Exercise-inducible circulating extracellular vesicle irisin promotes browning and the thermogenic program in white adipose tissue.

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.

Alleviative Effects of Exercise on Bone Remodeling in Fluorosis Mice.

Fluorine is widely present in nature in the form of fluoride. Prolonged high-dose fluoride exposure can cause skeletal fluorosis, resulting in osteosclerosis, osteoporosis or osteomalacia. It has been proved that exercise is one of the important factors affecting the health of the bone and promoting bone formation. To investigate the effects of exercise on bone remodeling in fluorosis mice, 120 male 3-week-old ICR mice were randomly divided into four groups: control group (C), exercise group (E), fluoride group (F), fluoride plus exercise group (F + E). After 8-week physical exercise and/or fluoride exposure, we evaluated the content of fluorine, the histopathological structure and microstructure of femur, bone metabolism biochemical indexes and oxidative stress related parameters, and the mRNA and protein levels of genes in BMP-2/Smads and OPG/RANKL/RANK signaling pathways. Our results showed that 100 mg/L NaF exposure increased the accumulation of fluoride in bone, altered histology of bone, and enhanced the activities of ALP and TRACP. Meanwhile, excessive fluoride induced oxidative stress in bone tissue by increasing the content of ROS and MDA, and decreasing the activities of antioxidant enzymes. In addition, the results of qRT-PCR suggested that NaF significantly increased the mRNA expression of BMP-2, Smad-5, Col IA1, Col IA2, OPG, RANKL and RANK, as well as the elevated proteins of OPG, RANKL and RANK. However, these fluoride-induced changes were alleviated after moderate exercise. Taken together, these findings indicated that moderate exercise decreased the toxicity of fluoride by reducing the accumulation of fluorine in the body to relieve the bone damage caused by fluorosis.

Effect of arsenic and/or fluoride gestational exposure on renal autophagy in offspring mice.

Both arsenic (As) and fluorine (F) are toxic substances widely found in the environment, which threaten to various organs of both human and animals, especially the kidney. In this study, to investigate the individual and combined effects of arsenic (15 mg/L As2O3(III)) and fluoride (100 mg/L NaF), arsenic (15 mg/L As2O3(III)) and fluoride-arsenic (15 mg/L As2O3(III)+100 mg/L NaF) on the renal autophagy during early life, a mouse model of gestationally exposed to As and/or F was established. The results showed that the mRNA expression levels of LC3, LC3I, LC3II, Beclin-1, ULK1, Atg13 and Atg14 were significantly increased with a concomitant decrease in mTOR and Bcl-2 up on individual exposure to As and F rather than in combined (As + F) exposure. In addition, the protein expression levels of LC3-II/LC3-I, Beclin-1, and LAMP1 were significantly increased with a concomitant decrease in mTOR and Bcl-2 in the mice subjected to individual exposure than the combined exposure. Based on the results, it was observed that renal tissue of mice was highly sensitive to F than As. Moreover, the toxicity of the combined (As + F) exposure was significantly lower than that of the individual exposure, which could be attributed due to the antagonism between As and F.