Brown fat-specific RNA labelling reveals a network of inter-organ communication by secreted microRNAs

Abstract

Extracellular microRNAs (miRNAs) are emerging as key regulators of organismal homeostasis. Here, using tissue-specific RNA labelling based on uracil phosphoribosyltransferase-mediated incorporation of 4-thiouracil 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 show that BAT secretes miRNAs in both small extracellular vesicles and is associated with plasma proteins, and that miRNAs in both compartments exhibit tissue-selective uptake in the 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 modelling 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. This study uses in vivo, 4TU-based, tissue-specific miRNA labelling to highlight the endocrine role of BAT-derived miRNAs that are taken up by tissues like the muscle, liver and hypothalamus, and demonstrates their role in regulating metabolic function in tissues such as muscle.