When considering all published data as a whole, it is striking that experiments using PPARα ligands do not lead to the same conclusions as those with PPARα knockout mice. In these mice, however, a whole new metabolic homeostasis may be installed which hampers distinction between direct and indirect effects of the absence of this transcription factor. Similar remarks have to be made when organisms are treated for long periods with synthetic agonists. Other cautionary notes are that expression levels of metabolic enzymes are not always predictive of pathway fluxes, and that there is only partial overlap of genes upregulated by PPARα during fasting and genes upregulated by synthetic PPARα agonists [6, 9]. Therefore, the most reliable system to judge the role of PPARα in carbohydrate metabolism is probably an acute activation of the transcription factor using physiological PPARα ligands.
