Interleukin-33 rescues perivascular adipose tissue anti-contractile function in obesity

Perivascular adipose tissue (PVAT) depots are metabolically active and play a major vasodilator role in healthy lean individuals. In obesity they become inflamed and eosinophil-depleted and the anti-contractile function is lost with the development of diabetes and hypertension. Moreover, eosinophil-deficient ΔdblGATA-1 mice lack PVAT anti-contractile function, and exhibit hypertension. Here we have investigated the effects of inducing eosinophilia on PVAT function in health and obesity. Control, obese and ΔdblGATA-1 mice were administered intraperitoneal injections of interleukin-33 (IL-33) for five days. Conscious restrained blood pressure was measured, and blood was collected for glucose and plasma measurements. Wire myography was used to assess the contractility of mesenteric resistance arteries. IL-33 injections induced a hypereosinophilic phenotype. Obese animals had significant elevations in blood pressure, blood glucose and plasma insulin, which were normalised with IL-33. Blood glucose and insulin levels were also lowered in lean treated mice. In arteries from control mice, PVAT exerted an anti-contractile effect on the vessels, which was enhanced with IL-33 treatment. In obese mice, loss of PVAT anti-contractile function was rescued by IL-33. Exogenous application of IL-33 to isolated arteries induced a rapidly decaying endothelium-dependent vasodilation. The therapeutic effects were not seen in IL-33 treated ΔdblGATA-1 mice thereby confirming that the eosinophil is crucial. In conclusion, IL-33 treatment restored PVAT anti-contractile function in obesity, and reversed development of hypertension, hyperglycaemia, and hyperinsulinemia. These data suggest that targeting eosinophil numbers in PVAT offers a novel approach to the treatment of hypertension and type-2 diabetes in obesity.