Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice

Jinhong Xu, Le Cui, Jiaqi Wang, Shasha Zheng, Huahua Zhang, Shuo Ke, Xiaoqin Cao, Yanteng Shi, Jing Li, Ke Zen, Antonio Vidal-Puig (), Chen-Yu Zhang (), Liang Li () and Xiaohong Jiang ()
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Jinhong Xu: Nanjing University
Le Cui: Nanjing University
Jiaqi Wang: Nanjing University
Shasha Zheng: Nanjing University
Huahua Zhang: Nanjing University
Shuo Ke: Nanjing University
Xiaoqin Cao: Nanjing University
Yanteng Shi: Nanjing University
Jing Li: Nanjing University
Ke Zen: Nanjing University
Antonio Vidal-Puig: University of Cambridge Metabolic Research Laboratories
Chen-Yu Zhang: Nanjing University
Liang Li: Nanjing University
Xiaohong Jiang: Nanjing University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract During cold exposure, activated brown adipose tissue (BAT) takes up a large amount of circulating glucose to fuel non-shivering thermogenesis and defend against hypothermia. However, little is known about the endocrine function of BAT controlling glucose homoeostasis under this thermoregulatory challenge. Here, we show that in male mice, activated BAT-derived extracellular vesicles (BDEVs) reprogram systemic glucose metabolism by promoting hepatic gluconeogenesis during cold stress. Cold exposure facilitates the selective packaging of miR-378a-3p—one of the BAT-enriched miRNAs—into EVs and delivery into the liver. BAT-derived miR-378a-3p enhances gluconeogenesis by targeting p110α. miR-378 KO mice display reduced hepatic gluconeogenesis during cold exposure, while restoration of miR-378a-3p in iBAT induces the expression of gluconeogenic genes in the liver. These findings provide a mechanistic understanding of BDEV-miRNA as stress-induced batokine to coordinate systemic glucose homoeostasis. This miR-378a-3p-mediated interorgan communication highlights a novel endocrine function of BAT in preventing hypoglycemia during cold stress.

Date: 2023
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DOI: 10.1038/s41467-023-41160-6

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