PPARα Is Required for PPARδ Action in Regulation of Body Weight and Hepatic Steatosis in Mice

Figure 4

Lack of GW501516 effect in PPARδ-KO mice and hepatic levels of endogenous ligand for PPARα. GW501516 treatment had no significant overall influence on weight gain (a), food intake (b), or hepatic lipids (c) in PPARδ-KO mice. (d) Hepatic mRNA expression levels of PPARδ downstream target genes such as Plin2, Angptl4, and Pdk4 were not changed by GW501516 treatment in PPARδ-KO animals. (e) 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) (endogenous PPARα ligand) increase over time upon GW501516 treatment in non-tg mice. (f) Relative levels of POPC in livers of PPARδ-KO animals are higher when compared to non-tg mice. (g) Phenotypic effects of PPARδ agonist GW501516 are entirely dependent on downstream PPARα signalling. Genetic ablation of either of these two receptors results in resistance to GW501516-promoted weight loss and liver lipid accumulation. PPARα appears to be downstream of PPARδ potentially activated by endogenous ligand POPC levels determined by PPARδ. Significance is indicated (; ; ; test), mice/group.

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