Cell Reports (Aug 2023)
Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function
- Motohiro Sekiya,
- Yang Ma,
- Kenta Kainoh,
- Kenji Saito,
- Daichi Yamazaki,
- Tomomi Tsuyuzaki,
- Wanpei Chen,
- Putu Indah Paramita Adi Putri,
- Hiroshi Ohno,
- Takafumi Miyamoto,
- Yoshinori Takeuchi,
- Yuki Murayama,
- Yoko Sugano,
- Yoshinori Osaki,
- Hitoshi Iwasaki,
- Naoya Yahagi,
- Hiroaki Suzuki,
- Kaori Motomura,
- Takashi Matsuzaka,
- Kazuya Murata,
- Seiya Mizuno,
- Satoru Takahashi,
- Hitoshi Shimano
Affiliations
- Motohiro Sekiya
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan; Corresponding author
- Yang Ma
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Kenta Kainoh
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Kenji Saito
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Daichi Yamazaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Tomomi Tsuyuzaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Wanpei Chen
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Putu Indah Paramita Adi Putri
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Hiroshi Ohno
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Takafumi Miyamoto
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Yoshinori Takeuchi
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Yuki Murayama
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Yoko Sugano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Yoshinori Osaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Hitoshi Iwasaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Naoya Yahagi
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Hiroaki Suzuki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Kaori Motomura
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Takashi Matsuzaka
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan; Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
- Kazuya Murata
- Laboratory Animal Resource Center in Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
- Seiya Mizuno
- Laboratory Animal Resource Center in Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
- Satoru Takahashi
- Laboratory Animal Resource Center in Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
- Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan
- Journal volume & issue
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Vol. 42,
no. 8
p. 112914
Abstract
Summary: 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.
