权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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。在体外，AdipoR1和AdipoR2是脂联素的受体，它们在肥胖中的减少似乎与脂联素敏感性的降低有关。在这项研究中，我们发现腺病毒介导的AdipoR1和R2在LepR(-/-)小鼠的肝脏中的表达分别增加了AMPK激活和PPAR-α信号通路。AMPK的激活减少了糖异生，而受体的表达在两种情况下都增加了脂肪酸氧化，并导致糖尿病的改善。另一种选择是，靶向阻断AdipoR1导致脂联素诱导的AMPK激活消失，而AdipoR2导致PPAR-α信号通路活性降低。同时破坏AdipoR1和R2取消了脂联素的结合和作用，导致组织甘油三酯…增加更多的内容，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。因此，AdipoR1和R2是体内脂联素的主要受体，在体内糖脂代谢、炎症和氧化应激(NAT)的调节中发挥重要作用。地中海医院。我们接下来研究了脂联素在中枢神经系统中的作用，在这项研究中，我们发现脂联素通过其受体AdipoR1增强弓状下丘脑(ARH)的AMPK活性来刺激食物摄取；这种由脂联素刺激的食物摄入量被ARE中显性负AMPK表达减弱。此外，脂联素还减少了能量消耗。脂联素缺乏的小鼠表现出ARH中AMPK磷酸化减少，食物摄入量减少，能量消耗增加，表现出对高脂饮食诱导的肥胖的抵抗。血清和脑脊液脂联素水平(临床。化学。53：1541,2007)，并且AdipoR1在ARH中的表达在禁食时增加，重新喂养后减少。我们得出结论，脂联素通过对中枢神经系统(细胞代谢)的影响，刺激食物的摄入，减少禁食期间的能量消耗。2007年6：55；FEBS Lett。582：74,2008)。较少