TY - JOUR
T1 - Neuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism
AU - Yamamoto, Junpei
AU - Imai, Junta
AU - Izumi, Tomohito
AU - Takahashi, Hironori
AU - Kawana, Yohei
AU - Takahashi, Kei
AU - Kodama, Shinjiro
AU - Kaneko, Keizo
AU - Gao, Junhong
AU - Uno, Kenji
AU - Sawada, Shojiro
AU - Asano, Tomoichiro
AU - Kalinichenko, Vladimir V.
AU - Susaki, Etsuo A.
AU - Kanzaki, Makoto
AU - Ueda, Hiroki R.
AU - Ishigaki, Yasushi
AU - Yamada, Tetsuya
AU - Katagiri, Hideki
N1 - Funding Information:
Professor Pradip Raychaudhuri of the University of Illinois at Chicago contributed to generation of the FoxM1-floxed mice. This work was supported by Grants-in-Aid for Scientific Research to H.K. and J.I. from the Japan Society for the Promotion of Science. We thank T. Takasugi, J. Fushimi, H. Hatakeyama, and A. Iwama (all of whom are members of the Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine) for technical support.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-01869-7
DO - 10.1038/s41467-017-01869-7
M3 - Article
C2 - 29208957
AN - SCOPUS:85037155623
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1930
ER -
