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

肥胖和2型糖尿病(T2D)与炎症反应的慢性激活有关，炎症反应在组织功能障碍和代谢改变中起因果作用。尤其是骨骼肌，是胰岛素作用的主要部位，随着肥胖和T2D的进展，骨骼肌变得炎症和胰岛素抵抗，最终导致异位脂肪沉积和萎缩。与非糖尿病患者相比，T2D患者的肌肉质量和力量随年龄的增加而加速丧失。作为疾病过程的结果，肥胖和T2D改变了对损伤的反应，从而使正常组织的修复反应受损并导致纤维化。事实上，正常组织修复反应的紊乱是T2D最突出的继发性并发症之一。在饮食中增加omega-3多不饱和脂肪酸或直接服用解毒剂可以缓解炎症并改善糖尿病的全身新陈代谢。我们最近发现，在肌肉损伤和再生过程中，从促炎症介质到促分解脂介质(分解素)的时间转变被称为脂质介质类别转换。我们发现，解决素D2(RvD2)可以减轻炎症，加速肌肉再生和功能的恢复。然而，这些有益影响背后的具体机制尚不完全清楚。溶血素及其omega-3多不饱和脂肪酸前体，特别是如果在饮食中提供，在肌肉损伤恢复期间，在代谢性疾病的背景下，其作用尚未得到评估。重要的是，从糖尿病肌肉中获得的初步脂质介质图谱表明，在损伤和再生过程中，脂质介质类别的转换受到了损害。我们建议全面研究营养omega-3多不饱和脂肪酸摄入、脂质介质产生、炎症消解、巨噬细胞信号和功能以及肌肉再生之间的关系。我们将进一步确定这些途径在代谢性疾病中是如何受到干扰的，以及靶向解决素疗法是否比omega-3多不饱和脂肪酸营养干预更有效。我们的研究将扩大我们对omega-3PUFA与RvD2在缓解慢性炎症和促进组织修复方面的比较有效性的理解。他们可能会发现omega-3多不饱和脂肪酸在代谢性疾病中的利用是否发生了变化，这可能会为进一步的omega-3多不饱和脂肪酸临床研究以及个性化药物提供信息。

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.