Since FGF21 has been shown to reduce steatosis and lipotoxic lipids13 30 we questioned whether the absence of FGF21 determines fasting-induced steatosis observed in Pparαhep−/− and Pparα−/− mice. FGF21 expression was rescued by adenoviral delivery both in Pparαhep−/− and in Pparα−/− mice (figure 5D). Comparable expression of FGF21 (figure 5E) was obtained in liver of WT, Pparαhep−/− and in Pparα−/− mice. FGF21-sensitive genes such as G6pd and Scd1 showed significantly different expression in response to FGF21 overexpression (figure 5E). However, FGF21 only reduced hepatic triglycerides and cholesterol esters in WT mice, but not in Pparαhep−/− and in Pparα−/− mice (figure 5F, G). These results indicate that the fasting-induced steatosis occurring in Pparαhep−/− and in Pparα−/− mice does not depend on the lack of FGF21. This is in line with our observations that FGF21- and PPARα-sensitive target genes are different (see online supplementary file 5A). Moreover, it is also consistent with the observation that FGF21 overexpression does not rescue the expression of PPARα target genes and conversely that PPARα-sensitive regulations occur in Fgf21−/− mice (see online supplementary file 5B, C).
