Probing of physiological significance of adipocyte-specific glycerol channel and its application to the treatment of diabetes mellitus.

水通道蛋白脂肪(Aquaporin Adpose，AQPap)是我们从人类脂肪组织中发现的，是脂肪细胞中的甘油通道(J Biol Chem 2000)。这种分子的表达在禁食时增加，在进食时减少，并被胰岛素抑制(J Biol Chem 2001)。我们还证明了AQPap和水通道蛋白9(AQP9)作为肝脏特异的甘油通道，通过胰岛素的抑制作用而被协同调节。然而，在肥胖的胰岛素抵抗小鼠中，该通道功能失调，导致葡萄糖抵抗(糖尿病2002)。在本研究中，我们研究了缺乏AQPap的小鼠的甘油和葡萄糖代谢，并证明了AQPap在体内作为甘油门户分子的功能。与野生型(WT)小鼠相比，AQPap基因敲除(KO)小鼠的血浆甘油水平较低，但血浆游离脂肪酸水平正常。-肾上腺素能激动剂引起的血浆甘露醇水平升高在KO小鼠中受到严重抑制。在AQPap基因敲除的脂肪细胞中，肾上腺素刺激的甘油分泌也受到损害。在长时间禁食期间，WT小鼠血浆甘油升高，血糖水平保持不变。相比之下，KO小鼠在长时间禁食期间表现出血浆甘油的紊乱上升和血糖的快速下降。这些发现表明，缺乏甘油通道分子有效地从脂肪细胞转运甘油，导致了对长时间禁食的不良适应。(PNAS 2004)。

Aquaporin adipose(AQPap), which we identified from human adipose tissue, is a glycerol channel in adipocyte (J Biol Chem 2000). The expression of this molecule increased in fasting, decreased in feeding and was inhibited by insulin (j Biol Chem 2001). We also demonstrated that there was a coordinated regulation of AQPap and aquaporin 9(AQP9), as a liver specific glycerol channel, through the inhibitory effect by insulin. However, the channel function was dysregulated in obese mice with insulin resistance, leading to glucose intorelance (Diabetes 2002).In the present study, we investigated glycerol and glucose metabolism in mice lacking AQPap and demonstrated that AQPap functions as a glycerol gateway molecule in vivo. AQPap knockout(KO) mice had lower plasma glycerol levels compared with wild-type(WT) mice but had normal plasma free fatty acid levels. The increase in plasma glycrol level in response to _-adrenergic agonist was severely impaired in KO mice. Epinephrin-stimulated glycerol secretion was also impaired in AQPap knockdown adipocytes. During prolonged fasting, plasma glycerol was elevated and the plasma glucose level was maintained in WT mice. In contrast, KO mice showed a disrupted increase of plasma glycerol and rapid reduction of plasma glucose during prolonged fasting. These findings suggest that the lack of effective glycerol transport from adipocytes by glycerol gateway molecule causes defective adaptation to prolonged fasting. (PNAS 2004).