Gene

Liver X receptor

Biology

Endocrinology

Metabolism

Receptor

Glucocorticoid receptor

Biochemistry

Immunology

Peroxisome proliferator-activated receptor

Immune system

Nuclear receptor

Ketogenesis

In vitro

Macrophage

Internal medicine

Transcription factor

Hepatocyte

Medicine

Innate immune system

Tumor necrosis factor alpha

Glucocorticoid

Ketone bodies

Cell Metabolism

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.

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis