A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism
Leen Catrysse,
Bastiaan Maes,
Parul Mehrotra,
Arne Martens,
Esther Hoste,
Liesbet Martens,
Christian Maueröder,
Anneleen Remmerie,
Anna Bujko,
Karolina Slowicka,
Mozes Sze,
Hanna Vikkula,
Bart Ghesquière,
Charlotte L. Scott,
Yvan Saeys,
Bart van de Sluis,
Kodi Ravichandran,
Sophie Janssens,
Geert van Loo
Affiliations
Leen Catrysse
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Bastiaan Maes
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, B-9052 Ghent, Belgium
Parul Mehrotra
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Arne Martens
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Esther Hoste
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Liesbet Martens
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Christian Maueröder
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Anneleen Remmerie
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Anna Bujko
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Karolina Slowicka
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Mozes Sze
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Hanna Vikkula
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Bart Ghesquière
Metabolomics Core Facility, VIB Center for Cancer Biology, VIB, B-3000 Leuven, Belgium
Charlotte L. Scott
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Yvan Saeys
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, B-9052 Ghent, Belgium
Bart van de Sluis
Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, NL- 9713 Groningen, the Netherlands
Kodi Ravichandran
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium; Center for Cell Clearance and Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA
Sophie Janssens
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, B-9052 Ghent, Belgium
Geert van Loo
VIB Center for Inflammation Research, B-9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium; Corresponding author
Summary: Obesity-induced inflammation is a major driving force in the development of insulin resistance, type 2 diabetes (T2D), and related metabolic disorders. During obesity, macrophages accumulate in the visceral adipose tissue, creating a low-grade inflammatory environment. Nuclear factor κB (NF-κB) signaling is a central coordinator of inflammatory responses and is tightly regulated by the anti-inflammatory protein A20. Here, we find that myeloid-specific A20-deficient mice are protected from diet-induced obesity and insulin resistance despite an inflammatory environment in their metabolic tissues. Macrophages lacking A20 show impaired mitochondrial respiratory function and metabolize more palmitate both in vitro and in vivo. We hypothesize that A20-deficient macrophages rely more on palmitate oxidation and metabolize the fat present in the diet, resulting in a lean phenotype and protection from metabolic disease. These findings reveal a role for A20 in regulating macrophage immunometabolism.
