Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

Figure 1

Contribution of the anti-inflammatory roles of PPARγ in the onset of WAT inflammation in the context of obesity and insulin resistance. In the lean state, PPARγ activity maintains homeostasis in mature adipocytes in preventing the secretion of chemokines such as MCP-1. In addition, alternatively activated macrophages (M2) and Treg cells are resident leukocytes in WAT coordinating numerous biological activities such as stimulating angiogenesis and cleaning of dead cells. The role of PPARγ in these cells is to prevent classical activation of macrophages and local inflammation to develop. When obesity is reached, mature adipocytes are exposed to excessive concentrations of free fatty acids (FFAs), which decrease Pparγ expression. In consequence, insulin sensitivity is also decreased in adipocytes, which elevates even more local FFAs concentrations as adipocytes are no longer able to properly store fatty acids and lipolysis also becomes activated. Furthermore, these FFAs activate macrophages shifting into an M1 phenotype, promoting the release of proinflammatory cytokines such as TNF-α and IL-1β. Secondly, as PPARγ transrepressional activity is decreased, adipocytes secrete high concentrations of chemokines (MCP-1), further promoting the recruitment of macrophages. Occurrence of this feed forward amplification loop between adipocytes and macrophages eventually leads to the elevation of local inflammation, further exacerbating local insulin resistance, which will turn systemic in the long term. MCP-1: monocyte chemoattractant protein-1; treg cells: regulatory T cells; FFA: free fatty acids; PPARγ: peroxisome proliferator-activated receptor γ; TNF-α: tumor necrosis factor-alpha; IL-1β: Interleukin-1 beta.