基于HO-1/脂联素轴探讨GLP-1改善肥胖血管周围脂肪功能异常的分子机理

Perivascular adipose tissue (PVAT) has both characteristics of white and brown fat and also can release a variety of factors regulating vascular function. In previous studies we found that high free fatty acid (FFA) could weaken the anti-vasoconstriction effects of PVAT through endothelium-dependent way with enhancement of white characteristics in PVAT in obesity. We also found that induction of heme oxygenase -1 (HO-1)/adiponectin axis could improve endothelial function through AMPK-PI3K/Akt-eNOS pathway. Glucagon-like peptide-1（GLP-1）, released from gut endocrine L cell, could promote browning of white adipose tissue and has endothelial protective effects, but it is not known whether it could improve PVAT dysfunction. Our preliminary experiments found that GLP-1 could improve FFA-induced PVAT dysfunction by inducing HO-1/adiponectin axis in PVAT. However, the molecular mechanism is still not known. Therefore, we intend to use the combination of animal, organ and cell experiments to confirm that GLP-1 could improve PVAT function and protect vessels by promoting browning of PVAT, inducing HO-1/adiponectin axis and activating AMPK-PI3K/Akt-eNOS pathway. This would provide ideas for the further prevention and treatment of obesity-related vascular diseases.

血管周围脂肪组织（PVAT）具有白色和棕色脂肪特性，可释放多种因子调控血管功能。我们前期研究发现，肥胖时PVAT白色脂肪特性增强，高游离脂肪酸（FFA）通过内皮依赖性途径减弱其抗血管收缩的保护作用；上调血红素加氧酶-1（HO-1）/脂联素轴可以通过激活AMPK-PI3K/Akt-eNOS通路改善内皮功能保护血管。胰高血糖素样多肽-1（GLP-1）是肠道L细胞分泌的肠促胰岛素，可促进白色脂肪棕色化，具有内皮保护作用，但尚不清楚是否改善PVAT功能异常。我们预实验发现GLP-1在体外上调PVAT HO-1/脂联素轴，改善高FFA所致PVAT功能异常，但具体机制仍不清楚。因此，我们拟通过动物、器官和细胞实验，证实GLP-1通过促进PVAT棕色化，上调HO-1/脂联素轴，继而激活AMPK-PI3K/Akt-eNOS通路，改善PVAT功能保护血管的假说，为早期防治肥胖相关血管病变提供可行的治疗思路。

血管周围脂肪组织（PVAT）具有白色和棕色脂肪特性，可释放多种因子调控血管功能。我们前期研究发现，肥胖时PVAT白色脂肪特性增强，高游离脂肪酸通过内皮依赖性途径减弱其抗血管收缩的保护作用；上调血红素加氧酶-1（HO-1）/脂联素轴可以通过激活AMPK-PIK/Akt-eNOS通路改善内皮功能保护血管。胰高血糖素样多肽-1（GLP-1）是肠道L细胞分泌的肠促胰岛素，可促进白色脂肪棕色化，具有内皮保护作用，但尚不清楚是否改善PVAT功能异常。我们研究发现GLP-1受体激动剂利拉鲁肽可以改善肥胖状态下PVAT的抗血管收缩反应；并且通过调控PVAT功能改善血管内皮功能。其保护机制与不依赖于cAMP途径的PKA激活、PVAT棕色化以及上调HO-1/脂联素轴有关。研究为早期防治肥胖相关血管病变提供可行的治疗思路。