Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21
Fritzi Ott,
Christiane Körner,
Kim Werner,
Martin Gericke,
Ines Liebscher,
Donald Lobsien,
Silvia Radrezza,
Andrej Shevchenko,
Ute Hofmann,
Jürgen Kratzsch,
Rolf Gebhardt,
Thomas Berg,
Madlen Matz-Soja
Affiliations
Fritzi Ott
Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Christiane Körner
Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Kim Werner
Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Martin Gericke
Institute for Anatomy, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Ines Liebscher
Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Donald Lobsien
Institute for Diagnostic and Interventional Radiology and Neuroradiology, Helios Clinic Erfurt, 99089 Erfurt, Germany
Silvia Radrezza
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Andrej Shevchenko
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
Ute Hofmann
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany
Jürgen Kratzsch
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Rolf Gebhardt
Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Thomas Berg
Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases, and Pneumology, University Hospital Leipzig, 04103 Leipzig, Germany
Madlen Matz-Soja
Rudolf-Schönheimer Institute for Biochemistry, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.
