In SRC-3 mice, PPARδ expression is thought to alternatively activate microglia from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype. In particular, there was a correlation between PPARδ expression in SRC-3-null mice and ramified microglia that expressed Ym1/2 and Mrc1, phenotypic markers for alternative activation. Interestingly, PPARδ activation has been shown to control the alternative activation of adipose tissue macrophages (ATMs) and Kupffer cells, hepatic macrophages [52, 53]. In the white adipose tissue of PPARδ-null mice, genes of alternatively activated macrophages, Clec7a, Retnla, Tgfb1, Jag1, and Mrc1, were reduced. The alternative activation of Kupffer cells was also decreased in PPARδ-null mice, as assessed by reduced expression of Arg1, Clec7a, Jag1, Pdcd1lg2, and Chia [53]. Reduced alternative activation of ATMs and Kupffer cells in PPARδ-null mice led to impaired glucose tolerance and insulin resistance [52, 53]. Whether PPARδ agonists can alternatively activate microglia remains to be determined.
