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 (m6A) 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.

Lipopolysaccharide (LPS) induces rapid increase in systemic inflammatory factors. As adipose tissue is a key contributor to the inflammatory response to numerous metabolic stimuli, it is important to understand the mechanism behind the LPS-induced inflammation in white adipose tissue (WAT). Homeobox a5 (Hoxa5) is an important transcription factor, which is highly expressed in adipose tissue, and its mRNA expression is increased at cold exposure in mice. So far, the function of Hoxa5 in adipose tissue browning has been poorly understood. So, the objective of this study was conducted to determine the role of Hoxa5 in adipose inflammatory response and white adipose browning in mice. LPS-induced inflammatory and cold-induced browning model were conducted. We compared the coordinated role of Hoxa5 in inflammation and thermogenesis of mice adipose. Transcriptional and methylation regulation was determined by luciferase assay, electrophoretic mobility shift assay, and bisulfite conversion experiment. Hoxa5 and tenascin C (TNC) were involved in WAT inflammation and browning in mice with LPS injection. Furthermore, Hoxa5 inhibited the TNC-involved activation of Toll-like receptor (TLR) 4/nuclear factor kappa B (NF-κB) signal pathway and promoted WAT browning. Moreover, we found that a BMP4/Smad1 signal, closely related to browning, was activated by Hoxa5. Hoxa5 relieved adipocyte inflammation by decreasing TNC-mediated TLR4 transducer and activator of the NF-κB pathway. Interestingly, descended methylation level increased Hoxa5 expression in cold exposure. Our findings demonstrated that Hoxa5 alleviated inflammation and enhanced browning of adipose tissue via negative control of TNC/TLR4/NF-κB inflammatory signaling and activating BMP4/Smad1 pathway. These findings indicated a novel potential means for the regulation of inflammation in adipocytes to prevent obesity and other inflammatory diseases.

Obesity‐induced chronic inflammation is associated with endoplasmic reticulum stress (ERS) in adipocytes and changes in both the number and phenotype of adipose tissue macrophages (ATMs). In addition, ERS enhances macrophage activation. So far, the function of Hoxa5 in obesity‐induced chronic inflammation has been poorly understood. Herein, we demonstrate the importance of the transcription factor, Hoxa5, in determining adipose tissue macrophage (ATM) polarity and ERS. Hoxa5 decreased bodyweight, reduced inflammatory cytokine secretion and corresponded with an increased number of M2 macrophages in the adipose tissue of high‐fat diet (HFD) mice. Transcriptome sequencing data showed that overexpression of Hoxa5 in adipocytes changed expression of endoplasmic reticulum (ER) protein processing‐related genes. Based on transcriptome sequencing data and bioinformatics prediction, we have been suggested that Hoxa5 alleviated inflammatory responses by inhibiting ERS and by activating PPARγ pathway in mouse adipose tissue. Hoxa5 alleviated ERS and inflammatory responses by inhibiting the eIF2α/PERK signalling pathway in adipocytes. Hoxa5 also inhibited chronic inflammation of adipocytes by promoting M2 macrophage polarization. In addition, Hoxa5 transcriptionally activated the PPARγ pathway to promote polarization of M2 macrophages, which in turn alleviated chronic inflammation of adipocytes. Taken together, these results shed light on the mechanisms underlying Hoxa5‐dependent inhibition of obesity‐induced chronic inflammation by reducing ERS and promoting polarization of M2 macrophages. These results suggest that Hoxa5 may be a potential therapeutic target for obesity and other metabolic syndromes.

The accumulation of excess white adipose tissue (WAT) has harmful consequences on metabolic health. WAT browning confers beneficial effects on adiposity, insulin resistance, and hyperlipidemia. In this study, it was found out that circNrxn2 sponged miR-103 and enhanced FGF10 levels in HFD mice WAT. We discovered that circNrxn2 promoted WAT browning and mitochondria functions. Furthermore, circNrxn2 also increased M2 macrophage polarization in HFD mouse adipose tissue, and the PPARγ signaling pathway participated in these biological processes. Moreover, eliminating adipose tissue macrophages (ATMs) by clodronate-crippled circNrxn2 promoted WAT browning, and the simulation co-culture of macrophages and adipocytes results suggested that circNrxn2 promoted WAT browning through increasing M2 macrophage polarization. Our finding revealed that circNrxn2 acted as an endogenous miR-103 sponge, blocked miR-103 effects, and relieved its inhibition of FGF10 expression to promote WAT browning through increasing M2 macrophage polarization. This study provides a good therapeutic strategy for treating obesity and improving obesity-related metabolic disorders.