Physiological and pathophysiological roles of adiponectin and AdipoR1/R2

脂联素是一种由脂肪细胞分泌的荷尔蒙，起着抗糖尿病脂肪因子的作用。肥胖症患者脂联素水平降低已被证明在代谢性疾病的发展中起着因果作用。我们发现，在肥胖中增加的炎性细胞因子可能在这些疾病(NAT)中起因果作用。细胞生物。2003年)。在这项研究中，我们研究了脂联素途径的生理和病理生理学作用。在以胰岛素敏感性增加为特征的PI3-KinsP85α调节亚基缺陷小鼠中，脂联素分泌上调。这些观察结果表明，“胰岛素刺激的脂肪细胞中的PI3-激酶-Akt活性”可能在调节脂联素的分泌中发挥重要作用(糖尿病，2004)。一种新型的胰岛素增敏剂，IκB Kinaseβ(IKKβ)抑制剂，可以改善胰岛素抵抗，同时通过取消下调的PI3-K-Akt激活IND…，潜在地上调血浆脂联素水平我们发现，多聚体受损和/或随之而来的分泌受损是具有这些突变的受试者中糖尿病表型或低脂联素血症的原因之一(JBC 2003)。此外，我们还发现，能够最有效地激活AMPK的HMW(高分子量)脂联素在肥胖中下调。此外，我们还建立了特异性测定HMW的酶联免疫吸附试验(CCA 2006)，结果显示HMW/总脂联素与胰岛素抵抗的关系更为密切，在代谢综合征的诊断中比总脂联素更有用(糖尿病护理，2006)。我们发现脂联素的切割似乎是由白细胞弹性蛋白酶介导的(内分泌学，2005)。接下来，我们产生了脂联素转基因小鼠，并与apoE缺陷小鼠杂交。脂联素转基因载脂蛋白E缺陷小鼠弓部和降主动脉En Face苏丹IV阳性病变面积明显小于非转基因载脂蛋白E缺陷小鼠。因此，脂联素的过度表达显著减少了动脉粥样硬化病变的形成(JBC 2003)。我们通过表达克隆的方法分离了脂联素受体(AdipoR1和R2)的编码基因(Natural 2003)。肥胖不仅降低了脂联素的表达水平，还降低了AdipoR1/R2的表达水平，从而减少了脂联素的作用，最终导致胰岛素抵抗(JBC 2004)。因此，我们的数据表明，不仅激活AdipoR1/R2，而且增加AdipoR1/R2的策略可能是一种合理的方法，为肥胖相关疾病提供一种新的治疗方式。同时破坏AdipoR1和R2会取消脂联素的结合和作用，导致组织甘油三酯含量增加，炎症和氧化应激，从而导致胰岛素抵抗和显著的糖耐量异常。此外，我们还发现肝脏中的AdipoR1和R2分别促进AMPK激活和PPAR-α信号通路(NAT。Med 2007)。此外，我们还发现，脂联素刺激了下丘脑中的AMPK，增加了食物的摄入量(Cell Metab。最后，我们发现，PPARα激动剂上调AdipoRs的表达，而PPARγ激动剂上调降低的HMW脂联素的表达(糖尿病，2005年)。此外，我们还发现，酵母AdipoR同源物(PHO36)的配体渗透素通过AdipoR在C2C12肌细胞(Mol.牢房。2005)。较少

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 metabolic diseases. We showed that inflammatory cytokines which are increased in obesity may play causal roles in these diseases (Nat. Cell Biol. 2003). In this study, we investigated the physiological and pathophysiological roles of adiponectin pathways.Adiponectin secretion was up-regulated in PI3-kinase p85α regulatory subunit-deficient mice, which were characterized by increased insulin sensitivity. These observations suggest that "insulin-stimulated PI3-kinase-Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion (Diabetes 2004). 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 ind … More uced by inflammatory cytokines (BBRC 2004).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 (JBC 2003). Moreover, we found that HMW (high molecular weight) adiponectin, which could activate AMPK most potently, was down-regulated in obesity. Moreover, we developed ELISA for specific measurement of HMW (CCA 2006), and showed that HMW/total adiponectin ratio was more tightly correlated with insulin resistance, and was more useful than total adiponectin in the diagnosis of metabolic syndrome (Diabetes Care, 2006). We found that adiponectin cleavage appeared to be mediated by leukocyte elastase (Endocrinology 2005).We next generated adiponectin transgenic mice and crossed with apoE deficient mice. The en face Sudan IV-positive lesion areas of the arch and the descending aorta in adiponectin transgenic apoE deficient mice were significantly smaller than in nontransgenic apoE deficient littermates. Thus, overexpression of adiponectin resulted in marked reduction of atherosclerotic lesion formation (JBC 2003).We isolated cDNA encoding adiponectin receptors (AdipoR1 and R2) by expression cloning (Nature 2003). Obesity decreased expression levels of not only adiponectin but also AdipoR1/R2, thereby reducing adiponectin actions, which finally leads to insulin resistance (JBC 2004). 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. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Moreover, we showed that AdipoR1 and R2 in the liver increased AMPK activation and PPAR-alpha signaling pathways, respectively (Nat. Med 2007). Furthermore, we also showed that adiponectin stimulated AMPK in the hypothalamus and increased food intake (Cell Metab. 2007).Finally, we found that PPARα agonist up-regulated expressions of AdipoRs, whereas PPARγ agonist up-regulated the reduced HMW adiponectin (Diabetes 2005). Morevoer, we showed osmotin, that is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes (Mol. Cell. 2005). Less