Physiological and pathophysiological roles and signal transduction of adiponectin receptors

脂联素是一种由脂肪细胞分泌的激素，是一种抗糖尿病的脂肪因子。肥胖症患者脂联素水平降低已被证明在这些疾病的发展中起因果作用。一种新型的胰岛素增敏剂I κ B激酶β（IKK β）抑制剂可改善胰岛素抵抗，同时上调脂联素的血浆水平，这可能是通过取消炎症细胞因子诱导的下调的PI3-kinase-Akt活化而实现的。此外，我们还发现，在肥胖时，对AMPK激活作用最强的高分子量脂联素（HMW）表达下调，而PPAR γ激动剂则上调了降低的HMW脂联素。此外，通过使用脂联素敲除小鼠，我们发现，PPAR γ激动剂通过脂联素依赖性胰岛素抵抗和糖尿病， ...更多信息 Lodish博士的研究小组报告说，在人类血浆中检测到少量的球状脂联素。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，几乎所有的脂联素似乎都以全长脂联素的形式存在于血浆中，因此脂联素在体内被白细胞弹性蛋白酶切割的病理生理学意义仍有待确定。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，并介导脂联素增加AMPK、PPAR配体活性、脂肪酸氧化和葡萄糖摄取。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，从而降低了脂联素的作用，最终导致胰岛素抵抗。因此，我们的数据表明，不仅激动AdipoR1/R2，而且增加AdipoR1/R2的策略可能是一个合乎逻辑的方法，为肥胖相关疾病提供一种新的治疗模式。最后，我们表明，AdipoR的酵母同系物（PHO36）的配体，通过AdipoR激活C2C12肌细胞中的AMPK。这可能有助于脂联素受体激动剂的有效开发。此外，我们还发现PPAR α激动剂上调AdipoRs的表达。这些数据表明，PPAR γ和PPAR的双重激活通过增加总脂联素和高分子量脂联素受体以及脂联素受体来增强脂联素的作用，从而改善肥胖诱导的胰岛素抵抗。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 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