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)

Dataset

Description

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

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