Role of leptin and melanocortin signaling in uremia-associated cachexia
Role of leptin and melanocortin signaling in uremia-associated cachexia
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DOI：
10.1172/jci22521
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发表时间：
2005-06-01
影响因子：
15.9
通讯作者：
Mak, RH
中科院分区：
文献类型：
--
作者：
Cheung, W;Yu, PX;Mak, RH
尿毒症患者恶病质的发病机制尚不清楚。我们检验了尿毒症相关恶病质是由瘦素通过下丘脑黑皮质素受体4（MC 4-R）信号传导引起的假设。我们对WT、瘦素受体缺陷（db/db）和MC 4-R敲除（MC 4-RKO）小鼠进行了肾次全切除术（N）或假手术。动物接受17%蛋白质饮食，尿毒症动物均未出现酸中毒。WT-N小鼠产生典型的恶病质综合征，其特征在于食物摄入减少、代谢率增加和瘦体重损失。校正的瘦素水平升高。db/db小鼠和MC 4-RKO小鼠抵抗尿毒症对体重增加、身体组成和代谢率的恶病质影响。同样，用颅内刺鼠相关肽治疗WT小鼠逆转了尿毒症对食欲、体重增加、身体组成和代谢率的恶病质影响。在尿毒症动物中，泛素C和蛋白酶体亚基C2、C3和C9的基因表达没有改变，这表明其他途径参与了非酸中毒性尿毒症恶病质模型。这项研究的结果表明，细胞因子，如瘦素的循环水平升高可能是尿毒症相关的恶病质的一个重要原因，通过信号传导通过中央黑皮质素系统。
The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.