What question did this study set out to answer?

This research aims to explore how microRNAs secreted by brown adipose tissue influence glucose metabolism and mitochondrial function in distant organs.

June 7, 2026

2527-P: Interorgan Cross Talk by Brown Fat-Secreted microRNAs Mediates Glucose Homeostasis and Mitochondrial Dynamics

Key Points

This research aims to explore how microRNAs secreted by brown adipose tissue influence glucose metabolism and mitochondrial function in distant organs.
Developed a tissue-specific RNA labeling technique using 4-thiouracil (4TU) to track BAT-miRNAs in plasma and tissues.
Analyzed the targeting of brown fat-derived miRNAs in liver, muscle, and hypothalamus using pathway analysis.
Monitored metabolic effects in BAT;Dicer knockout mice and assessed reversibility through transfection and transplantation.
Detected 55 BAT-miRNAs in plasma, with 1/3 in sEVs, 1/3 protein-bound, and 1/3 in both.
Loss of BAT miRNAs led to 50-90% decrease in abundance in recipient tissues and impaired glucose homeostasis.
Restoring miRNA levels reversed metabolic dysfunction in BAT;DicerKO mice.

Abstract

Introduction and Objective: Brown adipose tissue (BAT) is linked to good cardiometabolic health. BAT promotes metabolic function in distal tissues in part by secreted factors, including miRNAs. We and others have shown that miRNAs are released into the circulation both in small extracellular vesicles (sEVs) and bound to proteins. However, tracking miRNA transfer in vivo and defining their metabolic effects in recipient tissues has remained a challenge. Methods: To this end, we developed a novel, tissue-specific RNA labeling technique in which BAT-miRNAs are tagged with 4-thiouracil (4TU), allowing us to track their appearance in plasma and recipient tissues and determine their effects on distal tissue metabolism. Results: Of the 55 highly labelled BAT-miRNAs released in plasma, 1/3 were primarily in sEVs, 1/3 bound to proteins, and 1/3 secreted by both mechanisms. Independent of carrier, 4TU labelling revealed that 13 of these miRNAs became highly targeted to liver, 17 to muscle, and 25 to the hypothalamus. Pathway analyses indicated unique metabolic pathways targeted by these miRNAs in these tissues, including FoxO signaling in muscle, suppression of hepatocellular carcinoma in liver, and axon guidance in the hypothalamus. Loss of miRNAs in BAT by tissue-specific Dicer knockout led to a 50-90% decrease in multiple of the most abundant miRNAs in recipient tissues, indicating the importance of BAT-miRNAs in these tissues. Consistent with transfer, KO of Dicer in BAT led to lower whole body energy expenditure, systemic mitochondrial dysfunction, and impaired glucose homeostasis. Rescue of miRNA levels in recipient tissues of BAT;DicerKO mice via transfection or transplantation with wild-type BAT, reversed these phenotypes. Finally, using crosslinking, we could directly detect 4TU-tagged BAT-miRNAs and their target genes within the RISC complex in recipient tissues. Conclusion: Thus, BAT is a major source of miRNAs in multiple tissues and using BAT-specific RNA labeling, we have uncovered a new layer of endocrine regulation mediated by BAT-miRNAs. Disclosure M. Lino: None. G. Palermo Ruiz: None. S. Bhonsle: None. A. Ghosh: None. A. Nawaz: None. C. Kahn: Consultant; Current; TIXiMED, Alnylam Pharmaceuticals, Inc. Board Member; Current; 1825 Therapeutics. Consultant; Ended; Cellarity. Funding DK082659

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