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Aim: Exercise can reduce body weight and promote white fat browning, but the underlying mechanisms remain largely unknown. This study investigated the role of fibronectin type III domain‐containing protein 5 (FNDC5)/Irisin, a hormone released from exercising muscle, in the browning of white fat in circulating extracellular vesicles (EVs). Methods: Mice were subjected to a 4 weeks of running table exercise, and fat browning was analyzed via histology, protein blotting and qPCR. Circulating EVs were extracted by ultrahigh‐speed centrifugation, and ELISA was used to measure the irisin concentration in the circulating EVs. Circulating EVs that differentially expressed irisin were applied to adipocytes, and the effect of EV‐irisin on adipocyte energy metabolism was analyzed by immunofluorescence, protein blotting, and cellular oxygen consumption rate analysis. Results: During sustained exercise, the mice lost weight and developed fat browning. FNDC5 was induced, cleaved, and secreted into irisin, and irisin levels subsequently increased in the plasma during exercise. Interestingly, irisin was highly expressed in circulating EVs that effectively promoted adipose browning. Mechanistically, the circulating EV‐irisin complex is transported intracellularly by the adipocyte membrane receptor integrin αV, which in turn activates the AMPK signaling pathway, which is dependent on mitochondrial uncoupling protein 1 to cause mitochondrial plasmonic leakage and promote heat production. After inhibition of the AMPK signaling pathway, the effects of the EV‐irisin on promoting fat browning were minimal. Conclusion: Exercise leads to the accumulation of circulating EV‐irisin, which enhances adipose energy metabolism and thermogenesis and promotes white fat browning in mice, leading to weight loss. [ABSTRACT FROM AUTHOR]

Increasing energy expenditure and reducing energy intake are considered two classical methods to induce weight loss. Weight loss through physical methods instead of drugs has been a popular research topic nowadays, but how these methods function in adipose and cause weight loss in body remains unclear. In this study, we set up chronic cold exposure (CCE) and every-other-day fasting (EODF) as two distinct models in long-term treatment to induce weight loss, recording their own characteristics in changes of body temperature and metabolism. We investigated the different types of non-shivering thermogenesis induced by CCE and EODF in white and brown adipose tissue through sympathetic nervous system (SNS), creatine-driven pathway, and fibroblast growth factor 21 (FGF21)–adiponectin axis. CCE and EODF could reduce body weight, lipid composition, increase insulin sensitivity, promote the browning of white fat, and increase the expression of endogenous FGF21 in adipose tissue. CCE stimulated the SNS and increased the thermogenic function of brown fat, and EODF increased the activity of protein kinase in white fat. In this study, we further explained the thermogenic mechanism function in adipose and metabolic benefits of the stable phenotype through physical treatments used for weight loss, providing more details for the literature on weight loss models. The influence on metabolism, non-shivering thermogenesis, endogenous FGF21, and ADPN changes in the long-term treatment of distinct methods (increasing energy expenditure and decreasing energy intake) to induce weight loss [ABSTRACT FROM AUTHOR]