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

doi:10.1038/s41590-019-0396-z

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 journal › Article › Academic › peer-review

39 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 language	English
Pages (from-to)	677-686
Journal	Nature Immunology
Volume	20
Issue number	6
DOIs	https://doi.org/10.1038/s41590-019-0396-z
Publication status	Published - 20 May 2019

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10.1038/s41590-019-0396-z

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
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE101392
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Ji, Y., Sun, S., Shrestha, N., Darragh, L. B., Shirakawa, J., Xing, Y., He, Y., Carboneau, B. A., Kim, H., An, D., Ma, M., Oberholzer, J., Soleimanpour, S. A., Gannon, M., Liu, C., Naji, A., Kulkarni, R. N., Wang, Y., Kersten, S., & 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

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

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.",

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

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doi = "10.1038/s41590-019-0396-z",

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Ji, Y, Sun, S, Shrestha, N, Darragh, LB, Shirakawa, J, Xing, Y, He, Y, Carboneau, BA, Kim, H, An, D, Ma, M, Oberholzer, J, Soleimanpour, SA, Gannon, M, Liu, C, Naji, A, Kulkarni, RN, Wang, Y, Kersten, S & Qi, L 2019, 'Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity', Nature Immunology, vol. 20, no. 6, pp. 677-686. https://doi.org/10.1038/s41590-019-0396-z

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T1 - Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity

AU - Ji, Yewei

AU - Sun, Shengyi

AU - Shrestha, Neha

AU - Darragh, Laurel B.

AU - Shirakawa, Jun

AU - Xing, Yuan

AU - He, Yi

AU - Carboneau, Bethany A.

AU - Kim, Hana

AU - An, Duo

AU - Ma, Minglin

AU - Oberholzer, Jose

AU - Soleimanpour, Scott A.

AU - Gannon, Maureen

AU - Liu, Chengyang

AU - Naji, Ali

AU - Kulkarni, Rohit N.

AU - Wang, Yong

AU - Kersten, Sander

AU - Qi, Ling

PY - 2019/5/20

Y1 - 2019/5/20

N2 - 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.

AB - 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.

U2 - 10.1038/s41590-019-0396-z

DO - 10.1038/s41590-019-0396-z

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SN - 1529-2908

VL - 20

SP - 677

EP - 686

JO - Nature Immunology

JF - Nature Immunology

IS - 6

ER -

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

Abstract

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Toll-like receptors 2 and 4 control adaptive β-cell expansion in diet-induced obesity

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