title: Down regulation of peroxisome proliferator-activated receptorgamma expression by inflammatory cytokines and its reversal by thiazolidinediones.
abstract: OBJECTIVE
  Previous studies show that inflammatory cytokines play a part in the development of insulin resistance. Thiazolidinediones were developed as insulin-sensitizing drugs and are ligands for the peroxisome proliferator-activated receptory (PPARgamma). We hypothesized that the anti-diabetic mechanism of thiazolidinediones depends on the quantity of PPARgamma in the insulin resistant state in which inflammatory cytokines play a part.
  
  
  METHODS
  We isolated rat PPARgamma1 and gamma2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARgamma mRNA expression in rat mature adipocytes.
  
  
  RESULTS
  Various inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-1beta, IL-6 and leukaemia inhibitory factor decreased PPARgamma mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetate also decreased the expression of PPARgamma. The suppression of PPARgamma mRNA expression caused by 10 nmol/l of TNF-alpha was reversed 60% and 55% by treatment with 10(-4) mol/l of troglitazone and 10(-4) mol/l of pioglitazone, respectively. The suppression of glucose transporter 4 mRNA expression caused by TNF-alpha was also reversed by thiazolidinediones. Associated with the change of PPARgamma mRNA expression, troglitazone improved glucose uptake suppressed by TNF-alpha.
  
  
  CONCLUSIONS
  Our study suggests that inflammatory cytokines could be factors that regulate PPARgamma expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARgamma mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyouku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Itoh
authors.forename: K
authors.initials: K
authors.lastname: Doi
authors.forename: Y
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: K
authors.initials: K
authors.lastname: Hosoda
authors.forename: M
authors.initials: M
authors.lastname: Shintani
authors.forename: J
authors.initials: J
authors.lastname: Yamashita
authors.forename: T H
authors.initials: TH
authors.lastname: Chun
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Masatsugu
authors.forename: N
authors.initials: N
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: G
authors.initials: G
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D016207:Cytokines / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D015536:Down-Regulation; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C495694:Slc2a4 protein, rat; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D003847:Deoxyglucose; C089946:2,4-thiazolidinedione