Moreno-Arriola Elizabeth, El Hafidi Mohammed, Ortega-Cuéllar Daniel, Carvajal Karla
Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Mexico City, Mexico.
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología, Mexico City, Mexico.
PLoS One. 2016 Jan 29;11(1):e0148089. doi: 10.1371/journal.pone.0148089. eCollection 2016.
Cellular energy regulation relies on complex signaling pathways that respond to fuel availability and metabolic demands. Dysregulation of these networks is implicated in the development of human metabolic diseases such as obesity and metabolic syndrome. In Caenorhabditis elegans the AMP-activated protein kinase, AAK, has been associated with longevity and stress resistance; nevertheless its precise role in energy metabolism remains elusive. In the present study, we find an evolutionary conserved role of AAK in oxidative metabolism. Similar to mammals, AAK is activated by AICAR and metformin and leads to increased glycolytic and oxidative metabolic fluxes evidenced by an increase in lactate levels and mitochondrial oxygen consumption and a decrease in total fatty acids and lipid storage, whereas augmented glucose availability has the opposite effects. We found that these changes were largely dependent on the catalytic subunit AAK-2, since the aak-2 null strain lost the observed metabolic actions. Further results demonstrate that the effects due to AAK activation are associated to SBP-1 and NHR-49 transcriptional factors and MDT-15 transcriptional co-activator, suggesting a regulatory pathway that controls oxidative metabolism. Our findings establish C. elegans as a tractable model system to dissect the relationship between distinct molecules that play a critical role in the regulation of energy metabolism in human metabolic diseases.
细胞能量调节依赖于复杂的信号通路，这些通路对燃料可用性和代谢需求做出反应。这些网络的失调与肥胖和代谢综合征等人类代谢疾病的发展有关。在秀丽隐杆线虫中，AMP激活的蛋白激酶AAK与长寿和抗应激能力有关；然而，其在能量代谢中的精确作用仍不清楚。在本研究中，我们发现AAK在氧化代谢中具有进化保守作用。与哺乳动物相似，AAK被AICAR和二甲双胍激活，并导致糖酵解和氧化代谢通量增加，表现为乳酸水平升高、线粒体氧消耗增加以及总脂肪酸和脂质储存减少，而葡萄糖可用性增加则具有相反的效果。我们发现这些变化在很大程度上依赖于催化亚基AAK-2，因为aak-2基因敲除菌株失去了观察到的代谢作用。进一步的结果表明，AAK激活所产生的效应与SBP-1和NHR-49转录因子以及MDT-15转录共激活因子有关，提示存在一条控制氧化代谢的调节途径。我们的研究结果确立了秀丽隐杆线虫作为一个易于处理的模型系统，用于剖析在人类代谢疾病能量代谢调节中起关键作用的不同分子之间的关系。
