The brown fat-enriched exosomal miR-206-3p attenuates hepatic lipogenesis by decreasing pentose phosphate pathway

Brown adipose tissue (BAT) orchestrates interorgan crosstalk through secreted mediators, including proteins, lipids, and exosomal microRNAs (miRNAs). However, the precise molecular identities and functional contributions of these mediators remain elusive. In this study, we isolated exosomes from BAT and conducted miRNA sequencing, identifying miR-206-3p as a previously unrecognized exosomal miRNA with the potential to alleviate metabolic dysfunction-associated fatty liver disease (MAFLD). <i>In vivo</i>, adipose-specific knockout of miR-206-3p in mice exacerbated obesity-induced MAFLD, glucose intolerance, insulin resistance, and impaired energy expenditure. Mechanistically, BAT-derived miR-206-3p is selectively packaged into exosomes via a BAT-specific "exo motif" and transported to the liver, where it targets the 3' untranslated regions (3'-UTRs) of glucose-6-phosphate dehydrogenase (<i>G6pd</i>) and transketolase (<i>Tkt</i>), which are key enzymes in the pentose phosphate pathway (PPP). The PPP generates nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-phosphate (Ru-5-P) to support lipogenesis and nucleotide synthesis. miR-206-3p modulates these processes by decreasing NADPH production to inhibit hepatic lipid synthesis and increasing Ru-5-P availability to promote cell proliferation. Notably, obese individuals exhibit reduced serum exosomal miR-206-3p alongside upregulated hepatic PPP enzymes. Our study reveals that BAT-derived exosomal miR-206-3p serves as a mediator of BAT-liver crosstalk, suggesting its potential as a therapeutic target for obesity-related disorders, particularly MAFLD.