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Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2022 Jul 04; Vol. 219 (7). Date of Electronic Publication: 2022 Jun 02. - Publication Year :
- 2022
-
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.<br /> (© 2022 Wang et al.)
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 219
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 35652891
- Full Text :
- https://doi.org/10.1084/jem.20211779