Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity

Yewei Ji, Shengyi Sun, Neha Shrestha, Laurel B. Darragh, Jun Shirakawa, Yuan Xing, Yi He, Bethany A. Carboneau, Hana Kim, Duo An, Minglin Ma, Jose Oberholzer, Scott A. Soleimanpour, Maureen Gannon, Chengyang Liu, Ali Naji, Rohit N. Kulkarni, Yong Wang, Sander Kersten, Ling Qi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)677-686
JournalNature Immunology
Volume20
Issue number6
DOIs
Publication statusPublished - 20 May 2019

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Ji, Y., Sun, S., Shrestha, N., Darragh, L. B., Shirakawa, J., Xing, Y., ... Qi, L. (2019). Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity. Nature Immunology, 20(6), 677-686. https://doi.org/10.1038/s41590-019-0396-z