Analysis of function and signal transduction pathway of resistin using genetically-engineered animals

利用基因工程动物分析抵抗素的功能及信号转导通路

• 批准号: 17390260
• 负责人: TERAUCHI Yasuo
• 金额: $ 9.86万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390260/
• 关键词: diabetes; gene; signal transduction; PPAR; adiponectin; insulin; obesity; fat cell

We investigated the role of resistin in obesity-linked insulin resistance and central nervous system. Up-regulation of adiponectin by thiazolidinedione has been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/- … More ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur via adiponectin-dependent and and-independent pathways.Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoRl and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Adenovirus-mediated expression of AdipoRl and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoRl resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Thus, AdipoRl and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.We are also investigating the structure and role of resistin in central nervous system. Less

本研究探讨了β-氨基丁酸在肥胖相关的胰岛素抵抗和中枢神经系统中的作用。噻唑烷二酮上调脂联素被认为是噻唑烷二酮诱导改善肥胖相关胰岛素抵抗的主要机制。为了验证这一假设，我们产生了具有C57 B/6背景的脂联素敲除（adipo-/-）ob/ob小鼠。10 mg/kg吡格列酮给药14 d后，肥胖基因突变小鼠的胰岛素抵抗和糖尿病明显改善，血清脂联素水平显著上调。与此相反，在adipo-/-ob/ob小鼠中，胰岛素抵抗和糖尿病没有得到改善。30 mg/kg吡格列酮给药14天后，肥胖基因突变小鼠的胰岛素抵抗和糖尿病再次得到显著改善。有趣的是，adipo-/-ob/ob小鼠也显示出胰岛素抵抗和糖尿病的显著改善。ob/ob和adipo-/-的血清游离脂肪酸和甘油三酯水平以及脂肪细胞大小 ...更多信息 ob/ob小鼠在10 mg/kg吡格列酮后无变化，但在30 mg/kg吡格列酮后显著降低至相似程度。此外，10 mg/kg吡格列酮给药后ob/ob和adipo-/-ob/ob小鼠脂肪组织中TNF α和cDNAn的表达无变化，但30 mg/kg吡格列酮给药后降低。因此，吡格列酮可能通过脂联素依赖性和非依赖性途径改善胰岛素抵抗和糖尿病，脂联素作为抗糖尿病和抗动脉粥样硬化的脂肪因子发挥重要作用。AdipoRl和AdipoR 2在体外充当脂联素的受体，并且它们在肥胖中的减少似乎与脂联素敏感性的降低相关。腺病毒介导的AdipoRl和R2在Lepr（-/-）小鼠肝脏中的表达分别增加了AMP活化蛋白激酶（AMPK）活化和过氧化物酶体增殖物活化受体（PPAR）-α信号通路。AMPK的激活减少了糖尿病的发生，而在这两种情况下，受体的表达增加了脂肪酸的氧化，并导致糖尿病的改善。或者，AdipoRl的靶向破坏导致脂联素诱导的AMPK活化的消除，而AdipoR 2的靶向破坏导致PPAR-alpha信号通路的活性降低。因此，AdipoR 1和R2是脂联素在体内的主要受体，在调节体内糖脂代谢、炎症和氧化应激等方面发挥重要作用。少

项目成果

Targeted disruption of AdipoR1 and Adipo2 causes abrogation of adiponectin binding and metabolic actions.

有针对性地破坏 AdipoR1 和 Adipo2 会导致脂联素结合和代谢作用失效。

• 发表时间: 2007
• 期刊: Nat Med 13(3)
• 作者: Yamauchi T;et al.
• 通讯作者: et al.

Adiponectin-dependent and - independent pathways in insulin-sensitizing and antidiabetic actions of thiazolidinedions.

噻唑烷二酮的胰岛素增敏和抗糖尿病作用中脂联素依赖性和非依赖性途径。

• 发表时间: 2006
• 期刊: Diabetes. 55 Suppl 2
• 作者: Kubota N;Yamauchi T;Tobe K;Kadowaki T.
• 通讯作者: Kadowaki T.

Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin dependent and independent pathway.

吡格列酮通过脂联素依赖性和非依赖性途径改善胰岛素抵抗和糖尿病。

• 发表时间: 2006
• 期刊: J. Biol. Chem. 281(13)
• 作者: N.Kubota;T.Noda et al.(total 20;18th)
• 通讯作者: 18th)

Absence of an association between the polymorphisms in the genes encoding adiponectin receptors and type 2 diabetes

• DOI: 10.1007/s00125-005-1806-3
• 发表时间: 2005-07-01
• 期刊: DIABETOLOGIA
• 影响因子: 8.2
• 作者: Hara, K;Horikoshi, M;Kadowaki, T
• 通讯作者: Kadowaki, T

Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination.

• 发表时间: 2005
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: A. Tsuchida;T. Yamauchi;Sato Takekawa;Y. Hada;Yusuke Ito;Toshiyuki Maki;T. Kadowaki