Reversal of obesity by targeted ablation of adipose tissue
Reversal of obesity by targeted ablation of adipose tissue
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DOI：
10.1038/nm1048
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发表时间：
2004-06-01
期刊：
影响因子：
82.9
通讯作者：
Arap, W
中科院分区：
文献类型：
--
作者：
Kolonin, MG;Saha, PK;Arap, W
肥胖是发达国家日益普遍的人类状况。尽管对导致肥胖的分子机制的理解取得了重大进展，但尚未找到安全有效的治疗方法。在这里，我们报告了一种基于脂肪组织脉管系统细胞凋亡的靶向诱导的抗肥胖疗法。我们使用体内噬菌体展示来分离白色脂肪脉管系统的肽基序（序列 CKGGRAKDC）。我们发现 CKGGRAKDC 肽与抑制素（一种多功能膜蛋白）结合，并将抑制素确立为脂肪组织的血管标志物。将促凋亡肽靶向脂肪脉管系统中的抑制素，导致白色脂肪消融。已形成的白色脂肪组织的吸收和代谢的正常化导致肥胖迅速逆转，且没有可检测到的副作用。由于抑制素也在人类白色脂肪的血管中表达，这项工作可能会导致治疗肥胖患者的靶向药物的开发。
Obesity is an increasingly prevalent human condition in developed societies. Despite major progress in the understanding of the molecular mechanisms leading to obesity, no safe and effective treatment has yet been found. Here, we report an antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue. We used in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes to white fat vasculature. We show that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establish prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients.