Fenofibrate prevents skeletal muscle loss in mice with lung cancer.

Marcus D Goncalves,Benjamin D Hopkins,Chantal Pauli,Douglas T Fearon,Brooke M Emerling,Ryan M Loughran,Guoan Zhang,Zhe Cheng,Seo-Kyoung Hwang,Charles J Murphy,Lewis C Cantley,David Wu

doi:10.1073/pnas.1714703115

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.

Highlights

The authors note that the following statement should be added to the Acknowledgments: “Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award R35CA197588
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 prevalent in nonsmall cell lung cancer (NSCLC)
The loss of body weight included a reduction in skeletal muscle, as demonstrated by significant decrease in gastrocnemius mass (Fig. 1C), and white adipose tissue (WAT), as demonstrated by a significant decrease in the mass of the gonadal fat pad (Fig. 1D) compared with empty adenovirus vector (Empty)-treated mice

Summary

Introduction

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 prevalent in nonsmall cell lung cancer (NSCLC). Using noncachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the loss of peroxisome proliferatoractivated 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. The cancer anorexia cachexia syndrome (CACS) is a systemic metabolic disorder characterized by the catabolism of stored nutrients in muscle and adipose tissue This syndrome is characterized by loss of body weight, reduced food intake, increased markers of systemic inflammation, and progressive functional impairment [1]. The systemic signals leading to skeletal muscle destruction in cancer are unknown; several mechanisms have been proposed, including tumor-released factors [10, 11], tumor-induced changes to the stromal environment [12], up-regulation of inflammatory cytokines [13,14,15], and hormonal dysregulation [16]

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