Research projects

Activated macrophages are key drivers of the systemic chronic inflammation associated to obesity that ultimately results in insulin resistance and type 2 diabetes. Therefore, uncovering new pathways that modulate the inflammatory response in metabolic stress contexts could help redefine therapeutic strategies to fight these prevalent human disorders. The G protein-coupled receptor kinase 2 (GRK2) is a signalling hub known to be upregulated in key metabolic tissues in obesity and insulin resistance-related contexts. Over the last decade we have generated different mouse models of GRK2 deletion and established its role as an obesogenic, pro-diabetic, and pro-inflammatory factor. Importantly, myeloid GRK2 levels appear to be relevant to such overall phenotype via tissue crosstalk. We therefore postulate a central role for GRK2 interactomes in orchestrating macrophage activation and metabolic rewiring. Based on our preliminary data, we plan to explore the functional, possibly inhibitory connection between GRK2 and the RNA-binding protein and m6A reader IGF2BP2, reported to have anti-inflammatory effects, as a mechanism underlying the pleiotropic pro-inflammatory role of GRK2. Since IGF2BP2 is only targeted by GRK2 following phosphorylation of the kinase on Ser670, we will use mice expressing a phosphosite-defective GRK2 mutant to assess the significance of this modification in metabolic/inflammatory phenotypes upon nutritional overload. Furthermore, our recent unbiased GRK2 interactome analysis in primary macrophages has unveiled a very interesting array of candidate interactors linked to metabolic activation and energy metabolism reshaping. Therefore, the potential role of GRK2 and its partners (including IGF2BP2) in both processes will be investigated. Our findings may help identify key molecular players involved in inter-organ communication in metabolic pathologies.