Hypothalamic Mechanisms in Cachexia

描述（由申请人提供）：恶病质或疾病相关性消瘦在癌症、肾衰竭和感染性疾病中常见。这种破坏性的营养不良状态是由食欲急剧下降和脂肪和瘦体重代谢增加的协同组合带来的。在许多疾病中，恶病质的严重程度是生活质量和最终死亡率的主要决定因素。其他疾病引起的发病率，包括嗜睡和生殖能力丧失，也直接损害患者从可能挽救生命或延长干预措施（包括手术和细胞毒性化疗）中恢复的能力，并可能削弱积极对抗病情的动力。虽然早在两千多年前就有人描述过慢性疾病中的恶病质，但对这种能量稳态紊乱的中枢机制却知之甚少。此外，目前还没有有效的药物治疗。中枢黑皮质素系统在调节摄食行为、线性生长、代谢率和胰岛素敏感性中起关键作用。我们已经证明，通过遗传和药理学手段阻断通过4型黑皮质素受体（MC 4-R）的信号传导，可以预防在几种慢性疾病模型中急性炎症期间通常发生的恶病质的许多特征。这直接导致了抑制或阻断中枢黑皮质素信号传导的药物的开发，目前正在测试作为恶病质的治疗药物。该提议旨在进一步阐明炎症导致中枢黑皮质素信号过度激活的机制。虽然在疾病期间产生恶病质的主要细胞因子信号已被详细研究，但我们对参与处理这些信号的特定下丘脑细胞群的了解有限。我们已经表明，在疾病过程中释放的细胞因子激活阿黑皮素原（POMC）神经元的直接和间接的机制。我们还发现细胞因子影响MCH和食欲素神经元的功能，它们分别是食物摄入和唤醒的关键参与者。我们假设炎症改变了这些神经元的功能，这反过来又会产生疾病反应的各个方面，包括厌食症，运动减少，基础代谢率升高，嗜睡和能量分配的改变。我们进一步假设，这种细胞机制代表了在各种慢性疾病状态下产生恶病质的最终共同途径，特别是那些已知炎症起重要作用的疾病。

DESCRIPTION (provided by applicant): Cachexia, or disease-associated wasting, is a common occurrence in cancer, renal failure, and infectious disease. This devastating state of malnutrition is brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. The severity of cachexia in many illnesses is the primary determining factor in both quality of life, and in eventual mortality. Other illness induced morbidities including lethargy and loss of reproductive ability also directly compromise the ability of patients to recover from potentially life-saving or extending interventions, including surgery and cytotoxic chemotherapy, and can diminish the motivational drive to aggressively battle the condition. Although cachexia in chronic disease was described more than two thousand years ago, the central mechanisms underlying this disorder of energy homeostasis is poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. The central melanocortin system plays a critical role in regulating feeding behavior, linear growth, metabolic rate, and insulin sensitivity. We have demonstrated that blockade of signaling through the type 4 melanocortin receptor (MC4-R) by genetic and pharmacologic means prevents many of the features of cachexia that would normally occur during acute inflammation in several models of chronic disease. This has led directly to the development of drugs that dampen or block central melanocortin signaling that are currently being tested as therapeutics for cachexia. This proposal is designed to further elucidate the mechanism whereby inflammation leads to excessive activation of central melanocortin signaling. While the primary cytokine signals producing cachexia during illness have been studied in detail, we have limited understanding of the specific hypothalamic cell groups involved in processing these signals. We have shown that cytokines liberated during the disease process activate pro-opiomelanocortin (POMC) neurons by both direct and indirect mechanisms. We have also shown that cytokines affect the function of MCH and orexin neurons, key players in food intake and arousal, respectively. We hypothesize that inflammation alters the function of these neurons and that this in turn will produces various aspects of the illness response including anorexia, decreased movement, elevated basal metabolic rate, lethargy, and alterations in energy partitioning. We further hypothesize that this cellular mechanism represents a final common pathway for the production of cachexia in a variety of chronic disease states, particularly those in which inflammation is known to play an important role.