Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, Oregon, USA.
Tensive Controls Inc., MU Life Sciences Business Incubator at Monsanto Place, Columbia, Missouri, USA.
J Clin Invest. 2020 Sep 1;130(9):4921-4934. doi: 10.1172/JCI138392.
Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake, increased energy expenditure, excess catabolism, and inflammation. Cachexia is associated with poor prognosis and high mortality and frequently occurs in patients with cancer, chronic kidney disease, infection, and many other illnesses. There is no effective treatment for this condition. Hypothalamic melanocortins have a potent and long-lasting inhibitory effect on feeding and anabolism, and pathophysiological processes increase melanocortin signaling tone, leading to anorexia, metabolic changes, and eventual cachexia. We used 3 rat models of anorexia and cachexia (LPS, methylcholanthrene sarcoma, and 5/6 subtotal nephrectomy) to evaluate efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor. Our data show that peripheral treatment using TCMCB07 with intraperitoneal, subcutaneous, and oral administration increased food intake and body weight and preserved fat mass and lean mass during cachexia and LPS-induced anorexia. Furthermore, administration of TCMCB07 diminished hypothalamic inflammatory gene expression in cancer cachexia. These results suggest that peripheral TCMCB07 treatment effectively inhibits central melanocortin signaling and therefore stimulates appetite and enhances anabolism, indicating that TCMCB07 is a promising drug candidate for treating cachexia.
恶病质是一种严重的消耗性综合征，以严重的体重减轻为特征，伴有特定的肌肉和脂肪组织损失，其原因是食物摄入减少、能量消耗增加、过度分解代谢和炎症。恶病质与预后不良和高死亡率相关，常发生于癌症、慢性肾脏病、感染和许多其他疾病患者中。目前对此病症尚无有效的治疗方法。下丘脑黑素细胞皮质素对摄食和合成代谢有强烈且持久的抑制作用，病理生理过程增加黑素细胞皮质素信号强度，导致厌食、代谢变化，最终恶病质。我们使用了 3 种厌食和恶病质的大鼠模型（LPS、甲基胆蒽肉瘤和 5/6 肾部分切除术）来评估 TCMCB07 的疗效，TCMCB07 是一种黑素细胞皮质素-4 受体的合成拮抗剂。我们的数据表明，使用 TCMCB07 进行外周治疗，通过腹腔内、皮下和口服给药，可以增加食物摄入和体重，并在恶病质和 LPS 诱导的厌食症中保留脂肪量和瘦体重。此外，给予 TCMCB07 可减少癌症恶病质中下丘脑炎症基因的表达。这些结果表明，外周 TCMCB07 治疗可有效抑制中枢黑素细胞皮质素信号，从而刺激食欲并增强合成代谢，表明 TCMCB07 是治疗恶病质的有前途的候选药物。
