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Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming.

The Journal of experimental medicine (2022-06-03)
Ruo-Ran Wang, Xinyuan Qiu, Ran Pan, Hongxing Fu, Ziyin Zhang, Qintao Wang, Haide Chen, Qing-Qian Wu, Xiaowen Pan, Yanping Zhou, Pengfei Shan, Shusen Wang, Guoji Guo, Min Zheng, Lingyun Zhu, Zhuo-Xian Meng
RESUMEN

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.

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