Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming Academic Article uri icon

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abstract

  • Pancreatic β cell plasticity is the primary determinant of disease progression and remission of type 2 diabetes (T2D). However, the dynamic nature of β cell adaptation remains elusive. Here, we establish a mouse model exhibiting the compensation-to-decompensation adaptation of β cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues β cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention–induced preservation of β cell function. CTCF expression is markedly decreased in β cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate β cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for β cell glucose metabolism and stress response.

authors

  • Wang, Ruo-Ran
  • Qiu, Xinyuan
  • Pan, Ran
  • Fu, Hongxing
  • Zhang, Ziyin
  • Wang, Qintao
  • Chen, Haide
  • Wu, Qing-Qian
  • Pan, Xiaowen
  • Zhou, Yanping
  • Shan, Pengfei
  • Wang, Shusen
  • Guo, Guoji
  • Zheng, Min
  • Zhu, Lingyun
  • Meng, Zhuo-Xian

publication date

  • July 4, 2022