|Title||Toll-like receptors TLR2 and TLR4 block the replication of pancreatic β cells in diet-induced obesity|
|Author(s)||Ji, Yewei; Sun, Shengyi; Shrestha, Neha; Darragh, Laurel B.; Shirakawa, Jun; Xing, Yuan; He, Yi; Carboneau, Bethany A.; Kim, Hana; An, Duo; Ma, Minglin; Oberholzer, Jose; Soleimanpour, Scott A.; Gannon, Maureen; Liu, Chengyang; Naji, Ali; Kulkarni, Rohit N.; Wang, Yong; Kersten, Sander; Qi, Ling|
|Source||Nature Immunology 20 (2019)6. - ISSN 1529-2908 - p. 677 - 686.|
Nutrition, Metabolism and Genomics
|Publication type||Refereed Article in a scientific journal|
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.