Physiological and pathophysiological roles of adiponectin and AdipoR1/R2

脂联素是一种由脂肪细胞分泌的激素，作为抗糖尿病的脂肪因子。肥胖中脂联素水平的降低已被证明在代谢性疾病的发展中起着因果作用。我们发现肥胖增加的炎症细胞因子可能在这些疾病中起因果作用（Nat. Cell Biol. 2003）。在本研究中，我们探讨了脂联素通路的生理和病理生理作用。pi3激酶p85α调节亚基缺陷小鼠脂联素分泌上调，表现为胰岛素敏感性升高。这些观察结果表明，“胰岛素刺激脂肪细胞中pi3 -激酶- akt活性”可能在调节脂联素分泌中发挥重要作用（Diabetes 2004）。一种新的胰岛素增敏剂，IκB激酶β (IKKβ)抑制剂，改善胰岛素抵抗，同时可能通过消除炎症细胞因子引起的下调的pi3 -激酶- akt活化而上调血浆脂联素水平（BBRC 2004）。我们发现，在具有这些突变的受试者中，多聚受损和/或随之而来的分泌受损是糖尿病表型或低脂联素血症的原因之一（JBC 2003）。此外，我们发现最能激活AMPK的HMW（高分子量）脂联素在肥胖中下调。此外，我们开发了用于HMW特异性测量的ELISA (CCA 2006)，并表明HMW/总脂联素比与胰岛素抵抗更紧密相关，并且在代谢综合征的诊断中比总脂联素更有用（Diabetes Care, 2006）。我们发现脂联素切割似乎是由白细胞弹性酶介导的（内分泌学2005）。接下来，我们培育了脂联素转基因小鼠，并与apoE缺陷小鼠杂交。脂联素转基因apoE缺陷小鼠足弓和降主动脉表面苏丹iv阳性病变面积明显小于非转基因apoE缺陷小鼠。因此，脂联素的过度表达导致动脉粥样硬化病变形成的显著减少（JBC 2003）。我们通过表达克隆分离到了编码脂联素受体AdipoR1和R2的cDNA （Nature 2003）。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（JBC 2004）。因此，我们的数据表明，不仅AdipoR1/R2的激动作用，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会破坏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明显的葡萄糖耐受不良。此外，我们发现肝脏中的AdipoR1和R2分别增加了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下丘脑的AMPK并增加食物摄入量（Cell Metab. 2007）。最后，我们发现PPARα激动剂上调adipor的表达，而PPARγ激动剂上调降低的HMW脂联素（Diabetes 2005）。此外，我们发现渗透素（一种与AdipoR （PHO36）同源的酵母配体）在C2C12肌细胞中通过AdipoR激活AMPK （Mol. Cell. 2005）。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