Excessive glucose production by the liver is a key factor in the hyperglycemia observed in type 2 diabetes mellitus (T2DM). Here, we highlight a novel role of liver kinase B1 (Lkb1) in this regulation. We show that mice with a hepatocyte-specific deletion of Lkb1 have higher levels of hepatic amino acid catabolism, driving gluconeogenesis. This effect is observed during both fasting and the postprandial period, identifying Lkb1 as a critical suppressor of postprandial hepatic gluconeogenesis. Hepatic Lkb1 deletion is associated with major changes in whole-body metabolism, leading to a lower lean body mass and, in the longer term, sarcopenia and cachexia, as a consequence of the diversion of amino acids to liver metabolism at the expense of muscle. Using genetic, proteomic and pharmacological approaches, we identify the aminotransferases and specifically Agxt as effectors of the suppressor function of Lkb1 in amino acid-driven gluconeogenesis.

肝脏产生过多的葡萄糖是 2 型糖尿病 (T2DM) 中观察到的高血糖的关键因素。在这里，我们强调了肝激酶 B1 (Lkb1) 在该调节中的新作用。我们表明，肝细胞特异性Lkb1缺失的小鼠具有更高水平的肝氨基酸分解代谢，从而驱动糖异生。在禁食和餐后期间均观察到这种效应，表明 Lkb1 是餐后肝糖异生的关键抑制因子。肝Lkb1缺失与全身代谢的重大变化有关，导致瘦体重降低，从长远来看，肌肉减少症和恶病质是氨基酸转移到肝脏代谢而牺牲肌肉的结果。使用遗传、蛋白质组学和药理学方法，我们确定了氨基转移酶，特别是 Agxt 作为 Lkb1 在氨基酸驱动的糖异生中的抑制功能的效应物。