Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
J Exp Med. 2022 Jul 4;219(7). doi: 10.1084/jem.20211779. Epub 2022 Jun 2.
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.
胰岛β细胞的可塑性是 2 型糖尿病（T2D）疾病进展和缓解的主要决定因素。然而，β细胞适应性的动态性质仍然难以捉摸。在这里，我们建立了一个小鼠模型，该模型在响应高脂饮食（HFD）喂养时间的增加时表现出β细胞功能的代偿性到失代偿性适应。全面的胰岛功能和转录组分析揭示了转录网络的动态协调，其特征是染色质重塑的时间变化。有趣的是，糖尿病前期的饮食干预可以完全挽救β细胞功能障碍，同时伴随着胰岛染色质可及性和转录组中 HFD 诱导的重编程的显著逆转。从机制上讲，基于 ATAC 的基序分析确定 CTCF 是驱动饮食干预诱导β细胞功能保存的首选候选基因。肥胖和糖尿病小鼠和人类的β细胞中 CTCF 的表达明显降低。饮食干预和 AAV 介导的 CTCF 表达恢复均可改善体外和体内的β细胞功能障碍，通过将脂质毒性和炎症信号转导到β细胞葡萄糖代谢和应激反应的关键基因的转录重编程。
