Consumption of a high-energy Western diet triggers mild adaptive β cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity. Loss of TLR2 and TLR4 increased the nuclear abundance of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk. These data reveal a regulatory mechanism controlling the proliferation of β cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse β cell failure in patients with diabetes.
|Publication status||Published - 20 May 2019|
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Toll-like receptors 2 and 4 control adaptive β-cell expansion in diet-induced obesity
Ji, Y. (Creator), Sun, S. (Creator), Shrestha, N. (Creator), Darragh, L. B. (Creator), Shirakawa, J. (Creator), Xing, Y. (Creator), He, Y. (Creator), Carboneau, B. A. (Creator), Kim, G. (Creator), Kim, H. (Creator), An, D. (Creator), Ma, M. (Creator), Oberholzer, J. (Creator), Soleimanpour, S. A. (Creator), Gannon, M. (Creator), Liu, C. (Creator), Naji, A. (Creator), Kulkarni, R. N. (Creator), Wang, Y. (Creator), Kersten, S. (Creator) & Qi, L. (Creator), Wageningen University, 21 Mar 2019