P5 FPR2 agonism as a therapeutic approach for metabolic syndrome

Rising obesity rates are driving the incidence of metabolic syndrome, hence there is a need for new therapeutics targeting the chronic low-grade inflammation associated with its comorbidities, including cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). A potential therapeutic target is formyl peptide receptor 2 (FPR2), a G protein-coupled receptor found on immune cells which drives inflammation resolution. Here, we probe the potential benefits of FPR2 agonism in vivo in a mouse model of atherosclerosis, which become obese, glucose intolerant and develop NAFLD on a high fat/cholesterol diet (HFD). LDLR-/- mice were fed HFD for 10 weeks to induce metabolic disease and a baseline cull (n=12) performed prior to intervention, to assess the ability of FPR2 agonists to halt or reverse pathology development. The remaining cohort underwent 4 or 8 weeks treatment with saline or FPR2 agonists WKYMVm (1 μg/mouse) or BMS-986235 (3 μg/mouse) (n=12 per group, IP thrice weekly) and were weighed weekly. Echo MRI and glucose tolerance tests were performed prior to culls. All animal procedures were performed under a project license approved by the U.K. Home Office under the Animals (Scientific Procedures) Act 1986/ASPA Amendment Regulations 2012. Following terminal culls, tissues were assessed for disease progression by H&E staining and qPCR. WKYMVm and BMS-986235 did not prevent weight gain nor improve glucose homeostasis. However, following 8 weeks FPR2 agonism, WKYMVm and BMS decreased fat mass by 5.15 g and 4.32 g, respectively, with postmortem analysis revealing a ~6-fold upregulation in white adipose tissue UCP-1 after 4 weeks WKYMVm treatment. Analysis of hepatic tissues revealed changes in the inflammatory environment and attenuated steatosis after 8 weeks WKYMVm treatment, suggestive of remodelling and reduced lipid deposition. These findings demonstrate the potential for development of FPR2 agonists to target the chronic inflammation associated with metabolic syndrome.