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

Under insulin-resistant conditions such as obesity, pancreatic beta-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 beta-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 beta-cell FoxM1 pathway and suppresses beta-cell expansion. Inducible beta-cell-specific FoxM1 deficiency also blocks compensatory beta-cell proliferation. In isolated islets, carbachol and PACAP/VIP synergistically promote beta-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 beta-cells selectively, thereby efficiently promoting beta-cell proliferation and maintaining glucose homeostasis during obesity development. This neuronal signal-mediated mechanism holds potential for developing novel approaches to regenerating pancreatic beta-cells.