Hypothalamic Mechanisms in Cachexia

为了实现正常的生长、发育和生活质量，个人必须保持足够的营养摄入量，并且不受长期代谢紊乱的影响。不幸的是，患有急性病或慢性病的人往往表现出营养平衡失调。在某些情况下，会出现一种称为恶病质的破坏性营养不良状态，这是食欲急剧下降和脂肪代谢和瘦体重增加的协同作用造成的。这种组合在包括癌症、囊性纤维化、艾滋病、类风湿性关节炎和肾功能衰竭在内的许多疾病中都存在，是这些情况下发病率和死亡率的重要决定因素。实验模型已经证明了细胞因子在介导疾病引起的厌食症和恶病质中的重要性，但参与传递这一信号的神经系统还没有完全确定。在这个实验室和其他实验室的工作 研究表明，下丘脑黑素皮质素受体在调节摄食行为、线性生长、代谢率和胰岛素敏感性方面发挥关键作用。刺激下丘脑黑素皮质素-4受体(MC4-R)会产生相对的厌食症，而该受体的长期拮抗会刺激进食，导致过度的体重增加和生长。最近，我们已经能够证明在急性和慢性疾病模型中，阻断MC4-R导致恶病质的显著减轻。我们还证明，阻断黑素皮质素-3受体(MC3-R)会导致与疾病相关的恶病质增加，而刺激MC3-R会导致食物摄入量增加。目前的研究目标大致分为两个领域，正如这项拨款所描述的那样。首先，我们将探讨MC3-R在急慢性恶病质发病中的作用和独特作用。其次，将确定循环细胞因子和肿瘤衍生因子激活下丘脑黑素皮质素系统的机制。此外，对细胞因子介导的厌食症的习惯化过程将在中枢黑素皮质素功能的背景下进行调查。最终，这项工作可能会导致对这一广泛存在的医学问题的药物治疗的研究。

To achieve normal growth, development, and quality of life, individuals must maintain adequate intake of nutrition and be free from prolonged metabolic derangement. Unfortunately, people affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, and renal failure, and is an important determinant of morbidity and mortality in these conditions. Experimental models have demonstrated the importance of cytokines in mediating illness-induced anorexia and cachexia but the neuronal systems involved in transducing this signal have not been fully defined. Work in this lab and in others has demonstrated that hypothalamic melanocortin receptors play a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. Stimulation of the hypothalamic melanocortin-4 receptor (MC4-R) produces relative anorexia, while prolonged antagonism of this receptor stimulates feeding and results in excessive weight gain and growth. More recently, we have been able to demonstrate that in both acute and chronic disease models, blockade of the MC4-R results in a dramatic attenuation of cachexia. We have also demonstrated that blockade of the melanocortin-3 receptor (MC3-R) leads to enhanced disease-associated cachexia whereas stimulation of the MC3-R leads to increased food intake. Current research goals fall into two general areas as described in this grant. First, we will examine the contribution and unique function the MC3-R in acute and chronic cachexia. Second, the mechanisms by which circulating cytokines and tumor-derived factors activate the hypothalamic melanocortin system will be defined. Additionally, the process of habituation to cytokine-mediated anorexia will be investigated in the context of central melanocortin function. Ultimately, this work may lead to investigation of drug therapy for this widespread medical problem.