The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis

• Published in: Nature communications 2016-07, Vol.7 (1), p.12254-12254, Article 12254
• Main Authors: Coppo, Maddalena, Chinenov, Yurii, Sacta, Maria A., Rogatsky, Inez
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/31; 14/1; 38; 38/109; 38/15; 38/39; 38/90; 38/91; 631/250/2504/342; 631/443/319/1557; 631/80/85; 631/80/86; 64/110; 82/51; Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - metabolism; Adipocytes; Animals; Body fat; Cell Line; Cell Polarity - drug effects; Cytokines; Diet, High-Fat; Fatty Liver - metabolism; Fatty Liver - pathology; Genes; Genomics; Glucose Intolerance; Homeostasis; Homeostasis - drug effects; Humanities and Social Sciences; Immunology; Inflammation - metabolism; Inflammation - pathology; Insulin resistance; Interleukin-4 - pharmacology; Kruppel-Like Transcription Factors - metabolism; Macrophage Activation - drug effects; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Metabolic disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Models, Biological; multidisciplinary; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - metabolism; Obesity; Pathogenesis; Phenotype; Protein Binding; Proteins; Science; Science (multidisciplinary); Trans-Activators - metabolism; Tumor necrosis factor-TNF
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12254

Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor—glucocorticoid receptor (GR)-interacting protein (GRIP)1—cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4—a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. GRIP1 cooperates with the glucocorticoid receptor to repress inflammatory genes. Here the authors show that GRIP1 also controls macrophage polarization, by promoting KLF4-driven activation in response to IL-4, and that mice lacking GRIP1 in macrophages develop severe metabolic dysfunction on a high-fat diet.