title: Aryl hydrocarbon receptor deficiency enhances insulin sensitivity and reduces PPAR-α pathway activity in mice.
abstract: BACKGROUND
  Numerous man-made pollutants activate the aryl hydrocarbon receptor (AhR) and are risk factors for type 2 diabetes. AhR signaling also affects molecular clock genes to influence glucose metabolism.
  
  
  OBJECTIVE
  We investigated mechanisms by which AhR activation affects glucose metabolism.
  
  
  METHODS
  Glucose tolerance, insulin resistance, and expression of peroxisome proliferator-activated receptor-α (PPAR-α) and genes affecting glucose metabolism or fatty acid oxidation and clock gene rhythms were investigated in wild-type (WT) and AhR-deficient [knockout (KO)] mice. AhR agonists and small interfering RNA (siRNA) were used to examine the effect of AhR on PPAR-α expression and glycolysis in the liver cell line Hepa-1c1c7 (c7) and its c12 and c4 derivatives. Brain, muscle ARNT-like protein 1 (Bmal1) siRNA and Ahr or Bmal1 expression plasmids were used to analyze the effect of BMAL1 on PPAR-α expression in c7 cells.
  
  
  RESULTS
  KO mice displayed enhanced insulin sensitivity and improved glucose tolerance, accompanied by decreased PPAR-α and key gluconeogenic and fatty acid oxidation enzymes. AhR agonists increased PPAR-α expression in c7 cells. Both Ahr and Bmal1 siRNA reduced PPAR-α and metabolism genes. Moreover, rhythms of BMAL1 and blood glucose were altered in KO mice.
  
  
  CONCLUSIONS
  These results indicate a link between AhR signaling, circadian rhythms, and glucose metabolism. Furthermore, hepatic activation of the PPAR-α pathway provides a mechanism underlying AhR-mediated insulin resistance.
authors.affiliation: Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62974-9629, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.forename: Can-Xin
authors.initials: CX
authors.lastname: Xu
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Krager
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Bottum
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Tischkau
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006019:Glycolysis; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000172:deficiency*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D047493:PPAR alpha; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D005947:Glucose