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Hepatocyte PPARα is required for the sensing of adipose-derived fatty acids and for full brown adipose tissue activation during lipolysis
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International audience. Background and aims: Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor and a member of the PPAR family, which also includes PPARβ/δ and PPARγ. In hepatocytes, PPARα acts as a lipid sensor that controls the expression of genes involved in whole-body energy homeostasis during fasting, including fatty acid oxidation and ketogenesis. During fasting, PPARα is also required for the expression of the hormone fibroblast growth factor 21 (FGF21), a hepatokine with systemic metabolic effects. In this work, we investigated the role of hepatocyte PPARα activity in the dialogue between the liver and adipose tissues. Materials and methods: We used mouse models of selective deletion of PPARα in hepatocytes and of adipose triglyceride lipase (ATGL) in adipocytes as a model of defective lipolysis. First, we performed liver whole genome expression analysis in fasted mice upon cell-specific deletion of adipocyte ATGL or hepatocyte PPARα. Second, we tested the consequences of hepato-specific PPARα deficiency during pharmacological induction of adipocyte lipolysis with a β3-adrenergic receptor agonist.Results: In the absence of ATGL in adipocytes, ketone body and FGF21 production is impaired in response to starvation. Liver transcriptome analysis reveals that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting, with a strong induction of PPARα target gene expression. Adipose tissue lipolysis, induced by acute activation of the 3-adrenergic receptor, also triggers PPARα-dependent responses in the liver, including gene expression, FGF21 production and ketogenesis. Hepatic PPARβ/δ is dispensable for these 3-adrenergic responses. In addition, the absence of hepatocyte PPARα alters brown adipose tissue (BAT) morphology and reduces the expression of BAT markers upon stimulation of β3-adrenergic signaling while the deletion of FGF21 in hepatocytes does not affect BAT activation under this condition.Conclusion:Altogether, our results support a dominant role for adipose ATGL in generating fatty acids that trigger hepatocyte PPARα activity and underscore the critical role of hepatic PPARα not only in the sensing of lipolysis-derived lipids but also in triggering BAT activation independent of hepatocyte FGF21 production. Intact PPARα activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization.
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