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Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

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Abstract

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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Figure 1: Reduced GPS2 expression in AT macrophages of humans with obesity or diabetes is correlated with AT inflammation and hyperglycemia.
Figure 2: GPS2-deficient macrophages (MKO) display a pro-inflammatory gene signature and increased responsiveness toward TLR4 activation.
Figure 3: The loss of macrophage GPS2 dictates epigenomic changes linked to transcriptional activation at specific loci.
Figure 4: GPS2 communicates with c-Jun to repress inflammatory transcription.
Figure 5: Macrophage GPS2-deficiency enhances AT and systemic inflammation during HFD-induced obesity.
Figure 6: GPS2 overexpression inhibits AT inflammation and improves blood glucose control in mice with HFD-induced obesity and in ob/ob mice.

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Acknowledgements

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).

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Author notes

  1. Rongrong Fan, Amine Toubal, Saioa Goñi, Nicolas Venteclef and Eckardt Treuter: These authors equally contributed to this work.

Authors and Affiliations

  1. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

    Rongrong Fan, Saioa Goñi, Zhiqiang Huang, Ning Liang, Anastasios Damdimopoulos & Eckardt Treuter

  2. Sorbonne Universités, Université Pierre et Marie-Curie, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR_S 1138 Cordeliers Research, Paris, France

    Amine Toubal, Karima Drareni, Fawaz Alzaid, Raphaelle Ballaire, Isabelle Hainault, Antoine Soprani, Fabienne Foufelle, Jean-Francois Gautier & Nicolas Venteclef

  3. Institute of Cardiometabolism and Nutrition, Paris, France

    Amine Toubal, Karima Drareni, Fawaz Alzaid, Raphaelle Ballaire, Isabelle Hainault, Judith Aron-Wisnewsky, Fabienne Foufelle & Nicolas Venteclef

  4. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1062, INRA 1260, Aix-Marseille Université, Nutrition, Obésité et Risque Thrombotique, Marseille, France

    Patricia Ancel

  5. Clinique Geoffroy Saint-Hilaire, General de Santé, Paris, France

    Antoine Soprani

  6. Heart and Metabolism Division, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France

    Judith Aron-Wisnewsky

  7. Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Universités, Université Pierre et Marie-Curie (UPMC), UMR_S U1166, NutriOmics team, Paris, France

    Judith Aron-Wisnewsky

  8. Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, UM2, Marseille, France

    Toby Lawrence

  9. Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France

    Toby Lawrence

  10. Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France

    Toby Lawrence

  11. Department of Diabetes, Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Clinical Investigation Centre (CIC-9504), University Paris-Diderot, Paris, France

    Jean-Francois Gautier

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  1. Rongrong Fan
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  2. Amine Toubal
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Contributions

R.F., A.T. and S.G. share the first authorship. K.D. and Z.H. share the second authorship. R.F. and A.T. performed the majority of in vivo experiments, with contributions from K.D., I.H., R.B., and F.A., and analyzed data. S.G. performed the genomic and ChIP-seq studies, with major contribution from Z.H., and A.D. and R.F. analyzed genomic data. N.L. contributed to the in vitro studies. F.F., J.-F.G., J.A.-W., A.S., A.T., P.A., and N.V. collected, analyzed, and interpreted the human data. T.L. provided Jun KO mice and analyzed data. R.F., N.V., and E.T. conceived the study, interpreted data, and wrote the manuscript. N.V. and E.T. supervised the study and share the corresponding authorship.

Corresponding authors

Correspondence to Nicolas Venteclef or Eckardt Treuter.

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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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