瘦素蛋白是一类抑制食欲的激素，曾经被作为战胜肥胖难题的解决方法而受到追捧，但瘦素蛋白在肥胖的人体内会失效。日前，美国哈佛医学院的科学家称，他们揭开了瘦素蛋白战胜肥胖的“秘密”，可能会重新点燃使用瘦素蛋白减肥的希望之火，该研究发表在近日出版的《细胞—代谢》（Cell Metabolism）杂志上。
1995年，瘦素蛋白首先在一只胖老鼠的脂肪细胞中被发现，它的功能是告诉大脑饱胀感，因此可抑制食欲，达到减重的效果。波士顿儿童医院和哈佛医学院的马特·奥兹坎说，大多数肥胖的人都会对瘦素蛋白产生排斥，在此过程中，大脑不再对激素发出的停止饮食的信号作出反应。
奥兹坎团队发现，肥胖老鼠的大脑细胞在内质网上增加了压力（内质网是一个蛋白质聚合的细胞结构）。因为肥胖，内质网的结构被颠覆，停止工作，开始阻止前来的化学信号。这证明，压力会阻止瘦素蛋白的应答。
随后，研究人员尝试通过减少内质网的压力让大脑重新对瘦素蛋白敏感。他们使用了两种减少内质网压力的药物———四苯基丁酸和牛熊去氧胆酸钠。他们给喂食了高脂肪食物的肥胖老鼠食用任意一种药物，接着给老鼠注射瘦蛋白，结果，这些老鼠的体重明显下降。
研究人员称，内质网压力的减少使老鼠对瘦素蛋白更为敏感，这提供了治疗肥胖的新希望，下一步将在人体上进行试验。（生物谷Bioon.com）
生物谷推荐原始出处：
Cell Metabolism, doi:10.1016/j.cmet.2008.12.004，Lale Ozcan，Umut Ozcan
Endoplasmic Reticulum Stress Plays a Central Role in Development of Leptin Resistance
Lale Ozcan1,4,Ayse Seda Ergin1,4,Allen Lu1,Jason Chung1,Sumit Sarkar1,Duyu Nie2,Martin G. Myers3andUmut Ozcan1,,
1 Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA, 02115, USA
2 Division of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, MA, 02115, USA
3 Division of Metabolism, Endocrinology, and Diabetes, Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
4 These authors contributed equally to this work
Summary
Leptin has not evolved as a therapeutic modality for the treatment of obesity due to the prevalence of leptin resistance in a majority of the obese population. Nevertheless, the molecular mechanisms of leptin resistance remain poorly understood. Here, we show that increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in the hypothalamus of obese mice inhibits leptin receptor signaling. The genetic imposition of reduced ER capacity in mice results in severe leptin resistance and leads to a significant augmentation of obesity on a high-fat diet. Moreover, we show that chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA), which have the ability to decrease ER stress, act as leptin-sensitizing agents. Taken together, our results may provide the basis for a novel treatment of obesity.
