Pluto Bioinformatics

GSE80160: Role of transcriptional coregulator GRIP1 in control of macrophage polarization and metabolic homeostasis

Bulk RNA sequencing

Diet-induced obesity is characterized by macrophage (M) infiltration and low-grade chronic inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT M are highly heterogeneous in their origin, patterns of gene expression and activities: unlike infiltrating monocyte-derived M that promote inflammation and metabolic dysfunction, tissue-resident WAT M originally described as M2 are phenotypically anti-inflammatory and counteract obesity and insulin resistance. Despite the critical role of the balance between these M populations in metabolic homeostasis, the molecular mechanisms and key players that establish the resident M 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 M (cKO), we show that GRIP1 promotes M 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 M differentiation. Interestingly, in vivo, GRIP1 cKO mice challenged with high-fat diet develop massive M 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 M populations in vivo thereby protecting mice from obesity-induced metabolic disease. SOURCE: Inez RogatskyRogatsky Hospital for Special Surgery