1. Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity.
- Author
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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, and Qi L
- Subjects
- 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 ultrastructure, Islets of Langerhans drug effects, Islets of Langerhans metabolism, MAP Kinase Signaling System, Male, Mice, Mice, Knockout, Multiprotein Complexes metabolism, Obesity drug therapy, Parabiosis, Protein Binding, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism, Insulin-Secreting Cells metabolism, Obesity etiology, Obesity metabolism, Toll-Like Receptor 2 genetics, Toll-Like Receptor 4 genetics
- 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.
- Published
- 2019
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