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

Nat Immunol. 2019 Jun;20(6):677-686. doi: 10.1038/s41590-019-0396-z. Epub 2019 May 20.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cyclin D2 / metabolism
  • Cyclin-Dependent Kinase 4 / metabolism
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Female
  • Humans
  • Insulin / blood
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / ultrastructure
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Obesity / drug therapy
  • Obesity / etiology*
  • Obesity / metabolism*
  • Parabiosis
  • Protein Binding
  • Toll-Like Receptor 2 / genetics*
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / metabolism


  • Cyclin D2
  • Insulin
  • Multiprotein Complexes
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Cyclin-Dependent Kinase 4