Wanders Desiree, Stone Kirsten P, Forney Laura A, Cortez Cory C, Dille Kelly N, Simon Jacob, Xu Mark, Hotard Elisabeth C, Nikonorova Inna A, Pettit Ashley P, Anthony Tracy G, Gettys Thomas W
Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA.
Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ.
Diabetes. 2016 Jun;65(6):1499-510. doi: 10.2337/db15-1324. Epub 2016 Mar 2.
Restricting availability of essential amino acids (EAAs) limits aminoacylation of tRNAs by their cognate EAAs and activates the nutrient-sensing kinase, general control nonderepressible 2 (GCN2). Activated GCN2 phosphorylates eukaryotic initiation factor 2 (eIF2), altering gene-specific translation and initiating a transcriptional program collectively described as the integrated stress response (ISR). Central GCN2 activation by EAA deprivation is also linked to an acute aversive feeding response. Dietary methionine restriction (MR) produces a well-documented series of physiological responses (increased energy intake and expenditure, decreased adiposity, and increased insulin sensitivity), but the role of GCN2 in mediating them is unknown. Using Gcn2(-/-) mice, we found that the absence of GCN2 had no effect on the ability of MR to reduce body weight or adiposity, increase energy intake and expenditure, increase hepatic transcription and release of fibroblast growth factor 21, or improve insulin sensitivity. Interestingly, hepatic eIF2 phosphorylation by MR was uncompromised in Gcn2(-/-) mice. Instead, protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) was activated in both intact and Gcn2(-/-) mice. PERK activation corresponded with induction of the ISR and the nuclear respiratory factor 2 antioxidant program but not ER stress. These data uncover a novel glutathione-sensing mechanism that functions independently of GCN2 to link dietary MR to its metabolic phenotype.
限制必需氨基酸（EAA）的可利用性会限制其同源EAA对tRNA的氨酰化作用，并激活营养感应激酶——一般控制非抑制性2（GCN2）。被激活的GCN2会使真核起始因子2（eIF2）磷酸化，改变基因特异性翻译并启动一个统称为综合应激反应（ISR）的转录程序。EAA剥夺引起的核心GCN2激活也与急性厌恶性摄食反应有关。饮食蛋氨酸限制（MR）会产生一系列有充分记录的生理反应（能量摄入和消耗增加、肥胖减少以及胰岛素敏感性增加），但GCN2在介导这些反应中的作用尚不清楚。利用Gcn2基因敲除小鼠，我们发现GCN2的缺失对MR减轻体重或肥胖、增加能量摄入和消耗、增加肝脏成纤维细胞生长因子21的转录和释放或改善胰岛素敏感性的能力没有影响。有趣的是，在Gcn2基因敲除小鼠中，MR引起的肝脏eIF2磷酸化并未受损。相反，蛋白激酶R样内质网（ER）激酶（PERK）在完整小鼠和Gcn2基因敲除小鼠中均被激活。PERK激活与ISR的诱导以及核呼吸因子2抗氧化程序相关，但与内质网应激无关。这些数据揭示了一种新的谷胱甘肽感应机制，该机制独立于GCN2发挥作用，将饮食MR与其代谢表型联系起来。
