Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112914
• Main Authors: Sekiya, Motohiro, Ma, Yang, Kainoh, Kenta, Saito, Kenji, Yamazaki, Daichi, Tsuyuzaki, Tomomi, Chen, Wanpei, Adi Putri, Putu Indah Paramita, Ohno, Hiroshi, Miyamoto, Takafumi, Takeuchi, Yoshinori, Murayama, Yuki, Sugano, Yoko, Osaki, Yoshinori, Iwasaki, Hitoshi, Yahagi, Naoya, Suzuki, Hiroaki, Motomura, Kaori, Matsuzaka, Takashi, Murata, Kazuya, Mizuno, Seiya, Takahashi, Satoru, Shimano, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2023; Elsevier
• Subjects: CP: Metabolism; CP: Molecular biology; CtBP2; epigenetics; insulin; obesity; oxidative stress; pancreatic β cell; transcription; pancreatic β cell; insulin; transcription; CP: Metabolism; CtBP2; CP: Molecular biology; epigenetics; obesity; oxidative stress
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112914

The adaptive increase in insulin secretion in early stages of obesity serves as a safeguard mechanism to maintain glucose homeostasis that cannot be sustained, and the eventual decompensation of β cells is a key event in the pathogenesis of diabetes. Here we describe a crucial system orchestrated by a transcriptional cofactor CtBP2. In cultured β cells, insulin gene expression is coactivated by CtBP2. Global genomic mapping of CtBP2 binding sites identifies a key interaction between CtBP2 and NEUROD1 through which CtBP2 decompacts chromatin in the insulin gene promoter. CtBP2 expression is diminished in pancreatic islets in multiple mouse models of obesity, as well as human obesity. Pancreatic β cell-specific CtBP2-deficient mice manifest glucose intolerance with impaired insulin secretion. Our transcriptome analysis highlights an essential role of CtBP2 in the maintenance of β cell integrity. This system provides clues to the molecular basis in obesity and may be targetable to develop therapeutic approaches. [Display omitted] •CtBP2 coactivates key genes in the pancreatic β cells through an interaction with NEUROD1•CtBP2 protein expression is markedly reduced in the pancreatic β cells in obesity•CtBP2 protein undergoes polyubiquitination upon oxidative stress•Loss of CtBP2 impairs insulin secretion, leading to glucose intolerance Sekiya et al. demonstrated that a transcriptional cofactor, CtBP2, interacts with NEUROD1 to maintain pancreatic β cell functions. CtBP2 is vulnerable to oxidative stress, and its expression is markedly decreased in obesity. Since loss of CtBP2 impairs insulin secretion, this mechanism may underlie the progressive impairment of β cell function in obesity.