Hypothalamic food intake regulation in a cancer‐cachectic mouse model

Abstract

BackgroundAppetite is frequently affected in cancer patients leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer-cachectic mouse model with increased food intake. In this model, mice bearing C26 tumour have an increased food intake subsequently to the loss of body weight. We hypothesise that in this model, appetite-regulating systems in the hypothalamus, which apparently fail in anorexia, are still able to adapt adequately to changes in energy balance. Therefore, studying changes that occur on appetite regulators in the hypothalamus might reveal targets for treatment of cancer-induced eating disorders. By applying transcriptomics, many appetite-regulating systems in the hypothalamus could be taken into account, providing an overview of changes that occur in the hypothalamus during tumour growth.MethodsC26-colon adenocarcinoma cells were subcutaneously inoculated in 6 weeks old male CDF1 mice. Body weight and food intake were measured three times a week. On day 20, hypothalamus was dissected and used for transcriptomics using Affymetrix chips.ResultsFood intake increased significantly in cachectic tumour-bearing mice (TB), synchronously to the loss of body weight. Hypothalamic gene expression of orexigenic neuropeptides NPY and AgRP was higher, whereas expression of anorexigenic genes CCK and POMC were lower in TB compared to controls.In addition, serotonin and dopamine signalling pathways were found to be significantly altered in TB mice. Serotonin levels in brain showed to be lower in TB mice compared to control mice, while dopamine levels did not change. Moreover, serotonin levels inversely correlated with food intake.ConclusionsTranscriptomic analysis of the hypothalamus of cachectic TB mice with an increased food intake showed changes in NPY, AgRP and serotonin signalling. Serotonin levels in the brain showed to correlate with changes in food intake. Further research has to reveal whether targeting these systems will be a good strategy to avoid the development of cancer-induced eating disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s13539-013-0121-y) contains supplementary material.

Hypothalamic inflammation and food intake regulation during chronic illness

“…These data suggest that NPY release is necessary to adapt food intake to changes in energy expenditure. Paradoxically, hypothalamic NPY gene expression is reported to be increased in animal models for chronic inflammatory diseases that are characterized by the presence of cachexia, such as cancer cachexia and arthritis [86][87][88][89][90][91]. However, this increase in mRNA levels did not correspond to the decrease in food intake [87,89,[91][92][93] (Fig.…”

“…Consequently, counteracting the activation of the melanocortin system by MC4R antagonism prevented the development of LPS-induced anorexia [102,104,105]. In contrast to an acute immune response, during chronic inflammation such as in cancer, hypothalamic POMC expression is decreased [90,106]. These opposing differences on POMC expression in acute and chronic inflammation might be explained by changes in leptin plasma levels in these two conditions: LPS administration elevates plasma leptin [107], while in diseases characterized by the presence of cachexia, plasma leptin levels drop [108].…”

Anorexia of ageing: a key component in the pathogenesis of both sarcopenia and cachexia

“…The central regulation of feeding is a very complicated process 37. Multiple monoamines (especially serotonin and norepinephrine) and neuropeptides (e.g.…”

“…Multiple monoamines (especially serotonin and norepinephrine) and neuropeptides (e.g. neuropeptide Y, melanocortin, corticotrophin‐releasing factor) converge on the nitric oxide/methylmalnyl coenzyme A system to modulate food intake 16, 37, 38, 39, 40. Serotonin is a particularly anorectic agent, and in cancer, the effect of serotonin is potentiated 41.…”

“…Persons with illnesses are apt to develop depression with an increase in the anorectic neurotransmitters, serotonin and corticotrophin‐releasing factor 37, 38…”