Neuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism

Junpei Yamamoto, Junta Imai (), Tomohito Izumi, Hironori Takahashi, Yohei Kawana, Kei Takahashi, Shinjiro Kodama, Keizo Kaneko, Junhong Gao, Kenji Uno, Shojiro Sawada, Tomoichiro Asano, Vladimir V. Kalinichenko, Etsuo A. Susaki, Makoto Kanzaki, Hiroki R. Ueda, Yasushi Ishigaki, Tetsuya Yamada and Hideki Katagiri
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Junpei Yamamoto: Tohoku University Graduate School of Medicine
Junta Imai: Tohoku University Graduate School of Medicine
Tomohito Izumi: Tohoku University Graduate School of Medicine
Hironori Takahashi: Tohoku University Graduate School of Medicine
Yohei Kawana: Tohoku University Graduate School of Medicine
Kei Takahashi: Tohoku University Graduate School of Medicine
Shinjiro Kodama: Tohoku University Graduate School of Medicine
Keizo Kaneko: Tohoku University Graduate School of Medicine
Junhong Gao: Tohoku University Graduate School of Medicine
Kenji Uno: Tohoku University Graduate School of Medicine
Shojiro Sawada: Tohoku University Graduate School of Medicine
Tomoichiro Asano: University of Hiroshima
Vladimir V. Kalinichenko: Cincinnati Children’s Hospital Medical Center
Etsuo A. Susaki: Graduate School of Medicine, The University of Tokyo
Makoto Kanzaki: Tohoku University Graduate School of Biomedical Engineering
Hiroki R. Ueda: Graduate School of Medicine, The University of Tokyo
Yasushi Ishigaki: Tohoku University Graduate School of Medicine
Tetsuya Yamada: Tohoku University Graduate School of Medicine
Hideki Katagiri: Tohoku University Graduate School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver–brain–pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the β-cell FoxM1 pathway and suppresses β-cell expansion. Inducible β-cell-specific FoxM1 deficiency also blocks compensatory β-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote β-cell proliferation through a FoxM1-dependent mechanism. These findings indicate that vagal nerves that release several neurotransmitters may allow simultaneous activation of multiple pathways in β-cells selectively, thereby efficiently promoting β-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic β-cells.

Date: 2017
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DOI: 10.1038/s41467-017-01869-7

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