Hypothalamic Mechanisms in Cachexia

为了实现正常的生长、发育和生活质量，个体必须保持足够的营养摄入，并且免于长期的代谢紊乱。不幸的是，患有急性或慢性疾病的人往往表现出营养平衡失调。在某些情况下，一种被称为恶病质的营养不良的破坏性状态出现，由食欲急剧下降和脂肪和瘦体重代谢增加的协同组合引起。这种组合存在于许多疾病中，包括癌症、囊性纤维化、AIDS、类风湿性关节炎和肾衰竭，并且是这些病症中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诱导的厌食症和恶病质中的重要性，但是参与转导这种信号的神经系统尚未完全确定。在这个实验室和其他实验室的工作 表明下丘脑黑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中起关键作用。刺激下丘脑黑皮质素-4受体（MC 4-R）产生相对的厌食症，而该受体的长期拮抗作用刺激进食并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，MC 4-R的阻断导致恶病质的显著减弱。我们还证明，黑皮质素-3受体（MC 3-R）的阻断导致疾病相关性恶病质增强，而MC 3-R的刺激导致食物摄入增加。目前的研究目标分为两个一般领域，如本补助金所述。首先，我们将研究MC 3-R在急性和慢性恶病质中的贡献和独特功能。其次，循环细胞因子和肿瘤衍生因子激活下丘脑黑皮质素系统的机制将被定义。此外，将在中枢黑皮质素功能的背景下研究对马槟榔碱介导的厌食症的习惯化过程。最终，这项工作可能会导致对这一广泛的医学问题的药物治疗的调查。

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.