肥胖病現(xiàn)在是世界性流行病,，我國不論肥胖成人或小孩都在增多,。但至今沒有一個滿意的藥物,，鋪天蓋地的減肥保健品廣告并不可靠,，正式批準的兩個藥物之一——西布曲明最近也出了點問題,。
肥胖的根本問題是進食熱卡過剩及消耗代謝不足,，這兩者都是由中樞神經(jīng)控制的,。自從發(fā)現(xiàn)瘦素以后，本以為能解決肥胖問題,，實際上卻無效,。以后相繼又發(fā)現(xiàn)了許多有關(guān)物質(zhì)，如黑皮素,、神經(jīng)肽Y,、內(nèi)源大麻酚樣通道等，但療效均有限,，說明存在多種代償通道,。
2010年2月著名的《細胞代謝》雜志發(fā)表管小明等研究者的文章。他們首次找到能與鈴蟾素受體亞型3（BRS-3）結(jié)合的物質(zhì),，并深入研究,。BRS-3在自然界或人體內(nèi)與什么配體相結(jié)合，至今未明,。僅僅在1997年有人用基因方法知道鼠的BRS-3與代謝有關(guān),。此次管小明等發(fā)現(xiàn)，能與BRS-3強有力結(jié)合的有高度選擇性的非肽類配體,，而且能夠口服,，他們稱之為Bag-I，這是一種促效劑,。他們也發(fā)現(xiàn)了拮抗劑配體，稱為Bantag-I,。
管小明等對大鼠腦室內(nèi)滴注Bantag-I12天,，可使攝食增加12%，體重自50.2克增至69.4克,，增加的主要是脂肪組織,。給小鼠口服Bag-I30mg/kg及100mg/kg，小劑量者未見體重下降,，高劑量者對一般小鼠減少體重5%,，而對因過食致肥者減少體重11%。對肥胖鼠低劑量者也減少6%,，而且高劑量組可見進食減少23%,。小鼠在禁食時一般會自行減少能量消耗約30%，但用Bag-I后仍可增加能量消耗,，約維持10小時,。Bag-I對雜飼鼠增加空腹能量消耗約20%。
應(yīng)用放射性Bag,，用放射自顯影法可見下丘腦,、前腦,、尾腦及杏仁核和丘腦都有中到高度BRS-3結(jié)合，說明此受體主要分布在這些部位,，與攝食及代謝有關(guān),。另外還發(fā)現(xiàn)多巴胺能及血清素能神經(jīng)元密度也有少量結(jié)合?？诜﨎ag-I后在1,、6及20小時腦內(nèi)BRS-3的占有率各為80%、28%及<10%,，說明其半壽期短,。
另外他們用分別敲除有關(guān)攝食等各通道基因的小鼠做實驗，仍能使進食減少,，說明這些通道與BRS-3可能是互補的,，并不重復。
該雜志的編者對此文很重視,，請劍橋大學Coll教授寫了評論,。Coll認為此工作很好，很有希望,。但如果進入臨床,，還有些工作要做，例如副作用問題,。盡管該文作者對大鼠作復雜迷宮試驗,，證明對行為學無影響。但人究竟與鼠不同,，將來臨床研究證明副作用小,，才能推廣應(yīng)用。(生物谷Bioon.com)
生物谷推薦原文出處：
Cell Metabolism DOI: 10.1016/j.cmet.2009.12.008
Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3: Selective Receptor Agonists for the Treatment of Obesity
Xiao-Ming Guan, Howard Chen, Peter H. Dobbelaar, Yan Dong, Tung M. Fong, Karen Gagen, Judith Gorski, Shuwen He, Andrew D. Howard, Tianying Jian, Michael Jiang, Yanqing Kan, Theresa M. Kelly, Jennifer Kosinski, Linus S. Lin, Jian Liu, Donald J. Marsh, Joseph M. Metzger, Randy Miller, Ravi P. Nargund, Oksana Palyha, Lauren Shearman, Zhu Shen, Ralph Stearns, Alison M. Strack, Sloan Stribling, Yui Sing Tang, Sheng-Ping Wang, Amanda White, Hong Yu, Marc L. Reitman
Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3?/Y (BRS-3 null) mice but was maintained in Npy/Agrp/, Mc4r, Cnr1, and Leprdb/db mice. In addition, Brs3?/Y mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.
