Effects of pioglitazone on suppressor of cytokine signaling 3 expression - Potential mechanisms for its effects on insulin sensitivity and adiponectin expression
Effects of pioglitazone on suppressor of cytokine signaling 3 expression - Potential mechanisms for its effects on insulin sensitivity and adiponectin expression
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DOI：
10.2337/db06-1039
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发表时间：
2007-03-01
期刊：
影响因子：
7.7
通讯作者：
Kobayashi, Masashi
中科院分区：
文献类型：
--
作者：
Kanatani, Yukiko;Usui, Isao;Kobayashi, Masashi
吡格列酮广泛应用于糖尿病胰岛素抵抗患者的治疗。吡格列酮改善胰岛素敏感性的机制尚不完全清楚。近年来的研究表明，细胞因子信号传导抑制因子3 （SOCS3）的诱导与胰岛素抵抗的发生有关。在这里，我们研究了吡格列酮的胰岛素增敏作用是否会影响SOCS的诱导。在db/db小鼠和高脂喂养小鼠中，与瘦对照小鼠相比，脂肪组织中SOCS3 mRNA的表达增加，吡格列酮抑制SOCS3水平。在3T3-L1脂肪细胞中，胰岛素抵抗的介质如肿瘤坏死因子- α (tnf - α)、白细胞介素-6、生长激素和胰岛素可增加SOCS3的表达，吡格列酮可部分抑制SOCS3的表达。吡格列酮抑制tnf - α诱导SOCS3的能力因过氧化物酶体增殖物激活受体γ过表达而大大增强。SOCS3过表达和Janus激酶2抑制剂tyrphostin AG490或STAT3显性阴性表达部分抑制脂联素分泌，并伴有STAT3磷酸化降低。相反，吡格列酮增加db/db小鼠脂肪组织和3T3-L1脂肪细胞中脂联素分泌和STAT3磷酸化。这些结果表明，吡格列酮部分通过抑制SOCS3发挥其改善全身胰岛素敏感性的作用，SOCS3与脂肪组织中STAT3磷酸化和脂联素产生的增加有关。
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.