Hypothalamic Mechanisms in Cachexia

描述（由申请人提供）：恶病质，或疾病相关消耗，在癌症、肾衰竭和传染病中常见。这种毁灭性的营养不良状态是由食欲急剧下降和脂肪和瘦肉代谢增加的协同作用造成的。在许多疾病中，恶病质的严重程度是决定生活质量和最终死亡率的主要因素。其他疾病引起的发病率，包括嗜睡和生殖能力丧失，也直接损害了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，并可能减少积极对抗这种疾病的动力。尽管早在两千多年前就有关于慢性疾病中的恶病质的描述，但人们对这种能量稳态紊乱的主要机制知之甚少。此外，目前还没有有效的药物治疗。中枢黑素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方面起着关键作用。我们已经证明，通过遗传和药理学手段阻断4型黑素皮质素受体（MC4-R）的信号传导，可以防止在几种慢性疾病模型的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素皮质素信号的药物的发展，这些药物目前正在作为恶病质的治疗方法进行测试。该建议旨在进一步阐明炎症导致中央黑素皮质素信号过度激活的机制。虽然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。我们已经证明，在疾病过程中释放的细胞因子通过直接和间接的机制激活前阿皮黑色素皮质素（POMC）神经元。我们还表明，细胞因子影响MCH和食欲素神经元的功能，它们分别在食物摄入和觉醒中起关键作用。我们假设炎症改变了这些神经元的功能，这反过来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各种慢性疾病状态下恶病质产生的最终共同途径，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. PUBLIC HEALTH RELEVANCE: The severity of cachexia in chronic disease is often the primary determining factor in both quality of life, and in eventual mortality. Attempts at drug therapy for cachexia with a variety of agents have met with limited success. Our data argues strongly that the hypothalamic melanocortin system plays a critical role in the transduction of illness-induced cachexia and therefore represents an important target for future therapeutic intervention.