title: The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis.
abstract: 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.
authors.affiliation: The David Rosensweig Genomics Center, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, USA.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Coppo
authors.affiliation: The David Rosensweig Genomics Center, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, USA.
authors.forename: Yurii
authors.initials: Y
authors.lastname: Chinenov
authors.affiliation: Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Sacta
authors.affiliation: The David Rosensweig Genomics Center, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, USA.|Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, New York 10021, USA.|Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
authors.forename: Inez
authors.initials: I
authors.lastname: Rogatsky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D018149:Glucose Intolerance; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015847:Interleukin-4 / Q000494:pharmacology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491309:Grip1 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D015847:Interleukin-4