Eicosapentaenoic acid-rich oil supplementation activates PPAR-γ and delays skin wound healing in type 1 diabetic mice
Beatriz Burger, Roberta Nicolli Sagiorato, Jéssica Rondoni Silva, Thamiris Candreva, Mariana R. Pacheco, Daniel White, Bianca Gazieri Castelucci, Laís Passariello Pral, Helena L. Fisk, Izadora Lorrany Alves Rabelo, Jefferson Elias‐Oliveira, Wislei R. Osório, Sílvio Roberto Consonni, Alessandro S. Farias, Marco Aurélio Ramirez Vinolo, Claudiana Lameu, Daniela Carlos, Barbara A. Fielding, Martin Whyte, Fernando O. Martínez, Philip C. Calder, Hosana Gomes Rodrigues
Abstract
Delayed wound healing is a devastating complication of diabetes and supplementation with fish oil, a source of anti-inflammatory omega-3 (ω-3) fatty acids including eicosapentaenoic acid (EPA), seems an appealing treatment strategy. However, some studies have shown that ω-3 fatty acids may have a deleterious effect on skin repair and the effects of oral administration of EPA on wound healing in diabetes are unclear. We used streptozotocin-induced diabetes as a mouse model to investigate the effects of oral administration of an EPA-rich oil on wound closure and quality of new tissue formed. Gas chromatography analysis of serum and skin showed that EPA-rich oil increased the incorporation of ω-3 and decreased ω-6 fatty acids, resulting in reduction of the ω-6/ω-3 ratio. On the tenth day after wounding, EPA increased production of IL-10 by neutrophils in the wound, reduced collagen deposition, and ultimately delayed wound closure and impaired quality of the healed tissue. This effect was PPAR-γ-dependent. EPA and IL-10 reduced collagen production by fibroblasts in vitro . In vivo , topical PPAR-γ-blockade reversed the deleterious effects of EPA on wound closure and on collagen organization in diabetic mice. We also observed a reduction in IL-10 production by neutrophils in diabetic mice treated topically with the PPAR-γ blocker. These results show that oral supplementation with EPA-rich oil impairs skin wound healing in diabetes, acting on inflammatory and non-inflammatory cells.