Horvath Tamas L, Castañeda Tamara, Tang-Christensen Mads, Pagotto Uberto, Tschöp Matthias H
Dept. of Ob/Gyn, Yale University School of Medicine, New Haven, CT, USA.
Curr Pharm Des. 2003;9(17):1383-95. doi: 10.2174/1381612033454748.
In order to develop an effective pharmacological treatment for obesity, an endogenous factor that promotes a positive energy balance by increasing appetite and decreasing fat oxidation could represent the drug target scientists have been looking for. The recently discovered gastric endocrine agent ghrelin, which appears to be the only potent hunger-inducing factor to naturally circulate in our blood stream, was discovered in 1999. Since then the acylated peptide hormone ghrelin has evolved from an endogenous growth hormone secretagogue to a regulator of energy balance to a pleiotropic hormone with multiple sources, numerous target tissues and most likely several physiological functions. Although neither the exact mechanism of action by which ghrelin increases food intake and adiposity is known, nor the putatively differential effects of brain-derived and stomach-derived ghrelin on energy homeostasis have been determined, blocking or neutralizing ghrelin action still seems one of the more reasonable pharmacological approaches to reverse a chronically positive energy balance. However, based on growing experience with compounds targeting the neuroendocrine regulation of energy balance, it is quite possible that a ghrelin antagonist will either fail to cure obesity due to the existence of compensatory mechanisms or undesired effects might reveal the true biological function of ghrelin (e.g. cardiovascular mechanisms, anti-proliferative effects, reproduction).
为开发一种有效的肥胖症药物治疗方法，一种通过增加食欲和减少脂肪氧化来促进正能量平衡的内源性因子可能成为科学家一直在寻找的药物靶点。1999年发现了最近才被发现的胃内分泌因子胃饥饿素，它似乎是唯一能在我们血液中自然循环的强效饥饿诱导因子。从那时起，酰化肽激素胃饥饿素已从一种内源性生长激素促分泌素演变为能量平衡的调节剂，再到一种具有多种来源、众多靶组织且很可能具有多种生理功能的多效性激素。尽管胃饥饿素增加食物摄入量和肥胖的具体作用机制尚不清楚，脑源性和胃源性胃饥饿素对能量稳态的假定差异效应也未确定，但阻断或中和胃饥饿素的作用似乎仍是逆转长期正能量平衡的较为合理的药物学方法之一。然而，基于针对能量平衡神经内分泌调节的化合物的经验不断积累，胃饥饿素拮抗剂很可能由于存在补偿机制而无法治愈肥胖症，或者不良反应可能揭示胃饥饿素的真正生物学功能（如心血管机制、抗增殖作用、生殖）。
