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 - 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 -