hepatic Fgf21 expression44–48 and PPARα is also expressed in extrahepatic tissues.13 Our findings in Pparαhep−/− mice showed very little FGF21 without hepatic PPARα in both fed and fasted states. Pparα−/− mice are hypoglycaemic and hypothermic during fasting7 and FGF21 is known for its endocrine effect on glucose homeostasis and thermogenesis.13 However, compared with fasted Pparα−/− mice, fasted Pparαhep−/− mice showed reduced hypoglycaemia and hypothermia while FGF21 was equally absent in both models. This indicates that extrahepatocytic PPARα strongly influenced whole-body glucose homeostasis and temperature independently of hepatocyte PPARα and FGF21 production during fasting. In addition, while FGF21 prevents steatosis in different mouse models13 30 and FGF21 reduces hepatic lipids in WT mice, its overexpression is not sufficient to protect from lipid accumulation in Pparαhep−/− and in Pparα−/− mice. Therefore, the absence of FGF21 is not the primary cause for the steatosis observed in Pparαhep−/− mice.
