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

BackgroundThe 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.MethodsUsing 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.ResultsIn 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.ConclusionsThese 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.

The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

“…The major brain regions mediating this anorexigenic effect are the AP and the NTS. Systemic MIC-1/GDF15 administration induces rapid neuronal activation at these two sites (Johnen et al, 2007;Tsai et al, 2014;Yang et al, 2017;Mullican et al, 2017;Emmerson et al, 2017;Hsu et al, 2017;Xiong et al, 2017), and selective surgical lesioning of the AP/NTS renders rodents unresponsive to the anorexigenic effects of MIC-1/GDF15 (Tsai et al, 2014;Borner et al, 2017). Consistent with this, the major site of expression of the recently identified MIC-1/GDF15 receptor GFRAL is largely confined to these two hindbrain regions (Yang et al, 2017;Mullican et al, 2017;Emmerson et al, 2017;Hsu et al, 2017).…”

“…It may reduce gastric motility (Xiong et al, 2017), and there is some immunohistochemical evidence that it may bind to neuronal structures in the wall of the stomach colon and jejunum, which could be hypothesized to reduce food intake via vagal afferent pathways. However, contrary to this hypothesis, MIC-1/GDF15 does not require vagal input to reduce food intake, as selective vagotomy, if anything, enhanced rather than inhibited its anorexic actions (Yang et al, 2017;Borner et al, 2017). In obesity, MIC-1/GDF15 also increases lipolysis, oxidative metabolism, and thermogenesis, while reducing inflammation and insulin resistance by actions that are more likely to be indirect (Tsai et al, 2018;Chrysovergis et al, 2014;Wang et al, 2014aWang et al, , 2014bChung et al, 2017b).…”

Skeletal muscle wasting in chronic heart failure

“…34 Another contributing factor to sarcopenia is a variable degree of malnutrition 56 that may be caused by inflammatory cytokines, 57-59 which have been known to contribute to anorexia in chronic disease. [60][61][62][63] Malnutrition and sarcopenia are also common features of rehabilitation patients in whom the prevalence of malnutrition was 49-67% and that of sarcopenia 40-46.5%. 64 Malnutrition and sarcopenia have also been shown to be associated with early post-liver transplant morbidity/mortality, yet allocation indices do not include nutritional status.…”

Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat

“…The hepatoma tumour model and the Morris hepatoma 7777 cell culture procedures were described previously (Borner et al, 2016a).…”

“…CACS increases mortality, reduces treatment success and produces severe psychological suffering of patients and their families (Gordon et al, 2005;Kauth and Metz, 1987). We recently demonstrated the importance of the area postrema (AP) of the brainstem for the mediation of CACS in hepatoma tumour-bearing (TB) rats (Borner et al, 2016a). In order to identify a possible therapeutic target, our current study aimed to explore the role of the neuropeptide glucagon-like peptide-1 (GLP-1)…”