Effects of pioglitazone on suppressor of cytokine signaling 3 expression: potential mechanisms for its effects on insulin sensitivity and adiponectin expression.

Abstract	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.
Authors	Yukiko Kanatani, Isao Usui, Ken Ishizuka, Agussalim Bukhari, Shiho Fujisaka, Masaharu Urakaze, Tetsuro Haruta, Tadamitsu Kishimoto, Tetsuji Naka, Masashi Kobayashi
Journal	Diabetes (Diabetes) Vol. 56 Issue 3 Pg. 795-803 (Mar 2007) ISSN: 0012-1797 [Print] United States
PMID	17327450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adiponectin Adipoq protein, mouse Dietary Fats Hypoglycemic Agents PPAR gamma STAT3 Transcription Factor Socs3 protein, mouse Stat3 protein, mouse Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins Thiazolidinediones Tyrosine Pioglitazone
Topics	3T3-L1 Cells Adipocytes (metabolism) Adiponectin (genetics, metabolism) Adipose Tissue (metabolism) Animals Diabetes Mellitus Dietary Fats Epididymis (metabolism) Gene Expression Regulation (drug effects) Hypoglycemic Agents (pharmacology) Insulin Resistance (physiology) Male Mice Mice, Inbred C57BL PPAR gamma (metabolism) Phosphorylation Pioglitazone STAT3 Transcription Factor (metabolism) Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins (genetics, metabolism) Thiazolidinediones (pharmacology) Tyrosine (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!