The pathophysiological roles of adiponectin in the regulation of type 2 diabetes, hyperlipidemia and atherosclerosis

在发达国家和发展中国家，糖尿病和心血管疾病等与肥胖有关的疾病正在急剧增加。杂合PPARg或CBP敲除小鼠受到保护，免于高脂肪饮食诱导的肥胖和胰岛素抗性（Mol.Cell 4：597，1999; Nature Genetics 30：221，2002）。然后我们对这些小鼠进行了系统的基因谱分析，发现脂联素/Acrp 30过表达。包括脂联素转基因或敲除小鼠的产生的功能分析已经揭示脂联素作为胰岛素增敏脂肪因子（Nature Medicine 7：941，2001）。事实上，肥胖相关的脂联素下调是肥胖导致胰岛素抵抗和糖尿病的一种机制。我们进一步研究了脂联素的作用机制，发现脂联素可以激活AMP激酶途径和PPARa途径，导致脂肪燃烧和改善胰岛素抵抗（Nature Medicine 8：1288，2002）。最近，我们克隆了骨骼肌（AdipoR 1）和肝脏（AdipoR 2）中的脂联素受体，其似乎包含新的细胞表面受体家族（Nature 423：762，2003）。AdipoR 1/R2的表达似乎受几种生理和病理生理状态如禁食/再喂养和高胰岛素血症的调节，并且与脂联素敏感性相关（J.Biol.Chem.在线出版，2004年4月29日）。脂联素受体激动剂和脂联素增敏剂应作为肥胖相关疾病如糖尿病的通用治疗策略。

Obesity-linked diseases such as diabetes and cardiovascular disease are sharply increasing in developed and developing countries. Heterozygous PPARg or CBP knockout mice were protected from high-fat diet induced obesity and insulin resistance (Mol.Cell 4:597, 1999; Nature Genetics 30:221, 2002). We then carried out systematic gene profiling analysis of these mice and found that adiponectin/Acrp30 was overexpressed. Functional analyses including generation of adiponectin transgenic or knockout mice have revealed that adiponectin serves as an insulin sensitizing adipokine (Nature Medicine 7:941, 2001). In fact, obesity-linked down regulation of adiponectin was a mechanism whereby obesity can cause insulin resistance and diabetes. We further studied the mechanism of adiponectin action and found that adiponectin can activate AMP kinase pathway and PPARa pathway, leading to fat combustion and amelioration of insulin resistance (Nature Medicine 8:1288, 2002). Recently, we have cloned adiponectin receptors in the skeletal muscle (AdipoR1) and liver (AdipoR2), which appear to comprise a novel cell surface receptor family (Nature 423:762, 2003). The expression of AdipoR1/R2 appears to be regulated by several physiological and pathophysiological states such as, fasting/refeeding and hyperinsulinemia, and correlated with adiponectin sensitivity (J.Biol.Chem. published on line on Apr 29, 2004). Adiponectin receptor agonists and adiponectin sensitizers should serve as versatile treatment strategies for obesity linked diseases such as diabetes.