Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulation of MEF2D

  • J Diabetes Investig. 2025 May 8. doi: 10.1111/jdi.70054.
Chaoyue Sun  #  1 ,  Xin Wen  #  2 ,  Xiaolong Chu  2  3 ,  Fangyuan Yuan  2 ,  Yao Chen  2 ,  Chaoling Peng  2 ,  Meiyu Qian  2 ,  Jin Mei  2 ,  Juan Wang  2 ,  Yidan Jiang  2 ,  Shibo Xu  2 ,  Cuizhe Wang  2 ,  Wei Li  2  4 ,  Jun Zhang  1  2
Affiliations
  • 1. Ministry of Education Key Laboratory of Xinjiang Endemic and Ethnic Disease, Shihezi, Xinjiang, China.
  • 2. Medical College of Shihezi University, Shihezi, Xinjiang, China.
  • 3. Medical College of Tarim University, Alaer, Xinjiang, China.
  • 4. The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China.
  • # Contributed equally.
PMID: 40342203 DOI: 10.1111/jdi.70054
Abstract

Aims/introduction: Previous studies have found that miR-4472 is overexpressed in the serum of individuals with obesity and type 2 diabetes mellitus (T2DM), which may participate in the process of obesity-induced T2DM. However, a role for miR-4472 in the process has not been demonstrated. Here, we aim to investigate whether the increased content of miR-4472 in adipose tissue derived from exosomes inhibits glucose uptake in skeletal muscle by downregulating the expression of its target gene.

Materials and methods: In vitro C2C12 and 3T3-L1 cells, and in vivo diet-induced obesity mouse models and AT-Dicer KO mice were used to assess the impact of miR-4472 on glucose uptake and Insulin sensitivity. We also evaluated the effects of serum exosomes from normal and obese individuals on Insulin sensitivity in mice and the expression of miR-4472 and target genes in skeletal muscle.

Results: miR-4472 exhibits a strong positive correlation with BMI, waist circumference, hip circumference, and FPG. The content of miR-4472 derived from adipose tissue exosomes increases in the circulation in a state of obesity, which can induce Insulin resistance by targeting the expression of MEF2D/GLUT4, inhibiting the glucose consumption and uptake ability of skeletal muscle cells. Both exosome inhibitors and miR-4472 inhibitors can reverse the inhibitory effect of miR-4472 on MEF2D/GLUT4 expression and glucose intake and uptake ability. Additionally, they can improve Insulin resistance caused by increased miR-4472 levels in mice with obesity.

Conclusions: Adipocyte exosome miR-4472 inhibits glucose uptake in skeletal muscle through downregulating the expression of MEF2D/GLUT4.

Keywords
MEF2D; Skeletal muscle; miR‐4472.
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