密歇根大学齐岭团队宣布他们发现了Toll样受体TLR2和TLR4如何参与抑制由饮食肥胖所引起的胰岛β细胞增殖。 这一研究成果于2019年6月发表在国际学术期刊《Nature Immunology》上。

在该项研究中，研究人员发现在小鼠模型和人类中，Toll样受体TLR2和TLR4均参与抑制由饮食诱导的β细胞增殖。在小鼠模型中，TLR2和TLR4的双敲除能够促进β细胞的增殖，而并不影响α细胞，从而导致β细胞区域面积增大并引起饮食肥胖中的高胰岛素血症。进一步机理研究表明，TLR2和TLR4的缺失增加了细胞周期素D2（cyclin D2）和细胞周期蛋白依赖性激酶Cdk4在细胞核内的富集，这在一定程度上依赖于信号转导蛋白Erk。这些发现为饮食肥胖条件下β细胞代偿性增殖的调控机制提供了新的见解，并为通过促进β细胞增殖来实现糖尿病治疗提供了新的思路。

据介绍，含有高热量的西方饮食习惯会引发胰岛β细胞的轻微适应性增殖，以补偿外周胰岛素抵抗；然而，其潜在的分子机制仍然不清楚。

附：英文原文

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

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

Issue&Volume: Volume 20 Issue 6, June 2019

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.

DOI: 10.1038/s41590-019-0396-z

Source: https://www.nature.com/articles/s41590-019-0396-z