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
|
PDF (Paper)
Fearon PNAS 2018.pdf - Published Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (2MB) | Preview |
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | cachexia fenofibrate glucocorticoids ketones skeletal muscle |
| Subjects: | diseases & disorders > nutritional and metabolic diseases diseases & disorders > cancer > cancer types > lung cancer |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Signal Transduction CSHL labs > Fearon lab CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 23 January 2018 |
| Date Deposited: | 12 Jan 2018 15:51 |
| Last Modified: | 26 Oct 2020 16:03 |
| PMCID: | PMC5789923 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35813 |
Actions (login required)
 |
Administrator's edit/view item |
