Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR‐133/PRDM16 pathway.

Cancer‐related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS‐133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS‐133 into preadipocytes, promoting the differentiation of preadipocytes into brown‐like cells by activating PRDM16 and suppressing miR‐133. Moreover, knockdown of ciRS‐133 reduced cancer cachexia in tumor‐implanted mice, decreasing oxygen consumption and heat production. Thus, exosome‐delivered circRNAs are involved in WAT browning and play a key role in cancer‐associated cachexia. What's new? Although metabolic dysfunction has been proposed as a cause for tumor cachexia, a wasting disorder of adipose and skeletal muscle accompanied by systemic inflammation, the mechanisms remain unclear. Here, the authors reveal the role of exosome‐delivered circRNAs in cancer‐associated cachexia. They identify one exosome‐circRNA secreted by cancer cells that plays a key role in regulating differentiation of preadipocytes by working as a microR‐133 sponge. In both gastric cancer patients and animal models, tumor exosomes promote WAT browning. Furthermore, tumor‐derived circRNA accelerates oxygen consumption and glucose expenditure of brown‐like adipocytes in vitro; and in vivo, exosome‐circRNA aggravates cachexia in tumor‐implanted mice. [ABSTRACT FROM AUTHOR]