Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

Abstract

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.

• Authors: Marcus D Goncalves, Seo-Kyoung Hwang, Chantal Pauli, Charles J Murphy, Zhe Cheng, Benjamin D Hopkins, David Wu, Ryan M Loughran, Brooke M Emerling, Guoan Zhang, Douglas T Fearon, Lewis C Cantley
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 4 Pg. E743-E752 (01 23 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29311302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Ketone Bodies
• PPAR gamma
• Mechanistic Target of Rapamycin Complex 1
• Fenofibrate

Topics

• Amino Acids (metabolism)
• Animals
• Cachexia (blood, etiology, prevention & control)
• Carcinoma, Non-Small-Cell Lung (complications)
• Drug Evaluation, Preclinical
• Fenofibrate (pharmacology, therapeutic use)
• Gluconeogenesis
• Ketone Bodies (deficiency)
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Lung Neoplasms (complications)
• Male
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice
• Muscle, Skeletal (drug effects, metabolism, pathology)
• PPAR gamma (agonists, metabolism)