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

脂联素在调节2型糖尿病、高脂血症和动脉粥样硬化中的病理生理作用

基本信息

批准号：
14207045
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

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.

在发达国家和发展中国家，与肥胖相关的疾病（如糖尿病和心血管疾病）正在急剧增加。保护杂合PPARG或CBP基因敲除小鼠受到高脂饮食诱导的肥胖和胰岛素抵抗的保护（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分析分析，发现脂联素/ACRP30过表达。功能分析包括产生脂联素转基因或基因敲除小鼠，表明脂联素用作胰岛素敏化脂肪因子（自然医学7：941，2001）。实际上，肥胖与脂联蛋白的调节是一种机制，肥胖可以引起胰岛素抵抗和糖尿病。我们进一步研究了脂联素作用的机制，发现脂联素可以激活AMP激酶途径和PPARA途径，从而导致脂肪燃烧和胰岛素抵抗的改善（自然医学8：1288，2002）。最近，我们在骨骼肌（Adipor1）和肝脏（ADIPOR2）中克隆了脂联素受体，它们似乎包括一个新型的细胞表面受体家族（自然423：762，2003）。 ADIPOR1/R2的表达似乎受到几种生理和病理生理状态的调节，例如禁食/培养和高胰岛素血症，并与脂联素敏感性相关（J.Biol.Chem.Chem。于2004年4月29日在Line发表）。脂联素受体激动剂和脂联素敏化剂应作为肥胖症疾病（例如糖尿病）的多功能治疗策略。