Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes.
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.
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
Rongrong
R
Fan
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Amine
A
Toubal
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
Saioa
S
Goñi
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Karima
K
Drareni
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
Zhiqiang
Z
Huang
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Fawaz
F
Alzaid
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Raphaelle
R
Ballaire
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
P
Ancel
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
Ning
N
Liang
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
Anastasios
A
Damdimopoulos
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Isabelle
I
Hainault
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.|Clinique Geoffroy Saint-Hilaire, General de Santé, Paris, France.
Antoine
A
Soprani
Institute of Cardiometabolism and Nutrition, Paris, France.|Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Heart and Metabolism Division, Paris, France.|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
J
Aron-Wisnewsky
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Fabienne
F
Foufelle
Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université, UM2, Marseille, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France.|Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
Toby
T
Lawrence
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.|Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Department of Diabetes, Clinical Investigation Centre (CIC-9504), University Paris-Diderot, Paris, France.
Jean-Francois
JF
Gautier
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.|Institute of Cardiometabolism and Nutrition, Paris, France.
Nicolas
N
Venteclef
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
Eckardt
E
Treuter
D000273:Adipose Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007333:Insulin Resistance / Q000235:genetics* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000067996:RAW 264.7 Cells; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological
C103316:GPS2 protein, human; C572597:GPS2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering