Effects of pioglitazone on suppressor of cytokine signaling 3 expression: potential mechanisms for its effects on insulin sensitivity and adiponectin expression.
Pioglitazone is widely used for the treatment of diabetic patients with insulin resistance. The mechanism of pioglitazone to improve insulin sensitivity is not fully understood. Recent studies have shown that the induction of suppressor of cytokine signaling 3 (SOCS3) is related to the development of insulin resistance. Here, we examined whether the insulin-sensitizing effect of pioglitazone affects the SOCS induction. In db/db mice and high-fat-fed mice, expression of SOCS3 mRNA in fat tissue was increased compared with that in lean control mice, and pioglitazone suppressed SOCS3 levels. In 3T3-L1 adipocytes, mediators of insulin resistance such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6, growth hormone, and insulin increased SOCS3 expression, which was partially inhibited by pioglitazone. The ability of pioglitazone to suppress SOCS3 induction by TNF-alpha was greatly augmented by peroxisome proliferator-activated receptor gamma overexpression. SOCS3 overexpression and tyrphostin AG490, a Janus kinase 2 inhibitor, or dominant-negative STAT3 expression partially inhibited adiponectin secretion and was accompanied by decreased STAT3 phosphorylation. Conversely, pioglitazone increased adiponectin secretion and STAT3 phosphorylation in fat tissue of db/db mice and in 3T3-L1 adipocytes. These results suggest that pioglitazone exerts its effect to improve whole-body insulin sensitivity in part through the suppression of SOCS3, which is associated with the increase in STAT3 phosphorylation and adiponectin production in fat tissue.
Kanatani
Yukiko
Y
The First Department of Internal Medicine, University of Toyama, 2630 Sugitani Toyama 930-0194, Japan.
Usui
Isao
I
Ishizuka
Ken
K
Bukhari
Agussalim
A
Fujisaka
Shiho
S
Urakaze
Masaharu
M
Haruta
Tetsuro
T
Kishimoto
Tadamitsu
T
Naka
Tetsuji
T
Kobayashi
Masashi
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus; D004041:Dietary Fats; D004822:Epididymis / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D052242:Adiponectin; C499919:Adipoq protein, mouse; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; D014443:Tyrosine; D000077205:Pioglitazone