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

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



Adult pancreatic β cells are refractory to proliferation, a roadblock for the treatment of insulin-deficient diabetes. Consumption of energy-dense Western or high-fat diet (HFD) triggers mild adaptive β cell mass expansion to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. Here we show that Toll-like receptors (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged islet mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and CDK4 in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.
Date made available21 Mar 2019
PublisherWageningen University

Research Output

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

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., 20 May 2019, In : Nature Immunology. 20, 6, p. 677-686

Research output: Contribution to journalArticleAcademicpeer-review

  • 6 Citations (Scopus)

    Cite this

    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) (21 Mar 2019). Toll-like receptors 2 and 4 control adaptive β-cell expansion in diet-induced obesity. Wageningen University.