Food restriction induces PPARα activity, and endogenous PPARα ligand production requires hepatic lipogenesis, which increases upon feeding.34 35 Thus, PPARα may be important during fasting-induced lipid catabolism and in the response to anabolic fatty acid-derived signals. Our data revealed the context dependency of PPARα hepatocytic activity defined by DEGs. This activity was clearly the highest during fasting. During fasting, hepatocyte-specific PPARα deletion resulted in steatosis, increased plasma FFA and impaired ketone bodies. This supports the concept that FFA released from adipose stores during fasting may activate PPARα for hepatic use. Accordingly, we found that Pparαhep−/− mice accumulate high oleic and linolenic acids in the liver during fasting (see online supplementary file 4), which is in agreement with the fact that both of them are the main fatty acids stored in the white adipose tissues of mice fed a chow diet.36 Importantly, we found a high correlation between the kinetics of circulating FFA increase and expression of PPARα and several of its target genes. Moreover, treatment with a β3-adrenergic receptor agonist further enhanced this response in vivo through PPARα but did
