Normal thyroid thermogenesis but reduced viability and adiposity in mice lacking the mitochondrial glycerol phosphate dehydrogenase
Normal thyroid thermogenesis but reduced viability and adiposity in mice lacking the mitochondrial glycerol phosphate dehydrogenase
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DOI：
10.1074/jbc.m202408200
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发表时间：
2002-09-06
影响因子：
4.8
通讯作者：
MacDonald, MJ
中科院分区：
文献类型：
--
作者：
Brown, LJ;Koza, RA;MacDonald, MJ
线粒体甘油磷酸脱氢酶（mGPD）对于糖异生或能量产生的磷酸甘油代谢很重要，并与寒冷和甲状腺激素治疗诱导的产热有关。mGPD与胞质内磷酸甘油脱氢酶（cGPD）结合形成磷酸甘油穿梭体，催化磷酸二羟基丙酮与磷酸甘油的相互转化，胞质内NADH被净氧化。我们对Gdm1进行了靶向缺失，并产生了缺乏mGPD的小鼠。在C57BL/6J基因背景下，这些小鼠的生存能力比野生型小鼠降低了50%。褐色脂肪组织中的解偶联蛋白-1 mRNA水平在mGPD敲除和对照幼崽之间没有差异，表明产热正常。缺乏mGPD的幼崽肝脏ATP减少，肝脏磷酸甘油略有增加。相比之下，成年动物的肝脏和肌肉代谢产物正常。mGPD基因敲除的成年动物具有正常的耐寒性，正常的体温昼夜节律，并表现出对甲状腺激素的正常体温升高。然而，他们的身体质量指数较低，白色脂肪组织的重量减少了40%，空腹血糖也比对照组略低。在mGPD基因敲除动物中，这种表型可能继发于甘油代谢产生的细胞质内NADH的强制性产生。我们得出结论，尽管mGPD对甲状腺产热不是必需的，但其功能的变化会影响小鼠的生存能力和肥胖。
The mitochondrial glycerol phosphate dehydrogenase (mGPD) is important for metabolism of glycerol phosphate for gluconeogenesis or energy production and has been implicated in thermogenesis induced by cold and thyroid hormone treatment. mGPD in combination with the cytosolic glycerol phosphate dehydrogenase (cGPD) is proposed to form the glycerol phosphate shuttle, catalyzing the interconversion of dihydroxyacetone phosphate and glycerol phosphate with net oxidation of cytosolic NADH. We made a targeted deletion in Gdm1 and produced mice lacking mGPD. On a C57BL/6J background these mice showed a 50% reduction in viability compared with wild-type littermates. Uncoupling protein-1 mRNA levels in brown adipose tissue did not differ between mGPD knockout and control pups, suggesting normal thermogenesis. Pups lacking mGPD had decreased liver ATP and slightly increased liver glycerol phosphate. In contrast, liver and muscle metabolites were normal in adult animals. Adult mGPD knockout animals had a normal cold tolerance, normal circadian rhythm in body temperature, and demonstrated a normal temperature increase in response to thyroid hormone. However, they were found to have a lower body mass index, a 40% reduction in the weight of white adipose tissue, and a slightly lower fasting blood glucose than controls. The phenotype may be secondary to consequences of the obligatory production of cytosolic NADH from glycerol metabolism in the mGPD knockout animal. We conclude that, although mGPD is not essential for thyroid thermogenesis, variations in its function affect viability and adiposity in mice.