<br>血栓素 A2-TP 轴促进脂肪组织巨噬细胞 M1 极化，导致肥胖症中的胰岛素抵抗,BIOCHEMICAL PHARMACOLOGY

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血栓素 A2-TP 轴促进脂肪组织巨噬细胞 M1 极化，导致肥胖症中的胰岛素抵抗
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2023-02-26 , DOI: 10.1016/j.bcp.2023.115465
Ruijie Xu ₁ , Yufeng Dai ₁ , Xu Zheng ₁ , Yongheng Yan ₁ , Zhao He ₂ , Hao Zhang ₁ , Haitao Li ₁ , Wei Chen ₁

Affiliation

异常的花生四烯酸代谢与多种病理生理状况有关，下游前列腺素水平与肥胖症中的脂肪细胞功能障碍有关。然而，血栓素 A2 （TXA2）在肥胖中的作用仍不清楚。我们观察到 TXA2 通过其受体 TP 是肥胖和代谢紊乱的候选介质。TXA2 生物合成（TBXAS1）和 TXA2 受体（TP）表达上调的肥胖小鼠导致白色脂肪组织（WAT）中的胰岛素抵抗和巨噬细胞 M1 极化，这可以通过阿司匹林治疗来预防。从机制上讲，TXA2-TP 信号轴的激活导致蛋白激酶 Cɛ （PKCɛ）的积累，从而增强游离脂肪酸（FFA）诱导的 Toll 样受体 4 （TLR4）促炎巨噬细胞活化和脂肪组织中肿瘤坏死因子-a （TNF-a）的产生。重要的是，TP 敲除小鼠减少了 WAT 中促炎巨噬细胞和脂肪细胞肥大的积累。因此，我们的研究结果表明，TXA2-TP 轴在肥胖诱导的脂肪巨噬细胞功能障碍中起着至关重要的作用，合理靶向 TXA2 通路可能会在未来改善肥胖及其相关的代谢紊乱。在这项工作中，我们确定了 TXA2-TP 轴在 WAT 中以前未知的作用。这些发现可能为胰岛素抵抗的分子发病机制提供新的见解，并表明未来合理靶向 TXA2 通路以改善肥胖及其相关的代谢紊乱。

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Thromboxane A2-TP axis promotes adipose tissue macrophages M1 polarization leading to insulin resistance in obesity

Aberrant arachidonic acid metabolism has been implicated in multiple pathophysiological conditions, and the downstream prostanoids levels are associated with adipocyte dysfunction in obesity. However, the role of thromboxane A2 (TXA2) in obesity remains unclear. We observed that TXA2, through its receptor TP, is a candidate mediator in obesity and metabolic disorders. Obese mice with upregulated TXA2 biosynthesis (TBXAS1) and TXA2 receptor (TP) expression in caused insulin resistance and macrophage M1 polarization in white adipose tissue (WAT), which can be prevented by treatment with aspirin. Mechanistically, the activation of TXA2-TP signaling axis leads to accumulation of protein kinase Cɛ (PKCɛ), thereby enhancing free fat acid (FFA) induced Toll-like receptor4 (TLR4) proinflammatory macrophage activation and the tumor necrosis factor–a (TNF-a) production in adipose tissues. Importantly, TP knockout mice reduced the accumulation of proinflammatory macrophages and adipocyte hypertrophy in WAT. Thus, our findings demonstrate that TXA2-TP axis plays a crucial role in obesity-induced adipose macrophage dysfunction, and rational targeting TXA2 pathway may improve obesity and its associated metabolic disorders in future. In this work, we establish previously unknown role of TXA2-TP axis in WAT. These findings might provide new insight into the molecular pathogenesis of insulin resistance, and indicate rational targeting TXA2 pathway to improve obesity and its associated metabolic disorders in future.

更新日期：2023-02-26

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