Brown adipose tissue-derived exosomes mitigate the metabolic syndrome in high fat diet mice

Abstract

The ever-increasing incidence of obesity and related disorders impose serious challenges on public health worldwide. Brown adipose tissue (BAT) has strong capacity for promoting energy expenditure and has shown great potential in treating obesity. Exosomes are nanovesicles that share the characteristics of their donor cells. Whether BAT derived exosomes (BAT-Exos) might exert similar metabolic benefits on obesity is worthy of investigation. Methods: Obese mice were established by high-fat-diet (HFD) feeding and were treated with Seum-Exos or BAT-Exos isolated from young healthy mice. Blood glucose, glucose tolerance and blood lipids were tested in mice with indicated treatments. Histology examinations were performed on adipose tissue, liver and heart by HE staining and/or Oil Red O staining. Echocardiography was performed to evaluate cardiac function of mice. In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging and in vitro effects of exosomes were evaluated by cell metabolism analysis. Protein contents of BAT-Exos were analyzed by mass spectrometry. Results: The results showed that BAT-Exos reduced the body weight, lowered blood glucose and alleviated lipid accumulation in HFD mice independently of food intake. Echocardiography revealed that the abnormal cardiac functions of HFD mice were significantly restored after treatment with BAT-Exos. Cell metabolism analysis showed that treatment with BAT-Exos significantly promoted oxygen consumption in recipient cells. Protein profiling of exosomes demonstrated that BAT-Exos were rich in mitochondria components and involved in catalytic processes. Conclusions: Collectively, our study showed that BAT-Exos significantly mitigated the metabolic syndrome in HFD mice. Detailed elucidation of the reactive molecules and mechanism of action would provide new insights in combating obesity and related disorders.

MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways

“…Recent studies have shown that miR-22-3p antagonism improves insulin sensitivity and that loss of miR-22 prevents HFD-induced metabolic disorders 45 , 55 . One explanation could be that miR-22-deficient adipocytes might secrete some signaling molecules that potentially activate energy expenditure in other metabolic organs, such as the liver and muscle 56 , 57 . Indeed, fibroblast growth factor 21 (FGF21) is a master metabolic regulator that serves as an important paracrine signaling molecule with remarkable ability to reverse diabetes and obesity 58 .…”

The Remaining Mysteries about Brown Adipose Tissues

“…It is widely accepted that BAT-derived exosomes contribute to metabolism regulation (reviewed in [ 57 , 58 ]). They can even ameliorate metabolic syndromes in mice with high-fat diet [ 59 ]. Fat tissues, especially BATs, are recognized as important sources of circulating miRNAs, which are involved in regulating gene expressions of other tissues including the liver [ 60 ].…”

Exosomes in atherosclerosis: performers, bystanders, biomarkers, and therapeutic targets

“…For example, very long-chain acyl-CoA dehydrogenase (ACADVL), an enzyme located in mitochondria, was found to be highly enriched in exosomes derived from BAT. BAT-derived exosomes could transfer ACADVL as a functional protein into liver cells 121 . Thus, the roles of exosomal proteins and lipids in atherosclerosis are emerging research areas.…”

“…In addition to transporting lipids directly to recipient cells, exosomes can also regulate the expression of classical lipid transporters, such as reverse cholesterol transport mediated by ABCA1 120 . Furthermore, substantial evidence suggests that brown adipose tissue (BAT)-derived exosomes can alleviate lipid accumulation and improve cardiac function, indicating that exosomes are involved in lipid degradation and adipose tissue redistribution 121 . In turn, growing evidence suggests that lipid metabolism affects the biological functions of exosomes, including bioprocesses from signal transduction by receptor-ligand interactions and exosome internalization by or fusion with recipient cells, which provides a new perspective for better understanding the occurrence and development of atherosclerosis 118 .…”