Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
Department of Medicine, Weill Cornell Medicine, New York, NY 10021.
Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E743-E752. doi: 10.1073/pnas.1714703115. Epub 2018 Jan 8.
The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in nonsmall cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the present study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferator-activated receptor-α (PPARα) -dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a therapeutic strategy.
癌症恶病质厌食症综合征是一种全身性代谢紊乱，其特征是骨骼肌和脂肪组织中储存营养物质的分解代谢，尤其在非小细胞肺癌（NSCLC）中更为普遍。骨骼肌的丧失会导致功能障碍和死亡率增加。本研究的目的是描述 NSCLC 基因工程小鼠模型中全身代谢的变化。我们发现，其中一部分动物出现骨骼肌丧失、脂肪组织丧失和炎症标志物增加，类似于人类恶病质综合征。我们使用非恶病质和禁食动物作为对照，报告了一种独特的恶病质代谢物表型，包括肝脏中过氧化物酶体增殖物激活受体-α（PPARα）依赖性酮体生成的丧失。在这种情况下，糖皮质激素水平升高，并与骨骼肌降解和肝糖异生标志物相关。使用 PPARα 激动剂非诺贝特恢复酮体生成可防止骨骼肌质量和体重的丧失。这些结果表明，靶向肝脏代谢可以预防肺癌中的肌肉消耗，并为治疗策略提供了证据。
