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The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis

Author

Listed:
  • Maddalena Coppo

    (The David Rosensweig Genomics Center, Hospital for Special Surgery)

  • Yurii Chinenov

    (The David Rosensweig Genomics Center, Hospital for Special Surgery)

  • Maria A. Sacta

    (Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program)

  • Inez Rogatsky

    (The David Rosensweig Genomics Center, Hospital for Special Surgery
    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences
    Weill Medical College of Cornell University)

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.

Suggested Citation

  • Maddalena Coppo & Yurii Chinenov & Maria A. Sacta & Inez Rogatsky, 2016. "The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12254
    DOI: 10.1038/ncomms12254
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    Cited by:

    1. Dinesh K. Deochand & Marija Dacic & Michael J. Bale & Andrew W. Daman & Vidyanath Chaudhary & Steven Z. Josefowicz & David Oliver & Yurii Chinenov & Inez Rogatsky, 2024. "Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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