瘦素蛋白是一類抑制食欲的激素，曾經(jīng)被作為戰(zhàn)勝肥胖難題的解決方法而受到追捧,，但瘦素蛋白在肥胖的人體內(nèi)會失效,。日前，美國哈佛醫(yī)學(xué)院的科學(xué)家稱,，他們揭開了瘦素蛋白戰(zhàn)勝肥胖的“秘密”，可能會重新點燃使用瘦素蛋白減肥的希望之火,，該研究發(fā)表在近日出版的《細(xì)胞—代謝》（Cell Metabolism）雜志上,。
1995年，瘦素蛋白首先在一只胖老鼠的脂肪細(xì)胞中被發(fā)現(xiàn),，它的功能是告訴大腦飽脹感,，因此可抑制食欲，達(dá)到減重的效果,。波士頓兒童醫(yī)院和哈佛醫(yī)學(xué)院的馬特·奧茲坎說,，大多數(shù)肥胖的人都會對瘦素蛋白產(chǎn)生排斥，在此過程中,，大腦不再對激素發(fā)出的停止飲食的信號作出反應(yīng),。
奧茲坎團(tuán)隊發(fā)現(xiàn)，肥胖老鼠的大腦細(xì)胞在內(nèi)質(zhì)網(wǎng)上增加了壓力（內(nèi)質(zhì)網(wǎng)是一個蛋白質(zhì)聚合的細(xì)胞結(jié)構(gòu)）,。因為肥胖,，內(nèi)質(zhì)網(wǎng)的結(jié)構(gòu)被顛覆，停止工作,，開始阻止前來的化學(xué)信號,。這證明，壓力會阻止瘦素蛋白的應(yīng)答,。
隨后,，研究人員嘗試通過減少內(nèi)質(zhì)網(wǎng)的壓力讓大腦重新對瘦素蛋白敏感。他們使用了兩種減少內(nèi)質(zhì)網(wǎng)壓力的藥物———四苯基丁酸和牛熊去氧膽酸鈉,。他們給喂食了高脂肪食物的肥胖老鼠食用任意一種藥物,，接著給老鼠注射瘦蛋白，結(jié)果,，這些老鼠的體重明顯下降,。
研究人員稱,，內(nèi)質(zhì)網(wǎng)壓力的減少使老鼠對瘦素蛋白更為敏感，這提供了治療肥胖的新希望,，下一步將在人體上進(jìn)行試驗,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
