DHA-derived resolvin production andsignaling in tissue repair macrophages in metabolic disease

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Obesity and type 2 diabetes (T2D) are associated with chronic activation of inflammatory responses that play a causal role in tissue dysfunction and altered metabolism. Skeletal muscle in particular, is a major site of insulin action and becomes inflamed and insulin resistant with the progression of obesity and T2D, leading ultimately to ectopic lipid deposition and atrophy. Individuals with T2D exhibit accelerated loss of muscle mass and strength with age compared to non-diabetics. As a consequence of the disease process, obesity and T2D alter the response to injury such that the normal tissue reparative responses are impaired and lead to fibrosis. Indeed, perturbation of the normal tissue repair response is one of the most prominent secondary complications of T2D. Increasing omega-3 PUFA in the diet or direct administration of resolvins resolves inflammation and improves systemic metabolism in diabetes. We recently discovered a temporal shift from pro-inflammatory to pro-resolving lipid mediators (resolvins) during muscle injury and regeneration in a process termed lipid mediator class switching. We found that resolvin D2 (RvD2) decreases inflammation and hastens recovery of muscle regeneration and function. Nonetheless, the specific mechanisms underlying these beneficial effects are incompletely understood. The role of resolvins and their omega-3 PUFA precursors, particularly if provided in the diet, during recovery from muscle injury, in the context of metabolic disease has not been evaluated. Importantly, preliminary lipid mediator profiles obtained from diabetic muscles indicate an impairment in the lipid mediator class switching during injury and regeneration. We propose to comprehensively investigate the relationship between nutritional omega-3 PUFA intake, lipid mediator production, inflammation-resolution, macrophage signaling and function, and muscle regeneration. We will further determine how these pathways are perturbed in metabolic disease and whether targeted resolvin therapy is more efficacious than omega-3 PUFA nutritional interventions. Our studies will broaden our understanding about the comparative efficacy of omega-3 PUFA vs. RvD2 for resolving chronic inflammation and promoting tissue repair. They could uncover whether there are alterations in utilization of omega-3 PUFA in metabolic disease that could inform further clinical studies on omega-3 PUFA, as well as personalized medicine.