PDQ6: Loss of adiponectin as a contributing factor in cancer cachexia

描述(申请人提供)：近三分之一的癌症死亡可能归因于恶病质。导致这种意外减肥的因素包括厌食症、紊乱的能量代谢和炎症加剧。虽然骨骼肌量的丢失预示着预后不良和生活质量的降低，但脂肪组织的丢失是恶病质患者死亡率的最强预测因素。由于脂肪丢失与死亡率密切相关，而且在癌症恶病质发病的早期脂肪质量下降，减轻脂肪丢失可能是减缓恶病质进展的有效策略。在小鼠中，肿瘤引起的脂肪质量的减少与脂肪细胞功能的丧失是一致的，包括无法储存脂肪和分泌脂肪因子。脂肪因子，脂联素，可能是非常重要的，因为它是已知的，调节炎症和新陈代谢。在癌症恶病质的小鼠模型中，脂联素以时间依赖的方式下降。对于恶病质来说，重要的是，脂联素通过骨骼肌线粒体的生物生成减少炎症，改善胰岛素敏感性，并增加b-氧化。我们的中心假设是脂联素的丢失是癌症恶病质发病机制的关键驱动因素。在目标1中，我们将检查脂联素改变癌症恶病质的生理和代谢方面的能力。在第二个目标中，我们将确定脂联素对癌症恶病质小鼠骨骼肌再生生物标志物的影响。目前还缺乏治疗癌症恶病质的有效疗法。这项提案中概述的研究意义重大，因为它将探索脂联素的作用，脂联素是一种减少炎症和调节新陈代谢的细胞因子，它的丧失是肌肉损失的驱动因素。这些研究应该提供脂肪组织损失和肌肉损失之间的机制联系，而肌肉损失会导致癌症恶病质死亡。我们的长期目标是开发新的临床治疗方法，以改善癌症恶病质患者的功能状态、生活质量和生存率。

DESCRIPTION (provided by applicant): Nearly one third of cancer deaths may be attributed to cachexia. Factors that contribute to this unintended weight loss include anorexia, deranged energy metabolism, and elevated inflammation. While the loss of skeletal muscle mass predicts for poor prognosis and reduced quality of life, it is the loss of adipose tissue that is the strongst predictor for mortality in patients with cachexia. Because of the strong relationship of adipose loss with mortality, and because adipose mass declines early in the pathogenesis of cancer cachexia, mitigating adipose loss could be a useful strategy for slowing the progression of cachexia. In mice, tumor-induced loss of adipose mass occurs coincident with loss of adipocyte function including an inability to store lipid and to secrete adipokines. The adipokine, adiponectin, may be of great importance since it is known to modulate inflammation and metabolism. In a mouse model of cancer cachexia, adiponectin decreases in a time dependent manner. Importantly for cachexia, adiponectin decreases inflammation, improves insulin sensitivity and increases b-oxidation through mitochondrial biogenesis in skeletal muscle. Our central hypothesis is that loss of adiponectin is a key driver of the pathogenesis of cancer cachexia. In Aim #1, we will examine the ability of adiponectin to alter physiologic and metabolic aspects of cancer cachexia. In Aim #2, we will determine the effect of adiponectin on biomarkers of skeletal muscle regeneration in mice with cancer cachexia. Effective therapies for treating cancer cachexia are lacking. Research outlined in this proposal is significant because it will probe the role of adiponectin, a cytokine that decreases inflammation and modulates metabolism, the loss of which is a driver of muscle loss. These studies should provide a mechanistic link between the loss of adipose tissue with the loss of muscle that contributes to mortality from cancer cachexia. Our long-term goal is to develop novel clinical treatments to improve functional status, quality of life, and survival for patients with cancer cachexia.