Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

T. Tanaka, Hiroshi Itoh, K. Doi, Y. Fukunaga, K. Hosoda, M. Shintani, J. Yamashita, T. H. Chun, M. Inoue, K. Masatsugu, N. Sawada, T. Saito, G. Inoue, H. Nishimura, Y. Yoshimasa, K. Nakao

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Aims/hypothesis. 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 receptorγ (PPARγ). We hypothesized that the anti- diabetic mechanism of thiazolidinediones depends on the quantity of PPARγ in the insulin resistant state in which inflammatory cytokines play a part. Methods. We isolated rat PPARγ1 and γ2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARγ mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6 and leukaemia inhibitory factor decreased PPARγ mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13- acetate also decreased the expression of PPARγ. The suppression of PPARγ mRNA expression caused by 10 nmol/l of TNF-α 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-α was also reversed by thiazolidinediones. Associated with the change of PPARγ mRNA expression, troglitazone improved glucose uptake suppressed by TNF-α. Conclusion/interpretation. Our study suggests that inflammatory cytokines could be factors that regulate PPARγ expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARγ mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.

Original languageEnglish
Pages (from-to)702-710
Number of pages9
JournalDiabetologia
Volume42
Issue number6
DOIs
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

Thiazolidinediones
Peroxisome Proliferator-Activated Receptors
Down-Regulation
Cytokines
troglitazone
Messenger RNA
Tumor Necrosis Factor-alpha
pioglitazone
Interleukin-1
Insulin Resistance
Insulin
Leukemia Inhibitory Factor
Lysophosphatidylcholines
Facilitative Glucose Transport Proteins
Adipocytes
Hydrogen Peroxide
Interleukin-6
Acetates
Complementary DNA
Ligands

Keywords

  • Adipocyte
  • Cloning
  • Cytokines
  • Glucose uptake
  • Insulin resistance
  • PPARγ
  • Rat
  • Thiazolidinediones
  • TNF- α

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones. / Tanaka, T.; Itoh, Hiroshi; Doi, K.; Fukunaga, Y.; Hosoda, K.; Shintani, M.; Yamashita, J.; Chun, T. H.; Inoue, M.; Masatsugu, K.; Sawada, N.; Saito, T.; Inoue, G.; Nishimura, H.; Yoshimasa, Y.; Nakao, K.

In: Diabetologia, Vol. 42, No. 6, 1999, p. 702-710.

Research output: Contribution to journalArticle

Tanaka, T, Itoh, H, Doi, K, Fukunaga, Y, Hosoda, K, Shintani, M, Yamashita, J, Chun, TH, Inoue, M, Masatsugu, K, Sawada, N, Saito, T, Inoue, G, Nishimura, H, Yoshimasa, Y & Nakao, K 1999, 'Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones', Diabetologia, vol. 42, no. 6, pp. 702-710. https://doi.org/10.1007/s001250051218
Tanaka, T. ; Itoh, Hiroshi ; Doi, K. ; Fukunaga, Y. ; Hosoda, K. ; Shintani, M. ; Yamashita, J. ; Chun, T. H. ; Inoue, M. ; Masatsugu, K. ; Sawada, N. ; Saito, T. ; Inoue, G. ; Nishimura, H. ; Yoshimasa, Y. ; Nakao, K. / Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones. In: Diabetologia. 1999 ; Vol. 42, No. 6. pp. 702-710.
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AU - Tanaka, T.

AU - Itoh, Hiroshi

AU - Doi, K.

AU - Fukunaga, Y.

AU - Hosoda, K.

AU - Shintani, M.

AU - Yamashita, J.

AU - Chun, T. H.

AU - Inoue, M.

AU - Masatsugu, K.

AU - Sawada, N.

AU - Saito, T.

AU - Inoue, G.

AU - Nishimura, H.

AU - Yoshimasa, Y.

AU - Nakao, K.

PY - 1999

Y1 - 1999

N2 - Aims/hypothesis. 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 receptorγ (PPARγ). We hypothesized that the anti- diabetic mechanism of thiazolidinediones depends on the quantity of PPARγ in the insulin resistant state in which inflammatory cytokines play a part. Methods. We isolated rat PPARγ1 and γ2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARγ mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6 and leukaemia inhibitory factor decreased PPARγ mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13- acetate also decreased the expression of PPARγ. The suppression of PPARγ mRNA expression caused by 10 nmol/l of TNF-α 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-α was also reversed by thiazolidinediones. Associated with the change of PPARγ mRNA expression, troglitazone improved glucose uptake suppressed by TNF-α. Conclusion/interpretation. Our study suggests that inflammatory cytokines could be factors that regulate PPARγ expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARγ mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.

AB - Aims/hypothesis. 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 receptorγ (PPARγ). We hypothesized that the anti- diabetic mechanism of thiazolidinediones depends on the quantity of PPARγ in the insulin resistant state in which inflammatory cytokines play a part. Methods. We isolated rat PPARγ1 and γ2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARγ mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6 and leukaemia inhibitory factor decreased PPARγ mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13- acetate also decreased the expression of PPARγ. The suppression of PPARγ mRNA expression caused by 10 nmol/l of TNF-α 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-α was also reversed by thiazolidinediones. Associated with the change of PPARγ mRNA expression, troglitazone improved glucose uptake suppressed by TNF-α. Conclusion/interpretation. Our study suggests that inflammatory cytokines could be factors that regulate PPARγ expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARγ mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.

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