2. Academic Validation
  3. Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus

Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus

  • J Nanobiotechnology. 2024 Aug 24;22(1):509. doi: 10.1186/s12951-024-02766-0.
Xuyang Chen # 1 2,  Xinyi Tao # 1 2,  Min Wang # 1 2,  Richard D Cannon 3,  Bingnan Chen 1 2,  Xinyang Yu 1 2,  Hongbo Qi 2 4,  Richard Saffery 5,  Philip N Baker 6,  Xiaobo Zhou 7 8,  Ting-Li Han 9 10,  Hua Zhang 11 12
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China.
  • 2 Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China.
  • 3 Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.
  • 4 Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 5 Molecular Immunity, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia.
  • 6 College of Life Sciences, University of Leicester, Leicester, UK.
  • 7 Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China. xiaobo_zhou@cqmu.edu.cn.
  • 8 Department of Center for Reproductive Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China. xiaobo_zhou@cqmu.edu.cn.
  • 9 Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China. tinglihan@cqmu.edu.cn.
  • 10 Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Chongqing Medical University, No.74 Linjiang Road, Yuzhong District, Chongqing, 400010, China. tinglihan@cqmu.edu.cn.
  • 11 Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, China. zh2844@gmail.com.
  • 12 Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, China. zh2844@gmail.com.
  • # Contributed equally.
PMID: 39182087 DOI: 10.1186/s12951-024-02766-0
Abstract

Background: Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear.

Results: Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic Insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3'-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the Insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased Insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, Insulin resistance, and downregulation of STAT3 and FAM3A.

Conclusions: These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of Insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming.

Keywords

Extracellular vesicles; Gestational diabetes mellitus; Insulin resistance; MiR-1299/STAT3/FAM3A.

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