Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice

Abstract

Type 2 diabetes and obesity have emerged as global public health crises. Adipose tissue expansion in obesity promotes accumulation of classically activated macrophages that perpetuate chronic inflammation and sustain insulin resistance. Acute inflammation normally resolves in an actively orchestrated series of molecular and cellular events that ensures return to homeostasis after an inflammatory insult, a process regulated in part by endogenous lipid mediators such as the resolvins. In this study, we sought to determine whether stimulating resolution with resolvin D1 (RvD1) improves insulin sensitivity by resolving chronic inflammation associated with obesity. In male leptin receptor-deficient (db/db) mice, treatment with RvD1 (2 μg/kg) improved glucose tolerance, decreased fasting blood glucose, and increased insulin-stimulated Akt phosphorylation in adipose tissue relative to vehicle-treated mice. Treatment with RvD1 increased adiponectin production, while expression of IL-6 in adipose tissue was decreased. The formation of crown-like structures rich in inflammatory F4/80⁺ CD11c⁺ macrophages was reduced by >50% in adipose tissue by RvD1 and was associated with an increased percentage of F4/80⁺ cells expressing macrophage galactose-type C-type lectin 1 (MGL-1), a marker of alternatively activated macrophages. These results suggest that stimulating resolution with the endogenous proresolving mediator RvD1 could provide a novel therapeutic strategy for treating obesity-induced diabetes.—Hellmann, J., Tang, Y., Kosuri, M., Bhatnagar, A., Spite, M. Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice. FASEB J. 25, 2399–2407 (2011). www.fasebj.org