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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E743-E752. doi: 10.1073/pnas.1714703115. Epub 2018 Jan 8.

Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

Author information

1
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
2
Department of Medicine, Weill Cornell Medicine, New York, NY 10021.
3
Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021.
4
Institute for Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
5
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10021.
6
Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021.
7
CSHL Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
8
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021; lcantley@med.cornell.edu.

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.

KEYWORDS:

cachexia; fenofibrate; glucocorticoids; ketones; skeletal muscle

PMID:
29311302
PMCID:
PMC5789923
DOI:
10.1073/pnas.1714703115
[Indexed for MEDLINE]
Free PMC Article

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