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Physiological and pathophysiological roles ofAdiponectin receptors and identification of molecular targets for treatment of life-style related diseases

脂联素受体的生理和病理生理作用以及治疗生活方式相关疾病的分子靶标的鉴定

基本信息

批准号：
18209033
负责人：
KADOWAKI Takashi
金额：
$ 32.28万
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：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18209033/
关键词：
diabetes adipokine receptor

项目摘要

Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. In this study, we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride … More content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo (Nat. Med. 13:332, 2007).We next examined the effects of adiponectin in the central nervous system, In this study, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARE Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of Adiponectin (Clin. Chem. 53:1541, 2007) and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system (Cell Metab. 6:55, 2007; FEBS Lett. 582:74, 2008). Less

脂联素作为一种抗糖尿病和抗动脉粥样硬化的脂肪因子发挥着核心作用。AdipoR 1和AdipoR 2在体外作为脂联素的受体，它们在肥胖中的减少似乎与脂联素敏感性的降低相关。在这项研究中，我们发现腺病毒介导的AdipoR 1和R2在Lepr（-/-）小鼠肝脏中的表达分别增加了AMP激活蛋白激酶（AMPK）激活和过氧化物酶体增殖物激活受体（PPAR）-α信号通路。AMPK的激活减少了糖尿病的发生，而在这两种情况下，受体的表达增加了脂肪酸的氧化，并导致糖尿病的改善。或者，AdipoR 1的靶向破坏导致脂联素诱导的AMPK活化的消除，而AdipoR 2的靶向破坏导致PPAR-alpha信号通路的活性降低。同时破坏AdipoR 1和R2可消除脂联素的结合和作用，导致组织甘油三酯增加。 ...更多信息胰岛素抵抗和明显的葡萄糖耐受不良。因此，AdipoR 1和R2是脂联素在体内的主要受体，在体内糖脂代谢、炎症和氧化应激的调节中发挥重要作用（Nat.Med.13：332，2007）。我们接下来检查了脂联素在中枢神经系统中的作用。在该研究中，我们表明脂联素通过其受体AdipoR 1增强弓状下丘脑（ARH）中的AMPK活性以刺激食物摄入;在ARE中，显性负性AMPK表达减弱了脂联素对食物摄入的刺激。此外，脂联素还降低了能量消耗。脂联素缺乏小鼠ARH中AMPK磷酸化水平降低，食物摄入减少，能量消耗增加，表现出对高脂饮食诱导的肥胖的抵抗力。血清和脑脊液中脂联素水平（Clin.Chem.53：1541，2007）和ARH中AdipoR 1的表达在禁食期间增加，在再喂养后减少。我们得出结论，脂联素通过其在中枢神经系统中的作用在禁食期间刺激食物摄入并降低能量消耗（Cell Metab. 6：55，2007; FEBS Lett. 582：74，2008）。少