ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

Fougerat, A.; Schoiswohl, G.; Polizzi, A.; Regnier, M.; Wagner, C.; Smati, S.; Fougeray, T.; Lippi, Y.; Lasserre, F.; Melin, V.; Tramunt, B.; Alkhoury, C.; Emile, A.; Schupp, M.; Gourdy, P.; Dubot, P.; Levade, T.; Ellero-Simatos, S.; Gamet-Payrastre, L.; Panasyuk, G.; Amri, E.-Z.; Postic, C.; Wahli, W.; Loiseau, N.; Montagner, A.; Langin, D.; Lass, A.; Guillou, H.

doi:10.1101/2021.01.28.428684

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bioRxiv · 10.1101/2021.01.28.428684

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

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Abstract

ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor (PPAR) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPAR has not been investigated. MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPAR. Finally, we tested the consequences of hepatocyte-specific PPAR deficiency during pharmacological induction of adipocyte lipolysis with a {beta}3-adrenergic receptor agonist. ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPAR target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPAR. Adipose tissue lipolysis induced by acute activation of the {beta}3-adrenergic receptor also triggered PPAR-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPAR activity. In addition, the absence of hepatocyte PPAR altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the {beta}3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPAR showed decreased tolerance to acute cold exposure. ConclusionsThese results underscore the central role of hepatocyte PPAR in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPAR activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.

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Fougerat, A., Schoiswohl, G., Polizzi, A., Regnier, M., Wagner, C., Smati, S., Fougeray, T., Lippi, Y., Lasserre, F., Melin, V., Tramunt, B., Alkhoury, C., Emile, A., Schupp, M., Gourdy, P., Dubot, P., Levade, T., Ellero-Simatos, S., Gamet-Payrastre, L., Panasyuk, G., Amri, E.-Z., Postic, C., Wahli, W., Loiseau, N., Montagner, A., Langin, D., Lass, A., Guillou, H.. 2021-01-30. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity. https://doi.org/10.1101/2021.01.28.428684

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