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Summary: Biofluids contain various circulating cell-free RNAs (ccfRNAs). The composition of these ccfRNAs varies among biofluids. They constitute tantalizing biomarker candidates for several pathologies and have been demonstrated to be mediators of cellular communication. Little is known about their function in physiological and developmental settings, and most works are limited to in vitro studies. Here, we develop iTAG-RNA, a method for the unbiased tagging of RNA transcripts in mice in vivo. We use iTAG-RNA to isolate hepatocytes and kidney proximal epithelial cell-specific transcriptional responses to a dietary challenge without interfering with the tissue architecture and to identify multiple hepatocyte-secreted ccfRNAs in plasma. We also identify specific transfer of liver-derived ccfRNAs to adipose tissue and skeletal muscle, where they likely constitute a buffering system to maintain lipid homeostasis under acute high-fat-diet feeding. Our findings directly demonstrate in vivo transfer of RNAs between tissues and highlight its implications for endocrine signaling and homeostasis. : RNAs populate biofluids and are potential biomarkers. Their physiological function is not completely understood due to a lack of technologies allowing unbiased transcriptional labeling and source-to-sink RNA tracking. Darr et al. develop iTAG-RNA for unbiased tagging of RNA in vivo and identify a diet-sensitive liver-to-adipose and muscle endocrine axis. Keywords: RNA tagging, mouse genetics, circulating RNA, 5EU prodrug, epigenetics, RNA biomarker