title: Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15.
abstract: BACKGROUND
  The cancer-anorexia-cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour-derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour-derived macrophage inhibitory cytokine-1 (MIC-1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC-1 in mice.
  
  
  METHODS
  Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC-1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response.
  
  
  RESULTS
  In tumour-bearing sham-operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer-induced anorexia or body weight loss. Tumour-bearing rats had substantially increased MIC-1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake.
  
  
  CONCLUSIONS
  These findings demonstrate the importance of the AP in the mediation of cancer-dependent anorexia and body weight loss and support a pathological role of MIC-1 as a tumour-derived factor mediating CACS, possibly via an AP-dependent action.
authors.affiliation: Vetsuisse Faculty, Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Tito
authors.initials: T
authors.lastname: Borner
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Myrtha
authors.initials: M
authors.lastname: Arnold
authors.affiliation: Department of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ruud
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St Vincent's Hospital, University of New South Wales, Sydney, Australia.
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
authors.affiliation: Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Langhans
authors.affiliation: Vetsuisse Faculty, Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Lutz
authors.affiliation: Department of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Blomqvist
authors.affiliation: Vetsuisse Faculty, Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Riediger
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000855:Anorexia / Q000209:etiology* / Q000378:metabolism*; D031608:Area Postrema / Q000378:metabolism*; D001823:Body Composition; D001835:Body Weight; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D064593:Heterografts; D008113:Liver Neoplasms / Q000150:complications* / Q000473:pathology; D008297:Male; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014630:Vagus Nerve / Q000378:metabolism*
chemical_list: D055436:Growth Differentiation Factor 15
keywords: AP-lesion; Brainstem; Cancer; Energy balance; Food intake; Muscle; Subdiaphragmatic vagal deafferentation