Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.
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Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα
Nature Communications Open Access 11 April 2019
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We acknowledge Ozgene Pty, Ltd. for generating floxed GPS2 mice. We acknowledge V. Benes and the team at the EMBL Genomics Core Facility for ChIP-seq library preparation and sequencing. We thank S. Mandrup (University of Southern Denmark), K. de Bosscher (Ghent University), J. Taipale (Karolinska Institutet), and F. Zhang (Broad Institute) for providing plasmids, and T. Jakobsson for his advice in establishing the CRISPR–Cas9 system. We also thank F. Fagerström-Billai and co-workers at the BEA Core Facility (Karolinska Institutet) for microarray preparation and analysis. For assistance with pathological analysis and FACS sorting, we thank R. Kuiper, T. Schröder, and Å.-L. Dackland (Department of Laboratory Medicine, Karolinska Institutet). We thank R. Chiche, J. Cady, and S. Gueroult (Geoffroy Saint-Hilaire Clinic Paris) for human AT sampling, and J.-L. Nguewa for his help in PHRC Glucostress. This work was supported by grants from the Swedish Research Council (Vetenskapsrådet, E.T.); the Swedish Cancer Society (Cancerfonden, E.T.); the Swedish Diabetes Foundation (Diabetesfonden, E.T.); the Novo Nordisk Foundation (Novo Nordisk Fonden, E.T.); the Center for Biosciences (former CB, now CIMED) at Karolinska Institutet (E.T.); the French National Agency of Research (CONRAD, N.V.; ANR CE12 2014, FATMAC, T.B.); Region Ile de France (CORDDIM, N.V.); Paris city (EMERGENCE, N.V.); the French Foundation for Medical Research (Equipe FRM DEQ20140329504, N.V. and F.F.); a French government grant managed by the National Agency of Research (program 'Investments for the Future' reference ANR-10-IAH, ICAN MetaMACS, N.V. and F.F.); Assistance Publique des Hôpitaux de Paris (APHP), Programs of Clinical Investigation (CRC Fibrota AOO759-32 to J.A.-W.; and PHRC Glucostress P081122 to J.-F.G.). A.T. and K.D. received a doctoral fellowship from the 'Ministère de la Recherche et de l'Enseignement supérieur'. Z.H. received a doctoral fellowship from the China Scholarship Council (CRC), and N.L. received a doctoral faculty grant from the Karolinska Institutet (KID funding).
The authors declare no competing financial interests.
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Fan, R., Toubal, A., Goñi, S. et al. Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes. Nat Med 22, 780–791 (2016). https://doi.org/10.1038/nm.4114
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