title: Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice.
abstract: OBJECTIVE
  Recent studies have identified the involvement of inhibitor IkappaB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor kappaB (NF-kappaB), the distal target of IKK, in hepatic glucose metabolism.
  
  
  METHODS
  To inhibit NF-kappaB activity, db/db mice were infected with adenovirus expressing the IkappaBalpha super-repressor.
  
  
  RESULTS
  The IkappaBalpha super-repressor adenovirus infection caused a moderate reduction of NF-kappaB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A, also known as PGC-1alpha). Furthermore, the production of super-repressor IkappaBalpha suppressed the increase in blood glucose level after pyruvate injection.
  
  
  CONCLUSIONS
  Our results indicate that moderate inhibition of NF-kappaB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1alpha gene expression in db/db mice, and suggest that inhibition of NF-kappaB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.
authors.affiliation: Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tamura
authors.forename: T
authors.initials: T
authors.lastname: Ogihara
authors.forename: T
authors.initials: T
authors.lastname: Uchida
authors.forename: F
authors.initials: F
authors.lastname: Ikeda
authors.forename: N
authors.initials: N
authors.lastname: Kumashiro
authors.forename: T
authors.initials: T
authors.lastname: Nomiyama
authors.forename: F
authors.initials: F
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Hirose
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
authors.forename: R
authors.initials: R
authors.lastname: Kawamori
authors.forename: H
authors.initials: H
authors.lastname: Watada
mesh_terms: D055372:AMP-Activated Protein Kinases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose