Obesity is associated with macrophage infiltration and metabolic inflammation, both of which promote metabolic disease progression. Melatonin is reported to possess anti‐inflammatory properties by inhibiting inflammatory response of adipocytes and macrophages activation. However, the effects of melatonin on the communication between adipocytes and macrophages during adipose inflammation remain elusive. Here, we demonstrated melatonin alleviated inflammation and elevated α‐ketoglutarate (αKG) level in adipose tissue of obese mice. Mitochondrial isocitrate dehydrogenase 2 (Idh2) mRNA level was also elevated by melatonin in adipocytes leading to increase αKG level. Further analysis revealed αKG was the target for melatonin inhibition of adipose inflammation. Moreover, sirtuin 1 (Sirt1) physically interacted with IDH2 and formed a complex to increase the circadian amplitude of Idh2 and αKG content in melatonin‐inhibited adipose inflammation. Notably, melatonin promoted exosomes secretion from adipocyte and increased adipose‐derived exosomal αKG level. Our results also confirmed that melatonin alleviated adipocyte inflammation and increased ratio of M2 to M1 macrophages by transporting of exosomal αKG to macrophages and promoting TET‐mediated DNA demethylation. Furthermore, exosomal αKG attenuated signal transducers and activators of transduction‐3 (STAT3)/NF‐κB signal by its receptor oxoglutarate receptor 1 (OXGR1) in adipocytes. Melatonin also attenuated adipose inflammation and deceased macrophage number in chronic jet‐lag mice. In summary, our results demonstrate melatonin alleviates metabolic inflammation by increasing cellular and exosomal αKG level in adipose tissue. Our data reveal a novel function of melatonin on adipocytes and macrophages communication, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory disease.

中文翻译：

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褪黑素可通过升高α-酮戊二酸和将脂肪来源的外泌体转移至小鼠巨噬细胞来减轻脂肪炎症

肥胖与巨噬细胞浸润和代谢炎症有关，两者均促进代谢疾病的进展。据报道，褪黑素通过抑制脂肪细胞的炎症反应和巨噬细胞活化而具有抗炎特性。然而，褪黑素对脂肪炎症期间脂肪细胞和巨噬细胞之间的通讯的影响仍然难以捉摸。在这里，我们证明了褪黑激素减轻了肥胖小鼠脂肪组织中的炎症，并增加了α-酮戊二酸（αKG）的水平。线粒体异柠檬酸脱氢酶2（Idh2褪黑激素还可以使脂肪细胞中的mRNA水平升高，从而导致αKG水平升高。进一步的分析表明，αKG是褪黑激素抑制脂肪炎症的靶标。此外，Sirtuin 1（Sirt1）与IDH2物理相互作用并形成复合物以增加Idh2的昼夜节律幅度和褪黑激素抑制的脂肪炎症中的αKG含量。值得注意的是，褪黑激素可促进脂肪细胞分泌外泌体，并增加脂肪来源的外泌体αKG水平。我们的结果还证实，褪黑素通过将外泌体αKG转运至巨噬细胞并促进TET介导的DNA脱甲基化，减轻了脂肪细胞的炎症，并增加了M2与M1巨噬细胞的比例。此外，外泌体αKG通过脂肪细胞中的受体谷氨酸受体1（OXGR1）减弱了transduction-3（STAT3）/NF-κB信号的信号转导和激活。褪黑激素还可以减轻慢性时差小鼠的脂肪炎症和巨噬细胞数量的减少。总之，我们的结果表明褪黑激素可通过增加脂肪组织中细胞和外泌体的αKG水平减轻代谢性炎症。