A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis

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  • Anne Loft, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research, Syddansk Universitet
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  • Søren Fisker Schmidt, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research, Syddansk Universitet
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  • Giorgio Caratti, Institute for Comparative Molecular Endocrinology, Universität Ulm
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  • Ulrich Stifel, Institute for Comparative Molecular Endocrinology, Universität Ulm
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  • Jesper Havelund, Syddansk Universitet
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  • Revathi Sekar, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research
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  • Yun Kwon, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research
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  • Alba Sulaj, German Center for Diabetes Research, Heidelberg University Hospital (UKHD)
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  • Kan Kau Chow, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research
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  • Ana Jimena Alfaro, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research
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  • Thomas Schwarzmayr, Institute of Human Genetics, Helmholtz Zentrum München
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  • Nikolaj Rittig
  • Mads Svart
  • Foivos-Filippos Tsokanos, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , German Center for Diabetes Research
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  • Adriano Maida, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research
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  • Andreas Blutke, Research Unit Analytical Pathology, Helmholtz Center Munich
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  • Annette Feuchtinger, Research Unit Analytical Pathology, Helmholtz Center Munich
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  • Niels Møller
  • Matthias Blüher, Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI_MAG)
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  • Peter Nawroth, Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine, Heidelberg University Hospital
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  • Julia Szendrödi, Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine, Heidelberg University Hospital
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  • Nils J Færgeman, Syddansk Universitet
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  • Anja Zeigerer, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research
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  • Jan Tuckermann, Institute for Comparative Molecular Endocrinology, Universität Ulm
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  • Stephan Herzig, Institute for Diabetes and Cancer, Helmholtz Center Munich, Heidelberg University Hospital (UKHD) , Technical University of Munich, German Center for Diabetes Research

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.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind34
Nummer3
Sider (fra-til)473-486.e9
Antal sider14
ISSN1550-4131
DOI
StatusUdgivet - mar. 2022

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