The Mechanisms Of Brown Adipocyte-derived MiRNAs Reprogramming Energy Metabolism In Other Tissues

It is important to maintain glucose homeostasis.Each tissue can regulate its own metabolism by sensing endogenous signals,and it can also regulate the metabolism of other tissues and organs through secreted factors.Studies have shown that brown adipose tissue(BAT)is an important thermogenic organ.Meanwhile brown adipose tissue is also an important endocrine organ,which can modulate systemic metabolism by secretion of so-called batokines.Though,it's still unclear whether brown adipose tissue can secret batokines to regulate other tissues.Recent studies have shown that cell-secreted mi RNAs are a new class of secreted factors.Those mi RNAs can be transported to the target tissues and organs in the form of exosomes,which in turn regulates the target tissues.Secreted mi RNAs play an important role in regulating the metabolic homeostasis of the whole body.However it is still unknown whether brown adipose tissue can regulate other tissues through secreted mi RNAs as a novel "brown adipokines".In this study,we focused on how activated brown adipocyte-derived mi RNAs stimulated hepatic glucose output during cold temperature and how unactivated brown adipocyte-derived mi RNAs improve insulin sensitivity.In the first section,we studied the regulatory relationship between activated brown adipocyte-derived mi R-378 a and hepatic glucose output during cold exposure.Cold exposure increased the hepatic glucose output and at the same time,the glucose uptake by brown adipose tissue was also increased due to the up regulation of BAT oxidative activity.Through the BAT excised experiment,we found that BAT played a vital role in hepatic glucose output.Liver exhibited efficient in vivo and in vitro uptake of activated BAT-derived exosomes,which resulted in higher hepatic glucose production.Then we performed mi RNA chip and found that mi R-378 a had a higher expression level in activated brown adipocyte-derived exosomes compared to unactivated ones.Overexpression of mi R-378 a in primary hepatocytes stimulated glucose production by targeting catalytic subunits p110? of PI3 K and reduced phosphorylation of AKT.We injected a lentivirus vector bearing mi R-378 a or antisence-mi R-378 a or scramble directly into BAT,and we found that the expression levels of mi R-378 a in brown adipose tissue regulated the glucose production of liver.The second part,we studied the regulatory relationship between brown adipocyte-derived exosomal mi R-451 and insulin sensitivity in vivo and in vitro.BAT transplantation improved insulin sensitivity,and this was not only because brown adipose tissue consumed large amounts of energy for thermogenesis,but also the“batokines” secreted by it could modulate systemic metabolism.Liver,muscle and white adipose tissue exhibited efficient in vivo and in vitro uptake of BAT-derived exosomes.Vein tail injection of brown adipocyte-derived exosomes into high-fat diet mice improved mice insulin sensitivity compared to white adipocyte-derived exosomes treatment and this might be because of enhanced insulin signaling.Then we conducted in vitro exosomes co-culture studies,the insulin sensitivity enhanced in C2C12 myocytes,3T3L1 adipocytes and primary hepatocytes after brown adipocyte-exosomes treatment.Upon the mi RNA chip analysis,we found that brown adipocyte-derived exosomes expressed greater levels of mi R-451 compared to white adipocyte-derived exosomes.And in C2C12,3T3L1 and primary hepatocytes,transfection of mi R-451 enhanced insulin sensitivity in these cells.By using prediction software,we found that mi R-451 could bind in the 3'-UTR of PP2 A,an inhibitor of AKT phosphorylation.Finally,we conducted that brown adipocyte-derived exosomal mi R-451 enhanced insulin sensitivity might through up-regulation of insulin-stimulated phosphorylation of AKT by targeting PP2 A.In summary,we found that brown adipocyte-derived mi RNAs played vital roles in modulating systemic metabolism under different conditions.On one hand,when brown adipose tissue was activated by cold exposure,brown adipocyte-derived mi R-378 a could promote hepatic glucose output to maintain glucose homeostasis.And on the other hand,the unactivated brown adipocyte could secrete mi R-451 to improve insulin sensitivity through muscle,liver and white adipose tissue.