Differences in food intake of tumour‐bearing cachectic mice are associated with hypothalamic serotonin signalling

Abstract

BackgroundAnorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation.MethodsTwo tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips).ResultsIn both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion.ConclusionsAltered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a therapeutic target to prevent the development of cancer-induced eating disorders.

Prevention of body weight loss and sarcopenia by a novel selective androgen receptor modulator in cancer cachexia models

“…The mouse allograft model of C26 adenocarcinoma is a well-established model for investigating body weight loss caused by cancer cachexia (16)(17)(18). We found that SARM-2f at doses of 10, 30, and 100 mg/kg increased the body (1.1-fold, 1.1-fold, and 1.1-fold, respectively), carcass (1.1-fold, 1.1-fold, and 1.1-fold, respectively), and levator ani muscle weights (3.3-fold, 2.9-fold, and 3.8-fold respectively) in the castrated mice (Fig.…”

Hypothalamic inflammation and food intake regulation during chronic illness

“…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. 1).…”

“…Furthermore, these effects of serotonin on feeding and NPY levels are not apparently accomplished via affecting NPY gene expression [154,155]. Also in vitro, serotonin inhibits neuronal NPY secretion, while not affecting NPY gene expression [93]. Therefore, serotonin appears to play an active role in posttranscriptional failure of NPY in anorexia in chronic inflammation.…”

“…Hypothalamic serotonin is suggested to act as an integrator of peripheral triggers modulating energy balance, as it responds to changes in adipokines [126,127] and gut-derived hormones [128,129] and subsequently mediates anorexigenic signalling. Therefore, elevated hypothalamic serotonin levels are suggested to play a crucial role in the development of disease-associated anorexia [5,93,95] (Fig. 1).…”

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

“…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. Ghrelin produces its effects by stimulating nitric oxide synthase 42.…”