Loft Anne, Schmidt Søren Fisker, Caratti Giorgio, Stifel Ulrich, Havelund Jesper, Sekar Revathi, Kwon Yun, Sulaj Alba, Chow Kan Kau, Alfaro Ana Jimena, Schwarzmayr Thomas, Rittig Nikolaj, Svart Mads, Tsokanos Foivos-Filippos, Maida Adriano, Blutke Andreas, Feuchtinger Annette, Møller Niels, Blüher Matthias, Nawroth Peter, Szendrödi Julia, Færgeman Nils J, Zeigerer Anja, Tuckermann Jan, Herzig Stephan
Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine, Heidelberg University Hospital, Heidelberg 69120, Germany; Molecular Metabolic Control, Technical University Munich, Munich 80333, Germany; German Center for Diabetes Research, Neuherberg 85764, Germany; Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), Odense 5230, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), SDU, Odense 5230, Denmark.
Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg 85764, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine, Heidelberg University Hospital, Heidelberg 69120, Germany; Molecular Metabolic Control, Technical University Munich, Munich 80333, Germany; German Center for Diabetes Research, Neuherberg 85764, Germany; Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), Odense 5230, Denmark; Center for Functional Genomics and Tissue Plasticity (ATLAS), SDU, Odense 5230, Denmark.
Cell Metab. 2022 Mar 1;34(3):473-486.e9. doi: 10.1016/j.cmet.2022.01.004. Epub 2022 Feb 3.
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.
禁食代谢与免疫紧密相连；然而，在健康受试者禁食期间免疫细胞如何促进代谢稳态在很大程度上尚不清楚。在此，我们结合细胞类型解析基因组学和计算方法来绘制禁食期间肝细胞与肝巨噬细胞之间的相互作用图谱。我们确定糖皮质激素受体（GR）是禁食诱导巨噬细胞分泌组重编程的关键驱动因素，包括禁食抑制的细胞因子，并表明缺乏巨噬细胞GR会损害禁食期间生酮作用的诱导以及内毒素血症。从机制上讲，巨噬细胞GR抑制肿瘤坏死因子（TNF）的表达，并促进肝细胞GR的核转位，以激活由GR和过氧化物酶体增殖物激活受体α（PPARα）在肝细胞中协同诱导的脂肪氧化/生酮相关基因程序。总之，我们的结果证明了驻留肝巨噬细胞如何直接影响肝细胞中的生酮作用，从而也勾勒出一种免疫系统在炎症性疾病和感染期间设定代谢基调的策略。
