Overall, our data highlight hepatic PPARα activity regulation by fatty acids released from adipocytes. This contrasts with the previous evidence that PPARβ/δ rather than PPARα may act as a FFA sensor.38 However, our data support the possibility that this adipose-derived signal is time-restricted and specifically efficient in early night. Moreover, other pathways likely influence PPARα activity by providing ligands.34 35 39 40 Several insulin-sensitive signalling mechanisms influence hepatic PPARα, and adipocyte lipolysis is insulin sensitive.41 Thus, insulin may coordinate hepatic PPARα, both through cell-autonomous mechanisms and adipocyte lipolysis inducing interorgan communication mediated by FFA release. Our findings also correspond with the recent evidence that adipocyte lipolysis may regulate hepatic Fgf21.42 Circulating FGF21 was strictly dependent on hepatocytic PPARα activation during fasting. Most circulating FGF21 is liver-derived43 and Pparα−/− mice show very little FGF21.11 12 Other transcription factors can also regulate 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
