Depletion of White Adipose Tissue in Cancer Cachexia Syndrome Is Associated with Inflammatory Signaling and Disrupted Circadian Regulation

Maria Tsoli,Rudolf Zechner,Stephen Clarke,Anne S Vanniasinghe,Martina Schweiger,Arran Painter,Graham Robertson,Harpal Singh Randeva

doi:10.1371/journal.pone.0092966

Abstract

Involuntary weight loss in patients with cancer is the hallmark of cancer cachexia. The etiology of cachexia is multifactorial involving loss of skeletal muscle and adipose tissue associated with high systemic levels of acute phase proteins and inflammatory cytokines. While muscle wasting overtly impacts on cancer patient quality of life, loss of lipid depots represents a sustained energy imbalance. In this study fat depletion was examined in Colon-26 model of cancer cachexia, which is a widely used rodent model of this syndrome. We investigated diurnal expression of circadian rhythm regulators as well as key mediators of energy metabolism and cytokine signaling. Mice bearing the C26 tumour exhibited reduced adipose mass, elevated adipose tissue lipolysis and a 5-fold increase in plasma levels of free fatty acids. These changes were associated with activated IL-6 signaling in WAT through a 3-fold increase in phosphorylated STAT3 and high SOCS3 gene expression levels. In addition perturbations in circadian regulation of lipid metabolism were also observed. Lipid catabolism did not appear to be influenced by the classical PKA pathway activating the lipase HSL. ATGL protein levels were elevated 2-fold in cachectic mice while 4-fold increase phosphorylated ACC and a 2-fold decrease in phosphorylated 4EBP1 was observed indicating that lipid metabolism is modulated by the ATGL & AMPK/mTOR pathways. This study provides evidence for activation of cytokine signaling and concomitant alterations in circadian rhythm and regulators of lipid metabolism in WAT of cachectic animals.

Highlights

Cancer cachexia syndrome (CCS) is frequently experienced by advanced cancer patients being most prevalent in pancreatic, upper gastrointestinal and lung cancers and accounts for nearly 20% of cancer-related morbidities [1,2]
The reduction in white adipose tissue (WAT) weight was accompanied by an increase in plasma non-esterified fatty acids (NEFA) in cachectic mice (Figure 1G) and a decrease of plasma triglyceride levels (Figure 1H)
One of the most prominent symptoms of cancer cachexia is the involuntary loss of weight due to fat depletion and muscle wasting that cannot be accounted for by reduced food intake

Summary

Introduction

Cancer cachexia syndrome (CCS) is frequently experienced by advanced cancer patients being most prevalent in pancreatic, upper gastrointestinal and lung cancers and accounts for nearly 20% of cancer-related morbidities [1,2]. There are no effective treatments or prognostic tests to indicate those patients at risk of developing cachexia. CCS is a complex metabolic disorder characterized by involuntary weight loss, adipose tissue and skeletal muscle depletion, anorexia and fatigue. Cachexia is often associated with systemic inflammation indicated by elevated plasma CRP and reduced albumin levels [3]. IL-6 has been implicated in the development of cachexia in tumour-bearing rodent models and loss of adipose tissue in cancer patients [9,10] as well as directly stimulating lipolysis in adults [11]. The Colon-26 (C26) carcinoma is a well-established murine model of cancer cachexia resulting in high systemic levels of IL-6. Administration of agents that inhibit IL-6 signaling prevent wasting and other features of cachexia in several animal models of cachexia including Colon 26 [12,13,14]

Methods

Results

Conclusion