Goncalves, M. D., Hwang, S. K., Pauli, C., Murphy, C. J., Cheng, Z., Hopkins, B. D., Wu, D., Loughran, R. M., Emerling, B. M., Zhang, G., Fearon, D. T., Cantley, L. C. (January 2018) Fenofibrate prevents skeletal muscle loss in mice with lung cancer. Proc Natl Acad Sci U S A, 115 (4). E743-E752. ISSN 0027-8424
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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-alpha (PPARalpha) -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 PPARalpha 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.
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