Laviano A, Meguid M M, Yang Z J, Gleason J R, Cangiano C, Rossi Fanelli F
Department of Surgery, SUNY Health Science Center, Syracuse 13210, USA.
Nutrition. 1996 Oct;12(10):706-10. doi: 10.1016/s0899-9007(96)00164-5.
During tumor growth, anorexia and reduced food intake are among the major causes leading to malnutrition and eventually cachexia, which negatively affect patients' outcome. Consistent evidence from our laboratories in rats and humans indicates a key role for ventromedial hypothalamic (VMH) serotonergic system in the development of cancer anorexia. Thus, we postulated that during cancer, increased plasma tryptophan levels (the precursor of serotonin) lead to increased cerebrospinal fluid tryptophan concentrations and increased VMH serotonin synthesis, which then mediates the occurrence of anorexia. However, recent data strongly suggest that factors other than tryptophan supplied to the central nervous system might be involved in the pathogenesis of reduced food intake during tumor growth. Particularly, a significant role appears to be played by interleukin-1 (IL-1). We recently showed that IL-1 infusion in normal rats causes changes in food intake and its determinants, meal number and meal size, similar to those characterizing cancer anorexia, thus supporting the involvement of this cytokine in the development of anorexia. Interestingly, IL-1 and the VMH serotonergic system appear to be closely linked: peripherally infused IL-1 increases brain tryptophan and serotonin concentrations, while intracerebrally infused IL-1 increases neuronal firing rate and serotonin release. We therefore hypothesize that during tumor growth, increased production/secretion of IL-1 occurs, which facilitates the tryptophan supply to the brain. IL-1 can then also act on the VHM itself, where IL-1 receptors exist, to increase its neuronal activity and serotonin release. In other words, we believe that centrally acting IL-1 increases hypothalamic neuronal firing rate and serotonin release, while peripherally acting IL-1 is critical in supplying the hypothalamus with the precursor, tryptophan, in order to maintain the high rate of serotonin synthesis. Also, additional factors recently proposed as mediators of anorexia (including neuropeptide Y and nitric oxide) appear to be part of the hypothesized pathogenic mechanism.
在肿瘤生长过程中，厌食和食物摄入量减少是导致营养不良并最终发展为恶病质的主要原因之一，这会对患者的预后产生负面影响。我们实验室在大鼠和人类身上获得的一致证据表明，腹内侧下丘脑（VMH）的血清素能系统在癌症厌食症的发展中起关键作用。因此，我们推测在癌症期间，血浆色氨酸水平升高（血清素的前体）会导致脑脊液色氨酸浓度升高以及VMH血清素合成增加，进而介导厌食症的发生。然而，最近的数据强烈表明，供应给中枢神经系统的色氨酸以外的因素可能参与了肿瘤生长期间食物摄入量减少的发病机制。特别是，白细胞介素-1（IL-1）似乎起着重要作用。我们最近发现，向正常大鼠输注IL-1会导致食物摄入量及其决定因素、进餐次数和进餐量发生变化，类似于癌症厌食症的特征，从而支持了这种细胞因子参与厌食症的发展。有趣的是，IL-1与VMH血清素能系统似乎密切相关：外周注射IL-1会增加大脑色氨酸和血清素浓度，而脑内注射IL-1会增加神经元放电率和血清素释放。因此，我们假设在肿瘤生长期间，IL-1的产生/分泌增加，这有助于色氨酸供应到大脑。然后IL-1也可以作用于存在IL-1受体的VHM本身，以增加其神经元活性和血清素释放。换句话说，我们认为中枢作用的IL-1会增加下丘脑神经元放电率和血清素释放，而外周作用的IL-1对于向下丘脑供应前体色氨酸以维持高血清素合成率至关重要。此外，最近提出的作为厌食症介质的其他因素（包括神经肽Y和一氧化氮）似乎也是假设的致病机制的一部分。
