Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

Adipocyte-derived exosomes (Exos) serve as bioinformation-containing messengers in cell-to-cell communications, and numerous reports demonstrate that resistin, an adipokine, is strongly associated with hepatic steatosis and other fatty liver diseases, suggesting that adipose dysfunction-generated altered pattern of exosomal cytokines may contribute to shaping the physiological activities in liver. Admittedly, melatonin-mediated positive effects on various tissues/organs have been respectively reported, but regulatory mechanisms of melatonin on the crosstalk between adipose tissue and liver have been investigated rarely. Overall, we hypothesize that the crosstalk originating from adipose tissue may be another worthy regulatory pathway for melatonin ameliorating of hepatic steatosis. Here, we first found the amount of adipocyte-derived exosomal resistin to be significantly decreased by melatonin supplementation. Compared to mice with ExosHFD or Exosresistin treatment, ExosMT remarkably ameliorated hepatic steatosis. Further test demonstrated that resistin was a pivotal cytokine which repressed phosphorylation of 5' adenosine monophosphate-activated protein kinase α (pAMPKα Thr172 ) to trigger endoplasmic reticulum (ER) stress, resulting in hepatic steatosis, whereas ExosMT reversed these risks in hepatocytes. In adipocytes, we identified melatonin to reduce the production of resistin through the brain and muscle arnt-like protein 1 (Bmal1) transcriptional inhibition. Notably, we also confirmed that melatonin enhanced N6 -Methyladenosine (m6 A) RNA demethylation to degrade resistin mRNA in adipocytes. Overall, melatonin decreases traffic volume of adipocyte-generated exosomal resistin from adipocytes to hepatocytes, which further alleviates ER stress-induced hepatic steatosis. Our findings illustrate a novel melatonin-mediated regulatory pathway from adipocytes to hepatocytes, indicating that adipocyte-derived exosome is a new potential target for treating obesity and related hepatorenal syndrome.