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- Title
Effects of Pioglitazone on SOCS3 Expression: Potential Mechanisms for Its Effects on Insulin Sensitivity and Adiponectin Expression.
- Authors
Kanatani, Yukiko; Usui, Isao; Ishizuka, Ken; Fujisaka, Shiho; Bukhari, Agussalim; Jianying He; Yamazaki, Yu; Suzuki, Hikari; Iwata, Minoru; Ishiki, Manabu; Urakaze, Masaharu; Kobayashi, Masashi
- 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 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 TNFα, IL-6, growth hormone and insulin, increased SOCS3 expression, which was partially inhibited by pioglitazone. The ability of pioglitazone to suppress SOCS3 induction by TNFa was greatly augmented by PPARγ overexpression. Then, we hypothesized that SOCS3 expression in fat tissue may affect insulin sensitivity via changing the production of adiponectin. SOCS3 overexpression as well as tyrphostin AG490, a JAK2 inhibitor, or dominant-negative STAT3 expression partially inhibited adiponectin production, and was accompanied by decreased STAT3 phosphorylation. In contrast, pioglitazone increased both tyrosine phosphorylation of STAT3 and adiponectin secretion. These results suggest that STAT3 activation may be necessary for the full production of adiponectin in 3T3-L1 adipoeytes. Supporting these in vitro data, serum adiponectin levels and tyrosine phosphorylation of STAT3 were suppressed in fat tissues of db/db mice compared to those in the control mice, both of which were recovered by pioglitazone treatment. 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.
- Subjects
HYPOGLYCEMIC agents; TREATMENT of diabetes; PEOPLE with diabetes; INSULIN resistance; MESSENGER RNA; FAT cells; PHOSPHORYLATION; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA356
- ISSN
0012-1797
- Publication type
Article