title: High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway.
abstract: OBJECTIVE
  While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet.
  
  
  METHODS
  C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high-fat (60 kcal % fat) diet (HFD) for 8 weeks.
  
  
  RESULTS
  HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice.
  
  
  CONCLUSIONS
  HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Wan
authors.initials: W
authors.lastname: Gu
authors.forename: In-Ah
authors.initials: IA
authors.lastname: Lee
authors.forename: Eun-Ha
authors.initials: EH
authors.lastname: Joh
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000235:genetics; D000818:Animals; D003092:Colitis / Q000209:etiology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004731:Endotoxins / Q000097:blood / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology*; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D054892:Metagenome; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004731:Endotoxins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D018836:Inflammation Mediators; D051197:Toll-Like Receptor 4; D051057:Proto-Oncogene Proteins c-akt