Department of Clinical Nutrition, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Acta Biochim Biophys Sin (Shanghai). 2013 Dec;45(12):1030-8. doi: 10.1093/abbs/gmt092. Epub 2013 Aug 28.
Obesity is an important inducing factor for type 2 diabetes. However, the mechanism underlying high-fat-(HF) diet-induced obesity in pancreatic beta cell dysfunction is still unclear. Toll-like receptor-4 (TLR4) is a key mediator of innate immunity. To investigate the effects of TLR4 in obesity-induced pancreatic beta cell dysfunction, we used male diabetic (db/db), obese (ob/ob) mice, TLR4-wild type (WT), and TLR4-knockout mice that were fed with normal diet or HF diet for 24 weeks. Immunostaining of TLR4 and TLR4 mRNA level in pancreatic islet were assessed. The results from biological characteristics, glucose tolerance test, insulin tolerance test, and insulin release test showed that the function of pancreatic islet was impaired in HF-fed TLR4 WT mice, but was protected in HF-fed TLR4 deficient (TLR4(-/-)) mice. By electron microscope detection, we observed that beta cell insulin secretory vesicles increased in HF-fed TLR4 WT mice. Ultrastructure of beta cell in HF-fed TLR4(-/-) mice was similar to that in normal chow diet-fed TLR4 WT mice. Then, glucose-stimulated insulin secretion assay by using primary pancreatic islet showed that the secretion function of pancreatic islet in HF-fed TLR4(-/-) mice was better than that in HF-fed TLR4 WT mice. Furthermore, in HF-fed TLR4(-/-) mice, the mRNA levels of IL-6, TNF-α, and MCP-1 genes in pancreatic islet were significantly lower than those in HF-fed TLR4 WT mice. Consistent with the change in gene expression, HF-fed TLR4 WT mice but not HF-fed TLR4(-/-) mice exhibited macrophage invasion in pancreatic island. Taken together, our data indicated that HF diet-induced obesity can stimulate the up-regulation of TLR4 locating on the surface of pancreatic beta cell, and subsequently lead to the recruitment of macrophage into pancreatic islet, which finally results in pancreatic beta cell dysfunction. This process is a possible mechanism involved in obesity-induced pancreatic beta cell dysfunction.
肥胖是 2 型糖尿病的一个重要诱发因素。然而，高脂肪（HF）饮食诱导肥胖导致胰腺β细胞功能障碍的机制尚不清楚。Toll 样受体 4（TLR4）是先天免疫的关键介质。为了研究 TLR4 在肥胖诱导的胰腺β细胞功能障碍中的作用，我们使用雄性糖尿病（db/db）、肥胖（ob/ob）小鼠、TLR4 野生型（WT）和 TLR4 敲除（TLR4(-/-)) 小鼠，用正常饮食或 HF 饮食喂养 24 周。评估胰岛中 TLR4 的免疫染色和 TLR4 mRNA 水平。生物学特性、葡萄糖耐量试验、胰岛素耐量试验和胰岛素释放试验的结果表明，HF 喂养的 TLR4 WT 小鼠的胰岛功能受损，但在 HF 喂养的 TLR4 缺陷（TLR4(-/-)) 小鼠中得到保护。通过电子显微镜检测，我们观察到 HF 喂养的 TLR4 WT 小鼠中β细胞胰岛素分泌小泡增加。HF 喂养的 TLR4(-/-) 小鼠β细胞的超微结构与正常饲料喂养的 TLR4 WT 小鼠相似。然后，通过使用原代胰岛进行葡萄糖刺激的胰岛素分泌测定，我们发现 HF 喂养的 TLR4(-/-) 小鼠的胰岛分泌功能优于 HF 喂养的 TLR4 WT 小鼠。此外，在 HF 喂养的 TLR4(-/-) 小鼠中，胰岛中 IL-6、TNF-α 和 MCP-1 基因的 mRNA 水平明显低于 HF 喂养的 TLR4 WT 小鼠。与基因表达的变化一致，HF 喂养的 TLR4 WT 小鼠而非 HF 喂养的 TLR4(-/-) 小鼠表现出巨噬细胞浸润胰岛。总之，我们的数据表明，HF 饮食诱导的肥胖会刺激位于胰腺β细胞表面的 TLR4 上调，随后导致巨噬细胞募集到胰岛中，最终导致胰腺β细胞功能障碍。这个过程可能是肥胖诱导的胰腺β细胞功能障碍的一种机制。
