Physiological and pathophysiological roles and signal transduction of adiponectin receptors

脂联素受体的生理和病理生理作用及信号转导

• 批准号: 16209030
• 负责人: KADOWAKI Takashi
• 金额: $ 32.2万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209030/
• 关键词: Diabetes; insulin resistance; AMP kinase; PPAR; adipokine; receptor; obesity; gene targeting

Adiponectin is a hormone secreted by adipocytes that acts as an antidiabetic adipokine. Decreased adiponectin levels in obesity has been shown to play causal roles in the development of these diseases. A novel insulin sensitizer, IκB kinase β(IKKβ) inhibitor, ameliorated insulin resistance and at the same time up-regulated plasma levels of adiponectin potentially via cancellation of down-regulated PI3-kinase-Akt activation induced by inflammatory cytokines.We found that impaired multimerization and/or the consequent impaired secretion to be among the causes of a diabetic phenotype or hypoadiponectinemia in subjects having these mutations. Moreover, we found that HMW(high molecular weight) adiponectin, which could activate AMPK most potently, was down-regulated in obesity, and that PPARγ agonist up-regulated the reduced HMW adiponectin. Moreover, by using adiponectin knockout mice, we showed that PPARγ agonist up-ameliorated insulin resistance and diabetes via both adiponectin-dependent … More and independent pathways.Dr.Lodish's group reported that a small amount of globular adiponectin was detected in human plasma. We found that adiponectin cleavage appeared to be mediated by leukocyte elastase. However, almost all the adiponectin appears to exist as full-length adiponectin in plasma, thus the pathophysiological importance of adiponectin cleavage by leukocyte elastase in vivo remains to be determinedWe isolated cDNA encoding adiponectin receptors (AdipoR1 and R2) by expression cloning. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 revealed that AdipoR1 and R2 serve as receptors for globular and full-length adiponectin, and mediate increased AMPK, PPAR ligands activities, the fatty-acid oxidation and glucose uptake by adiponectin. Obesity decreased expression levels of not only adiponectin but also AdipoR1/R2, thereby reducing adiponectin actions, which finally leads to insulin resistance. Thus our data suggest that not only agonism of AdipoR1/R2 but also strategies to increase AdipoR1/R2 may be a logical approach to provide a novel treatment modality for obesity-linked diseases.Finally, we showed osmotin, that is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes. This may facilitate efficient development of adiponectin receptor agonists. Moreover, we found that PPARα agonist up-regulated expressions of AdipoRs. These data suggest that dual activation of PPARγ and PPAR enhances the action of adiponectin by increasing both total and HMW adiponectin and adiponectin receptors, which can result in amelioration of obesity-induced insulin resistance. Less

脂联素是脂肪细胞分泌的一种激素，可作为抗糖尿病脂肪因子。肥胖症中脂联素水平的降低已被证明在这些疾病的发展中起着因果作用。一种新型胰岛素增敏剂 IκB 激酶 β (IKKβ) 抑制剂可改善胰岛素抵抗，同时可能通过取消炎症细胞因子诱导的下调 PI3-激酶-Akt 激活来上调血浆脂联素水平。我们发现，多聚化受损和/或随之而来的分泌受损是导致胰岛素抵抗的原因之一。 具有这些突变的受试者的糖尿病表型或低脂联素血症。此外，我们发现最有效地激活 AMPK 的 HMW（高分子量）脂联素在肥胖中表达下调，而 PPARγ 激动剂则上调降低的 HMW 脂联素。此外，通过使用脂联素敲除小鼠，我们发现 PPARγ 激动剂通过脂联素依赖性和独立途径改善胰岛素抵抗和糖尿病。Lodish 博士的研究小组报告称，在人血浆中检测到了少量的球状脂联素。我们发现脂联素裂解似乎是由白细胞弹性蛋白酶介导的。然而，几乎所有脂联素似乎都以全长脂联素形式存在于血浆中，因此体内白细胞弹性蛋白酶裂解脂联素的病理生理学重要性仍有待确定。我们通过表达克隆分离了编码脂联素受体（AdipoR1和R2）的cDNA。 AdipoR1/R2 的表达或 AdipoR1/R2 的抑制表明 AdipoR1 和 R2 作为球状和全长脂联素的受体，并介导 AMPK、PPAR 配体活性的增加、脂联素的脂肪酸氧化和葡萄糖摄取。肥胖不仅会降低脂联素的表达水平，还会降低AdipoR1/R2的表达水平，从而降低脂联素的作用，最终导致胰岛素抵抗。因此，我们的数据表明，不仅是 AdipoR1/R2 的激动作用，而且增加 AdipoR1/R2 的策略可能是为肥胖相关疾病提供新的治疗方式的合理方法。最后，我们发现渗透素（AdipoR 的酵母同源物 (PHO36) 的配体）在 C2C12 肌细胞中通过 AdipoR 激活 AMPK。这可能有助于脂联素受体激动剂的有效开发。此外，我们发现 PPARα 激动剂上调 AdipoR 的表达。这些数据表明，PPARγ和PPAR的双重激活通过增加总脂联素和HMW脂联素以及脂联素受体来增强脂联素的作用，从而改善肥胖引起的胰岛素抵抗。较少的

项目成果

A novel IKKβ inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance

• DOI: 10.1016/j.bbrc.2004.08.083
• 发表时间: 2004-10-08
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Kamon, J;Yamauchi, T;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

Osmosin is a homolog of human adiponectin and controls apoptosis in yeast through a homolog of human adiponectin receptor.

Osmosin 是人脂联素的同系物，通过人脂联素受体的同系物控制酵母细胞凋亡。

• 发表时间: 2005
• 期刊: Molecular Cell 17
• 作者: Narasimhan;LM;et al.
• 通讯作者: et al.

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