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

脂联素作为一种抗糖尿病和抗动脉粥样硬化的脂肪因子起着核心作用。AdipoR1和AdipoR2在体外作为脂联素受体，它们对肥胖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（-/-）小鼠肝脏中的表达分别增加了amp激活的蛋白激酶（AMPK）激活和过氧化物酶体增殖体激活受体(PPAR) α信号通路。AMPK的激活减少了糖异生，而在这两种情况下，受体的表达增加了脂肪酸氧化，导致糖尿病的改善。另外，靶向破坏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破坏脂联素的结合和作用，导致组织甘油三酯含量增加，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不良。因此，AdipoR1和R2是体内脂联素的主要受体，在体内糖脂代谢、炎症和氧化应激的调节中发挥重要作用（Nat. Med. 13:332, 2007）。在这项研究中，我们发现脂联素通过其受体AdipoR1增强了弓形下丘脑（ARH）中AMPK的活性，从而刺激食物摄入；AMPK在ARE中的显性负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。脂联素缺乏的小鼠显示ARH中AMPK磷酸化降低，食物摄入减少，能量消耗增加，表现出对高脂肪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)，ARH中AdipoR1的表达在禁食时增加，再喂食后减少。我们得出结论，脂联素通过其对中枢神经系统的影响，刺激食物摄入并减少禁食期间的能量消耗（Cell Metab. 6:55, 2007; FEBS Lett. 582:74, 2008）。少

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