Amri, E.-Z. | bioRxiv Science

bioRxiv2021

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

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.

physiology↗

bioRxiv2020

Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic disorders

Obesity is a growing societal scourge responsible for approximately 4 million deaths worldwide. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal western diet feeding for five consecutive generations in mice induces a gradual enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males develop a "healthy" overweight phenotype that is not reversed after 4 subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

genetics↗