title: Depletion of white adipose tissue in cancer cachexia syndrome is associated with inflammatory signaling and disrupted circadian regulation.
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.
authors.affiliation: Experimental Therapeutics, Children's Cancer Institute for Medical Research, Randwick, NSW, Australia; Cancer Pharmacology Unit, Anzac Research Institute, Concord Repatriation General Hospital, Concord West, NSW, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Tsoli
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: Experimental Therapeutics, Children's Cancer Institute for Medical Research, Randwick, NSW, Australia; Cancer Pharmacology Unit, Anzac Research Institute, Concord Repatriation General Hospital, Concord West, NSW, Australia.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Vanniasinghe
authors.affiliation: Cancer Pharmacology Unit, Anzac Research Institute, Concord Repatriation General Hospital, Concord West, NSW, Australia.
authors.forename: Arran
authors.initials: A
authors.lastname: Painter
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Northern Clinical School, University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.affiliation: Cancer Pharmacology Unit, Anzac Research Institute, Concord Repatriation General Hospital, Concord West, NSW, Australia; Tumorkine Research, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Robertson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D052436:Adipose Tissue, White / Q000473:pathology*; D000818:Animals; D002100:Cachexia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D003110:Colonic Neoplasms / Q000473:pathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D050155:Lipogenesis; D008066:Lipolysis; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D015850:Interleukin-6; D010750:Phosphoproteins; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases