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Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

  • Goncalves MD Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Hwang SK Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Pauli C Institute for Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Murphy CJ Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Cheng Z Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021.
  • Hopkins BD Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Wu D Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Loughran RM Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Emerling BM Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Zhang G Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021.
  • Fearon DT Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • Cantley LC Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021; lcantley@med.cornell.edu.
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  • 2018-01-10
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2018
cachexia
fenofibrate
glucocorticoids
ketones
skeletal muscle
Amino Acids
Animals
Cachexia
Carcinoma, Non-Small-Cell Lung
Drug Evaluation, Preclinical
Fenofibrate
Gluconeogenesis
Ketone Bodies
Lipid Metabolism
Liver
Lung Neoplasms
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Muscle, Skeletal
PPAR gamma
English 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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/191290
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