title: TLR4 is required for the obesity-induced pancreatic beta cell dysfunction.
abstract: 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.
authors.affiliation: Department of Clinical Nutrition, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Weiping J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Dajin
authors.initials: D
authors.lastname: Zou
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000008:administration & dosage; D015870:Gene Expression; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015850:Interleukin-6 / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D008854:Microscopy, Electron; D009765:Obesity / Q000097:blood / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D007328:Insulin; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha