A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis

Anne Loft, Søren Fisker Schmidt, Giorgio Caratti, Ulrich Stifel, Jesper Havelund, Revathi Sekar, Yun Kwon, Alba Sulaj, Kan Kau Chow, Ana Jimena Alfaro, Thomas Schwarzmayr, Nikolaj Rittig, Mads Svart, Foivos-Filippos Tsokanos, Adriano Maida, Andreas Blutke, Annette Feuchtinger, Niels Møller, Matthias Blüher, Peter NawrothJulia Szendrödi, Nils J Færgeman, Anja Zeigerer, Jan Tuckermann, Stephan Herzig

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection.

Original languageEnglish
JournalCell Metabolism
Volume34
Issue number3
Pages (from-to)473-486.e9
ISSN1550-4131
DOIs
Publication statusPublished - 1. Mar 2022

Keywords

  • fasting
  • genomics
  • glucocorticoid receptor
  • hepatocyte
  • ketogenesis
  • liver
  • macrophage
  • nuclear receptor
  • transcripional regulation
  • tumor necrosis factor

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