Irisin改善肥胖状态下高FFA所致血管周围脂肪组织功能不全的机制研究

Perivascular adipose tissue (PVAT) has both characteristics of white adipose tissue and brown adipose tissue, with the protective effects of anti-vasoconstriction. However, we found that elevated free fatty acid (FFA) levels in obesity state could induce PVAT dysfunction, facilitating the vasoconstriction and endothelial dysfunction via endothelial-dependent pathway. Irisin, which can promote browning of white adipose tissue, is a newly discovered cytokine secreted by muscle tissue and a new target for the therapy of metabolic disease. Our preliminary study found that there is a relationship between the low level of irish and vascular endothelial dysfunction in obesity, and irish can protect the vessels through improving PVAT dysfunction induced by high FFA levels in vitro, with the mechanism remaining unclear. Therefore, in the present study, we explore the regulatory effects of Irish on PVAT function in obesity state from the in vivo animal models, organ-tissue level and in vitro cell culture, and analyze the molecular mechanism of the effects of irisin on PVAT function, to demonstrate that irisin could protect the vessels via improving PVAT dysfunction induced by high FFA levels in obesity state through promoting browning of PVATand the production of adiponectin via activating PPARα pathway, and through promoting the production of nitric oxygen via AMPK-PI3K/Akt-eNOS pathway.This would provide a new idea for clinical prevention and a new target of drug effects of the obesity-related cardiovascular disease.

血管周围脂肪组织（PVAT）兼有白色脂肪和棕色脂肪特性，具有抗血管收缩保护作用。我们发现肥胖状态下高游离脂肪酸（FFA）可通过内皮依赖性途径导致PVAT功能不全，促进血管收缩及内皮功能不全。肌肉组织分泌的Irisin能促进白色脂肪棕色化，是代谢性疾病防治的新靶点。我们前期研究发现肥胖患者低Irisin水平与血管内皮功能不全存在相关性，且Irisin在体外可以改善高FFA所致的PVAT功能不全对血管起保护作用，但具体机制仍不明确。因此，本课题将从动物水平-器官组织水平-细胞水平探索肥胖状态下Irisin对PVAT功能的调控作用，证实Irisin可以通过激活PPARα促进PVAT棕色化和脂联素生成，继而通过激活AMPK-PI3K/Akt-eNOS通路促进一氧化氮生成，改善肥胖状态下高FFA所致PVAT功能不全从而对血管起保护作用的假说，为临床防治肥胖相关性心血管疾病提供新的思路和药物作用新靶点。

血管周围脂肪组织（PVAT）兼有白色脂肪和棕色脂肪特性，具有抗血管收缩保护作用。我们前期实验发现肥胖状态下高游离脂肪酸（FFA）可通过内皮依赖性途径导致PVAT功能不全，促进血管收缩及内皮功能不全。肌肉组织分泌的Irisin能促进白色脂肪棕色化，是代谢性疾病防治的新靶点。我们最终研究发现肥胖患者低Irisin水平与血管内皮功能不全存在相关性; Irisin通过激活AMPK-eNOS通路改善肥胖状态下血管内皮功能不全; Irisin直接改善PVAT的抗血管收缩反应，以及通过调控PVAT功能改善血管内皮功能，从而对肥胖状态下血管起保护作用，其机制与促进PVAT棕色化和上调HO-1/脂联素轴有关。提示Irisin可作为临床防治肥胖相关性心血管疾病的药物作用新靶点。