Brown Fat-Specific RNA Labeling Reveals A Network of Inter-Organ Communication by Secreted microRNAs

Here, using tissue-specific RNA labeling based on uracil phosphoribosyltransferase (UPRT)-mediated incorporation of 4-thiouracil (4TU) in male mice, we develop a roadmap of miRNA transfer from brown adipose tissue (BAT) to other tissues, where they can act to regulate energy metabolism. We demonstrate that BAT secretes miRNAs in both small extracellular vesicles (sEVs) and associated with plasma proteins, and that miRNAs in both compartments exhibit tissue-selective uptake in liver, muscle, and hypothalamus.

Disruption of DICER in BAT leads to a significant depletion of multiple miRNAs in both BAT and distal tissues, including 80-90% decreases in the most abundant miRNAs in muscle. Target analyses, in vitro modeling, and PAR-CLIP analysis in muscle in vivo confirm that these BAT-secreted miRNAs directly interact with target mRNAs and alter mitochondrial function in recipient tissues. These findings provide a framework for understanding the role of BAT-secreted miRNAs in inter-organ communication.