title: TLR4 Expression by Liver Resident Cells Mediates the Development of Glucose Intolerance and Insulin Resistance in Experimental Periodontitis.
abstract: BACKGROUND
  Results from epidemiological studies indicate a close association between periodontitis and type 2 diabetes mellitus. However, the mechanism linking periodontitis to glucose intolerance (GI) and insulin resistance (IR) is unknown. We therefore tested the hypothesis that periodontitis induces the development of GI/IR through a liver Toll-like receptor 4 (TLR4) dependent mechanism.
  
  
  METHODS
  TLR4 chimeric mice were developed by bone marrow transplantation using green fluorescent protein expressing TLR4WT mouse (GFPWT) as donor and TLR4 WT or TLR4-/- as recipient mice (GFPWT:WT and GFPWT:KO chimeras respectively). These chimeras were subjected to experimental chronic periodontitis induced by repeated applications of LPS to the gingival sulci for 18 weeks. The levels of GI/IR were monitored and plasma cytokines and LPS were determined at 18 weeks when differences in glucose tolerance were most apparent. Cytokine gene expression was measured in liver tissue by qPCR.
  
  
  RESULTS
  Alveolar bone loss was significantly greater in GFPWT:WT chimeras treated with LPS compared with chimeras treated with PBS or GFPWT:KO chimeras. However, the degree of gingival inflammation was similar between GFPWT:WT and GFPWT:KO mice with LPS application. Severe GI/IR occurred in GFPWT:WT chimeras but not in the GFPWT:KO chimeras that were subjected to 18 weeks of LPS. Serum LPS was detected only in animals to which LPS was applied and the level was similar in GFPWT:WT and GFPWT:KO mice at the 18 week time point. Surprisingly, there was no significant difference in the plasma levels of IL1β, IL6 and TNFα at 18 weeks in spite of the severe GI/IR in the GFPWT:WT chimeras with LPS application. Also, no difference in the expression of TNFα or IL6 mRNA was detected in the liver of GFPWT:WT vs GFPWT:KO mice. In contrast, liver IL1β expression was significantly greater in GFPWT:WT chimeras compared to GFPWT:KO chimeras treated with LPS.
  
  
  CONCLUSIONS
  We observed that GFPWT:WT, but not GFPWT:KO chimeras, treated with LPS developed GI/IR despite similar degrees of gingival inflammation, circulating cytokine levels, and LPS concentrations. We conclude that LPS from periodontitis sites has a pivotal role in triggering the development of GI/IR through a mechanism that involves TLR4 expression by resident macrophages/Kupffer cells in the liver.
authors: Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Vladimir
authors: V
authors: Ilievski
authors: Undergraduate Program, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Yale
authors: Y
authors: Cho
authors: Undergraduate Program, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Priya
authors: P
authors: Katwala
authors: Undergraduate Program, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Heriberto
authors: H
authors: Rodriguez
authors: Undergraduate Program, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Margaret
authors: M
authors: Tulowiecka
authors: Undergraduate Program, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: David
authors: D
authors: Kurian
authors: Department of Radiology, University of Chicago, Chicago, Illinois, United States of America.
authors: Lara
authors: L
authors: Leoni
authors: Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio, United States of America.
authors: John W
authors: JW
authors: Christman
authors: Departments of Medicine and Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, and Jesse Brown VA Medical Center, Chicago, Illinois, United States of America.
authors: Terry G
authors: TG
authors: Unterman
authors: Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Keiko
authors: K
authors: Watanabe
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010518:Periodontitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics; D018183:Transplantation Chimera
chemical_list: D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4