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.
Highlights
Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance
The key transcriptional networks in the two macrophage populations differ: infiltrating macrophage transcriptome is dominated by nuclear factor (NF)kB which drives the production of inflammatory mediators[11], whereas resident macrophages are programmed by coordinated actions of STAT6, Kruppel-like factor (KLF)[4] and a nuclear receptor (NR) peroxisome proliferator-activated receptor (PPAR)g12–16
To investigate whether GRIP1 is involved in glucocorticoid receptor (GR)-mediated induction of Klf[4], we first evaluated by quantitative PCR with reverse transcription (RT-qPCR) Klf[4] expression in bone marrow-derived macrophages (BMDM) from Mx1-Cre À / À ; GRIP1fl/fl (wild type (WT)) and Mx1-Creþ/þ; GRIP1fl/fl (conditional knockout) mice[23]
Summary
Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, 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. ATMF comprise diverse populations of cells that differ in their functional characteristics, phenotypic features, intracellular metabolic state and even developmental origin Despite their inherent plasticity and ability to adjust phenotypes to different environmental cues, ATMF can be broadly categorized into monocyte-derived inflammatory, which have been historically referred to as ‘classically activated’ or ‘M1’ and the tissue-resident macrophages originally termed ‘alternatively activated’ or ‘M2’ We showed recently that Klf[4] in bone marrow-derived macrophages (BMDM) is strongly induced by GCs24 suggesting that GR may promote homeostatic macrophage phenotype by inducing Klf[4] expression and, potentially, GRIP1 may contribute to this process by serving as a conventional GR coactivator
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