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. 2017 Jun;8(3):417-427.
doi: 10.1002/jcsm.12169. Epub 2016 Dec 26.

Anorexia-cachexia Syndrome in Hepatoma Tumour-Bearing Rats Requires the Area Postrema but Not Vagal Afferents and Is Paralleled by Increased MIC-1/GDF15

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Anorexia-cachexia Syndrome in Hepatoma Tumour-Bearing Rats Requires the Area Postrema but Not Vagal Afferents and Is Paralleled by Increased MIC-1/GDF15

Tito Borner et al. J Cachexia Sarcopenia Muscle. .
Free PMC article

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.

Keywords: AP-lesion; Brainstem; Cancer; Energy balance; Food intake; Muscle; Subdiaphragmatic vagal deafferentation.

Figures

Figure 1
Figure 1
Tumour‐induced body weight loss and muscle degradation are partly independent of anorexia. (A–C) Tumour‐bearing rats developed anorexia and lost body weight. Pair‐feeding only led to an attenuation of body weight gain that was calculated by subtracting the body weight at the time of tumour induction from the body weight at the end of the experiment. (D) Tumour‐bearing animals had lower lean and fat carcass mass compared with both control groups. (E) Tumour‐bearing rats had lower gastrocnemius and tibialis muscle mass compared with Non‐Tumour‐bearing animals and lower gastrocnemius muscle mass compared with the pair‐fed group. Data analysed with Student's t‐test (A) or with one‐way ANOVA followed by Tukey's post‐hoc test (B–E). Means with different letter or symbols are significantly different from each other; * P < 0.05, ** P < 0.01, *** P < 0.001, same for # and §).
Figure 2
Figure 2
Tumour growth reduced metabolic rate without affecting locomotor activity. Tumour‐bearing rats developed anorexia (A) and showed reduced body weight gain (B), but did not show differences in metabolic rate (C) or locomotor activity (D), except during Week 3 in which tumour‐bearing rats showed reduced metabolic rate. Data analysed with Student's t‐test (A–B), * P < 0.05, ** P < 0.01, *** P < 0.001. Data analysed with one‐way ANOVA followed by Tukey's post‐hoc test (C–D). Means with different letters are significantly different from each other (P < 0.05).
Figure 3
Figure 3
Lesion of the area postrema attenuated anorexia, body weight loss and muscle degradation induced by tumour growth. (A–B) Area postrema lesioned (APX) animals were protected against tumour‐induced anorexia and showed markedly attenuated body weight loss following tumour induction. (C) Area postrema lesioned rats show higher gastrocnemius and soleus mass compared to area postrema‐sham lesioned (sham‐APX) tumour‐bearing animals. (D) Coronal sections of the area postrema/nucleus tractus solitarii of a sham‐lesioned control (upper image) and an area postrema lesioned animal (lower image). AP, area postrema; NTS, nucleus tractus solitarii; DMN, dorsal motor nucleus of the vagus; Gr, gracile nucleus; CC, central canal. Data analysed with one‐way ANOVA followed by Tukey's post‐hoc test (A–B), means with different letters are significantly different from each other (P < 0.05). Changes in food intake, differences in body weight change between Weeks 2 and 4, and muscle weights were analysed using the Student's t‐test (A‐C), * P < 0.05, ** P < 0.01, *** P < 0.001.
Figure 4
Figure 4
Subdiaphragmatic vagal deafferentation did not attenuate cancer‐anorexia‐cachexia syndrome. (A) Tumour growth induced a strong anorectic response in both subdiaphragmatic vagal deafferentation (SDA) and sham‐operated (sham‐SDA) animals. (B) In both groups anorexia was paralleled by a similar reduction of body weight gain in Week 2 and a net body weight loss in Week 3. (C) Schematic illustration of afferent and efferent vagal fibres targeted by the subdiaphragmatic vagal deafferentation and of the procedures used to verify its completeness. The subdiaphragmatic vagal deafferentation consists in a left intracranial rhizotomy of all dorsal vagal fibres (i.e. afferent) (1) and a complete subdiaphragmatic dissection (afferent and efferent fibers) of the left trunk of the vagus nerve (2). With this surgical procedure all vagal afferents are dissected, leaving 50% of the vagal efferents intact. Biotinylated dextran amine (BDA) was applied directly into the nodose ganglion of the vagus nerve 5 days prior to sacrifice (3). Fluorogold (FG) was injected intraperitoneally 48 h prior to sacrifice (4). D–E) Coronal sections of the area postrema/nucleus tractus solitarii region of a sham‐lesioned control and a subdiaphragmatic vagal deafferentation animal. (D) While biotinylated dextran amine‐positive fibers were present in the nucleus tractus solitarii of sham rats, no labelling was observed in the nucleus tractus solitarii of subdiaphragmatic vagal deafferentation animals. (E) While bilateral Fluorogold staining in the dorsal motor nucleus (DMN) of sham rats was observed, only unilateral staining of the dorsal motor nucleus occurred in subdiaphragmatic vagal deafferentation animals. CC, central canal. One‐way ANOVA followed by Tukey's post‐hoc test, means with different letters are significantly different from each other (P < 0.05).
Figure 5
Figure 5
Macrophage inhibitory cytokine‐1 levels increased with tumour progression and correlated with tumour size and the severity of anorexia (A) macrophage inhibitory cytokine‐1 plasma levels were significantly higher in tumour‐bearing rats compared to controls at the end of the experiment. (B) macrophage inhibitory cytokine‐1 levels were elevated 11 days after tumour induction (i.e. 3 days after anorexia onset) and further increased with cancer progression. (C) Macrophage inhibitory cytokine‐1 levels correlated with tumour weight. (D) Macrophage inhibitory cytokine‐1 levels negatively correlated with food intake during tumour growth. Data analysed with one‐way ANOVA followed by Tukey's post‐hoc test (A–B), means with different letters are significantly different from each other (P < 0.05).

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