L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome
L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome
复制标题
DOI：
10.1093/hmg/dds407
复制
发表时间：
2013-01-01
影响因子：
3.5
通讯作者：
Isbrandt, Dirk
中科院分区：
文献类型：
--
作者：
Choe, Chi-un;Nabuurs, Christine;Isbrandt, Dirk
磷酸化肌酸（Cr）可作为能量需求高度波动的器官中ATP补充的能量缓冲。铬在大脑和肌肉中的中心作用被铬缺乏引起的严重神经代谢紊乱所强调。肌酸合成或分布先天性缺陷的常见症状包括智力迟钝和肌肉无力。人类L-精氨酸：甘氨酸脒基转移酶（AGAT）（Cr合成的第一个酶）突变导致Cr和胍基乙酸（GuA）水平严重降低。在这里，我们报告的生成和代谢特性的AGAT缺陷的小鼠，没有铬及其前体瓜。AGAT缺陷小鼠表现出减少脂肪沉积，减弱血管生成，降低胆固醇水平和增强葡萄糖耐量。此外，铬缺乏完全保护从饮食引起的肥胖引起的代谢综合征的发展。生化分析表明，慢性铬依赖性激活的AMP-活化蛋白激酶（AMPK），刺激分解代谢途径的代谢相关组织，如脑，骨骼肌，脂肪组织和肝脏，表明代谢表型的机制。总之，我们的研究结果表明，在第一个AGAT缺乏症动物模型中，Cr缺乏症通过AMPK的慢性激活产生显著的代谢效应。除了深入了解铬缺乏综合征的代谢变化外，我们的遗传模型还揭示了一种新的机制，作为肥胖和2型糖尿病的潜在治疗选择。
Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l-arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus.