Role of PPAR-γ on immunometabolic effects of adipose tissue and macrophages, in a model of induced colon cancer treated with high-fat diet.

Introduction: Colon cancer is the second type of cancer that affects the largest number of cases in Brazil. Obesity is currently a risk factor for colon cancer, on the other hand, some authors found that the use of high-fat diet associated with the colon carcinogenesis model increased survival time, body weight recovery and reduced the size of the tumor region. Therefore, this relationship between colon cancer and obesity needs to be further investigated. PPARγ is a nuclear factor that has metabolic, anti-carcinogenic and anti-inflammatory properties, which is expressed in adipocytes and macrophages. PPARγ agonists may increase survival and quality of life, although it is not known whether this effect results from reduced fat loss as well as its metabolic and endocrine functions or whether these effects are more pronounced by the controlled anti-inflammatory response by PPARγ, mainly seen in macrophages. However, the aim of this work was to investigate the role of PPARγ in colon carcinogenesis, identifying how, in fact, the deletion of this nuclear receptor in macrophages will affect the carcinogenesis process in obese animals and in CACO-2 cells. Methods: PPARγ CreLox mice with specific deletion in myeloid cells (KO) and control littermates (WT) were divided into: standard diet; high-fat diet; high-fat diet and colon cancer induction; high fat diet, cancer and pioglitazone during 12 weeks. Human cells of the CACO-2 lineage were treated with PPARγ agonist and antagonist. The protein content of PPARγ, inflammatory cytokines, adipokines, flow cytometry, cell cycle analysis and cell death were evaluated. Results: KO animals have a lower percentage of CD80+Ly6Chigh macrophages in the colon; and the high fat diet decreases the percentage of Ly6Chigh macrophages in the adipose tissue. The PPARγ deletion was effective in attenuating cancer-promoted weight loss and reducing the gene expression of IL-10, IL-6 and IL-1β in subcutaneous adipose tissue. Cancer attenuated the percentage of Ly6clow macrophages in the subcutaneous adipose tissue and pioglitazone regained this percentage. The cancer led to an increase in the percentage of CD80+ Ly6Chigh macrophages and the total of Ly6clow macrophages in the large intestine of KO mice. In CACO-2 cells the use of PPARγ agonist and antagonist did not modulate intestinal permeability, apoptosis, cell cycle, but both reduced MCP-1 concentration. Conclusion: PPARγ modulation is changing the profile of macrophages present in the subcutaneous adipose tissue and in the colon, besides to altering the inflammatory response to the inflammatory response of the subcutaneous adipose tissue. The absence of PPARγ in myeloid cells reduced inflammatory markers in the adipose tissue of tumor-bearing animals, however this was not effective in improving survival. (AU)