Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA; Institute for Innovation, Ajinomoto Co. Inc., Japan.
Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA.
Mol Metab. 2018 Nov;17:61-70. doi: 10.1016/j.molmet.2018.08.002. Epub 2018 Aug 11.
AMP activated protein kinase (AMPK) is recognized as an important nutrient sensor contributing to regulation of cellular, tissue, and systemic metabolism. We aimed to identify specific amino acids which could modulate AMPK and determine effects on cellular and systemic metabolism.
We performed an unbiased amino acid screen to identify activators of AMPK. Detailed analysis of cellular signaling and metabolism was performed in cultured hepatoma cells, and in vivo glucose metabolism and metabolomic patterns were assessed in both chow-fed mice and mice made obese by high-fat diet feeding.
Alanine acutely activates AMP kinase in both cultured hepatic cells and in liver from mice treated in vivo with Ala. Oral alanine administration improves systemic glucose tolerance in both chow and high fat diet fed mice, with reduced efficacy of Ala in mice with reduced AMPK activity. Our data indicate that Ala activation of AMPK is mediated by intracellular Ala metabolism, which reduces TCA cycle metabolites, increases AMP/ATP ratio, and activates NH generation.
Ala may serve as a distinct amino acid energy sensor, providing a positive signal to activate the beneficial AMPK signaling pathway.
AMP 激活的蛋白激酶（AMPK）被认为是一种重要的营养传感器，有助于调节细胞、组织和全身代谢。我们旨在确定能够调节 AMPK 的特定氨基酸，并确定其对细胞和全身代谢的影响。
我们进行了一项无偏的氨基酸筛选，以确定 AMPK 的激活剂。在培养的肝癌细胞中进行了细胞信号和代谢的详细分析，并在正常饮食喂养的小鼠和高脂肪饮食喂养肥胖的小鼠中评估了体内葡萄糖代谢和代谢组学模式。
丙氨酸在培养的肝细胞和体内用 Ala 处理的小鼠肝脏中均可急性激活 AMP 激酶。口服丙氨酸可改善正常饮食和高脂肪饮食喂养小鼠的全身葡萄糖耐量，而在 AMPK 活性降低的小鼠中，Ala 的疗效降低。我们的数据表明，Ala 对 AMPK 的激活是通过细胞内 Ala 代谢介导的，这降低了 TCA 循环代谢物，增加了 AMP/ATP 比，并激活了 NH 的产生。
Ala 可能作为一种独特的氨基酸能量传感器，提供激活有益的 AMPK 信号通路的正信号。
