Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling [A286_GEO_LLM]

Background: Anorexia 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. Methods: Two 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). Results: In 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. Conclusions: Altered 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. Lewis Lung tumour cells were intramuscularly inoculated 6w old male C57BL/6 mice. Body weight and food intake were measured 3 times a week. On day 10, 14 and 17 hypothalamus was dissected and used for gene expression profiling.

背景：食欲减退（Anorexia）是癌症患者的常见症状，可诱发营养不良，并严重损害生活质量。目前认为，肿瘤诱导的食欲减退源于肿瘤生长过程中，下丘脑（hypothalamus）内的进食调控系统无法对能量负平衡做出充分应答。本研究证实，进食调控的这种应答受损，可能由5-羟色胺（serotonin）信号通路异常，以及转录后神经肽Y（NPY）调控失败所介导。
方法：本研究采用两种进食行为存在差异的肿瘤恶病质（tumour cachexia）小鼠模型：分别为进食量增加的C26结肠腺癌模型，以及进食量减少的路易斯肺癌（Lewis lung carcinoma）模型。本研究利用两种荷瘤（tumour-bearing, TB）小鼠在面对不同肿瘤生长时的进食行为差异，来区分恶病质相关进程与进食调控的关键机制。本研究以下丘脑组织进行转录组学（transcriptomics）分析，所用平台为Affymetrix芯片。
结果：在两种模型中，下丘脑内促食欲神经肽Y（NPY）的表达量均显著高于对照组，提示该变化并非直接反映进食状态，而是可能与恶病质中的能量负平衡相关。参与5-羟色胺信号通路的基因表达，在C26荷瘤小鼠与路易斯肺癌荷瘤小鼠间存在差异，且与进食量呈负相关。体外实验中，通过下丘脑细胞系观察到，5-羟色胺可抑制下丘脑神经元的NPY分泌，但不影响NPY的信使RNA（messenger RNA, mRNA）表达，提示5-羟色胺信号通路可干扰NPY的合成、转运或分泌。
结论：肿瘤恶病质荷瘤小鼠中，5-羟色胺信号通路异常与进食行为改变相关。癌症恶病质状态下，5-羟色胺对进食的抑制作用可能通过调控NPY系统实现。因此，调控5-羟色胺信号通路或可作为预防肿瘤诱导性进食障碍的治疗靶点。
实验细节：将路易斯肺癌细胞肌肉接种于6周龄雄性C57BL/6小鼠；每周测量3次小鼠体重与进食量；分别于接种后第10、14、17天取下丘脑组织，用于基因表达谱分析。