Melatonin alleviates adipose inflammation through elevating -ketoglutarate and diverting adipose-derived exosomes to macrophages in mice

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 -ketoglutarate (KG) level in adipose tissue of obese mice. Mitochondrial isocitrate dehydrogenase 2 (Idh2) mRNA level was also elevated by melatonin in adipocytes leading to increase KG level. Further analysis revealed KG 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 KG content in melatonin-inhibited adipose inflammation. Notably, melatonin promoted exosomes secretion from adipocyte and increased adipose-derived exosomal KG level. Our results also confirmed that melatonin alleviated adipocyte inflammation and increased ratio of M2 to M1 macrophages by transporting of exosomal KG to macrophages and promoting TET-mediated DNA demethylation. Furthermore, exosomal KG attenuated signal transducers and activators of transduction-3 (STAT3)/NF-B 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 KG 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.