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，避免长期的代谢紊乱。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毁灭性的营养不良状态会出现，这是由食欲急剧下降和脂肪和瘦体重代谢增加的协同作用造成的。这种组合存在于许多疾病中，包括癌症、囊性纤维化、艾滋病、类风湿关节炎和肾衰竭，并且是这些疾病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，但参与转导这一信号的神经元系统尚未完全定义。在这个实验室和其他实验室的工作

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.