Journal Article

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

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

2019

Overview

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. High-energy diet triggers mild β cell proliferation to compensate for peripheral insulin resistance. Qi and colleagues show that TLR2 and TLR4 inhibit the diet-induced replication of β cells in mice and humans.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/262/2106 / 692/420/256/2515 / Animals / Beta cells / Biomedical and Life Sciences / Biomedicine / Cell cycle / Cell growth / Cell Proliferation / Chair Nutrition Metabolism and Genomics / Cyclin D2 / Cyclin D2 - metabolism / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - metabolism / Diabetes mellitus / Diet / Diet, High-Fat - adverse effects / Disease Models, Animal / Female / HNE Nutrition, Metabolism and Genomics / HNE Voeding, Metabolisme en Genomics / Humans / Hyperinsulinemia / Immunology / Infectious Diseases / Insulin / Insulin - blood / Insulin - metabolism / Insulin resistance / Insulin-Secreting Cells - metabolism / Insulin-Secreting Cells - ultrastructure / Islets of Langerhans - drug effects / Islets of Langerhans - metabolism / Male / MAP Kinase Signaling System / Mice / Mice, Knockout / Multiprotein Complexes - metabolism / Nutrition, Metabolism and Genomics / Obesity / Obesity - drug therapy / Obesity - etiology / Obesity - metabolism / Pancreas / Parabiosis / Protein Binding / Replication / TLR2 protein / TLR4 protein / Toll-Like Receptor 2 - genetics / Toll-Like Receptor 2 - metabolism / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - metabolism / Toll-like receptors / VLAG / Voeding, Metabolisme en Genomica