@article{294eaaf0e1214fc68d4123b5527e8abb,
title = "A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism",
abstract = "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.",
author = "Leen Catrysse and Bastiaan Maes and Parul Mehrotra and Arne Martens and Esther Hoste and Liesbet Martens and Christian Mauer{\"o}der and Anneleen Remmerie and Anna Bujko and Karolina Slowicka and Mozes Sze and Hanna Vikkula and Bart Ghesqui{\`e}re and Scott, {Charlotte L.} and Yvan Saeys and {van de Sluis}, Bart and Kodi Ravichandran and Sophie Janssens and {van Loo}, Geert",
note = "Funding Information: We thank Manolis Pasparakis (Koln University), Vishva Dixit (Genentech), and the Knockout Mouse Programme (KOMP) Repository for generous supply of mutant mice, and Louis Boon (Bioceros) for TNF- and IL6-neutralizing antibodies. We thank Laetitia Bellen and Dimitri Huyghebaert for animal care and are grateful to Marnik Vuylsteke for help with statistics. We acknowledge the VIB BioImaging Core, the VIB Nucleomics Core, and the VIB Flowcore for technical assistance. L.C. was supported as a PhD fellow by the “Instituut voor Innovatie door Wetenschap en Technologie” (IWT) and by a research grant from “Kom op tegen Kanker.” E.H. holds an FWO postdoctoral fellowship and C.M. a postdoctoral fellowship from the German Research Foundation (DFG) (MA 7770/1-1). Research in the van Loo lab was also supported by research grants from the FWO, the “Belgian Foundation against Cancer,” the “Geneeskundige Stichting Koningin Elisabeth” (GSKE), the “Interuniversity Attraction Poles program” (IAP7), and the “Concerted Research Actions” (GOA) of the Ghent University. L.C. and B.M. performed the bulk of the experiments, analyzed the data, and wrote the manuscript. P.M. performed the Seahorse experiments. E.H. performed the bone marrow transfer experiment. C.S. A.R. and A.B. performed the flow cytometry of the liver. K.S. helped with the experiments to investigate the fat uptake in the small intestine. A.M. and M.S. performed the in vitro 13C tracing experiments. B.G. performed the mass spectrometry analysis. L.M. and Y.S. analyzed the raw RNA-seq data. M.S. and H.V. provided help to L.C. during several experiments. C.M and K.R. provided tools and ideas. B.v.d.S. performed the indirect calorimetry experiments. R.K. and S.J. provided ideas and analyzed the data. G.v.L. provided ideas, analyzed the data, coordinated the project, and wrote the manuscript. The authors declare no competing interests. Funding Information: We thank Manolis Pasparakis (Koln University), Vishva Dixit (Genentech), and the Knockout Mouse Programme (KOMP) Repository for generous supply of mutant mice, and Louis Boon (Bioceros) for TNF- and IL6-neutralizing antibodies. We thank Laetitia Bellen and Dimitri Huyghebaert for animal care and are grateful to Marnik Vuylsteke for help with statistics. We acknowledge the VIB BioImaging Core, the VIB Nucleomics Core, and the VIB Flowcore for technical assistance. L.C. was supported as a PhD fellow by the “ Instituut voor Innovatie door Wetenschap en Technologie ” (IWT) and by a research grant from “ Kom op tegen Kanker .” E.H. holds an FWO postdoctoral fellowship and C.M. a postdoctoral fellowship from the German Research Foundation (DFG) ( MA 7770/1-1 ). Research in the van Loo lab was also supported by research grants from the FWO , the “ Belgian Foundation against Cancer ,” the “ Geneeskundige Stichting Koningin Elisabeth ” (GSKE), the “ Interuniversity Attraction Poles program ” (IAP7), and the “ Concerted Research Actions ” (GOA) of the Ghent University. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = sep,
day = "21",
doi = "10.1016/j.celrep.2021.109748",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
number = "12",
}