Role of transcriptional coregulator GRIP1 in control of macrophage polarization and metabolic homeostasis

Diet-induced obesity is characterized by macrophage (MΦ) infiltration and low-grade chronic inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT MΦ are highly heterogeneous in their origin, patterns of gene expression and activities: unlike infiltrating monocyte-derived MΦ that promote inflammation and metabolic dysfunction, tissue-resident WAT MΦ originally described as ‘M2’ are phenotypically anti-inflammatory and counteract obesity and insulin resistance. Despite the critical role of the balance between these MΦ populations in metabolic homeostasis, the molecular mechanisms and key players that establish the resident MΦ transcription program are poorly understood. We recently reported that glucocorticoid receptor (GR)-interacting protein (GRIP)1 - a nuclear receptor coactivator - cooperates with GR to repress transcription of inflammatory genes. Here, using mice conditionally lacking GRIP1 in MΦ (cKO), we show that GRIP1 promotes MΦ polarization in response to IL4 (M2(IL4)) via a nuclear receptor-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4 – a critical driver of tissue MΦ differentiation. Interestingly, in vivo, GRIP1 cKO mice challenged with high-fat diet develop massive MΦ infiltration and chronic inflammation in WAT and liver, fatty livers, hyperglycemia, hyperinsulinemia and glucose intolerance consistent with metabolic syndrome phenotype. Together, our findings identify GRIP1 as a critical regulator of immunometabolism, which relies on distinct transcriptional mechanisms to coordinate the balance between MΦ populations in vivo thereby protecting mice from obesity-induced metabolic disease. 1. Examination of IL4 induced transcriptome in in vitro differentiated primary bone marrow-derived macrophages. 2. Examination of macrophage transcriptome in macrophages isolated from the white adipose tissue of the WT and GRIP1(cKO) conditional KO animals