rich in FOS and oral supplementation of TB in preventing carcinogenesis of colon and the possible effect on the support of tumorigenesis by white adipose tissue.Methods: Initially, the animals C57/BL6 receive diet rich in FOS and TB for 4 weeks, then will be divided into 4 groups: control group (CT) treated with standard diet only; Group colon carcinogenesis (CC) treated with standard diet and induced carcinogenesis; TB group: treated with diet rich in TB and induced carcinogenesis; and FOS Group: treated with diet rich in FOS induced carcinogenesis. On day 0, the animals will be treated with intraperitoneal application AOM, 10 mg/kg of animal weight. On day 5, the animals begin 3 cycles of 21 days with DSS ingestion diluted with water. Then, will be euthanized on day 65 after initiation of carcinogenesis induction and tissues of interest removed. They will evaluate the effects of treatment on tumor metabolism and retroperitoneal and subcutaneous white adipose tissue. It will also be seen lipolysis and lipogenesis in isolated adipocytes and adipocyte morphology of the profile of cytokines and pro and anti-inflammatory gene expression and protein related to lipolysis, lipogenesis and inflammation. In tumor and adipose tissues will be checked protein expression of inflammatory cytokines by ELISA as well as cell proliferation markers. They will also be evaluated histological parameters of the subcutaneous adipose tissue, retroperitoneal and distal colon and immunohistochemistry to evaluate cell proliferation markers and apoptosis in the tumor.