Larsen Philip J, Vrang Niels, Tang-Christensen Mads
Rheoscience, Glerupvej 2, 2610 Rødovre, Denmark.
Curr Pharm Des. 2003;9(17):1373-82. doi: 10.2174/1381612033454775.
Modern societies have moved from famine to feast and obesity and its co-morbidities now sweep the world as a global epidemic. Numerous scientific laboratories and pharmaceutical companies have taken the challenge and are now exploiting novel molecular targets for treatment of obesity. The pre-proglucagon system constitutes interesting candidates as potential targets for new anti-obesity drugs. In the periphery, pre-proglucagon derived peptides, Glucagon-Like Peptide-1 (GLP-1), Glucagon-Like Peptide-2 (GLP-2) and oxyntomodulin (OXM) are involved in a wide variety of physiological functions, including glucose homeostasis, gastric emptying, intestinal growth, insulin secretion as well as the regulation of food intake. Peripheral administration of GLP-1 derivatives and analogues to both rodents and man have shown promising effects on food intake and body weight suggesting that such therapies constitute potential anti-obesity treatment. In the central nervous system, pre-proglucagon and hence GLP-1, GLP-2 and OXM are exclusively found in a small population of nerve cells in the nucleus of the solitary tract. These constitute a neural pathway linking the "viscero-sensory" brainstem to hypothalamic nuclei involved in energy homeostasis. Intracerebroventricular administration of all of the three derived peptides robustly decrease food intake. It is evident that central GLP-1 agonism probably in combination with GLP-2 and/or OXM agonism constitute a potential pharmacological tool to reduce food intake and maybe also enhance energy expenditure. This and other aspects of the current state of the role of central pre-proglucagon in energy homeostasis are reviewed.
现代社会已从饥荒走向富足，肥胖及其相关疾病如今正作为一种全球流行病席卷全球。众多科学实验室和制药公司已接受这一挑战，目前正在探索治疗肥胖的新型分子靶点。前胰高血糖素系统作为新型抗肥胖药物的潜在靶点，构成了有趣的候选对象。在周围组织中，前胰高血糖素衍生的肽类，如胰高血糖素样肽 -1（GLP -1）、胰高血糖素样肽 -2（GLP -2）和胃动素（OXM）参与多种生理功能，包括葡萄糖稳态、胃排空、肠道生长、胰岛素分泌以及食物摄入的调节。对啮齿动物和人类外周给予GLP -1衍生物和类似物已显示出对食物摄入和体重有良好效果，表明此类疗法构成潜在的抗肥胖治疗方法。在中枢神经系统中，前胰高血糖素以及因此的GLP -1、GLP -2和OXM仅在孤束核中的一小部分神经细胞中发现。这些构成了一条将“内脏感觉”脑干与参与能量稳态的下丘脑核相连的神经通路。脑室内给予所有这三种衍生肽均可显著减少食物摄入。显然，中枢GLP -1激动作用可能与GLP -2和/或OXM激动作用相结合，构成一种减少食物摄入以及可能还增强能量消耗的潜在药理学工具。本文对中枢前胰高血糖素在能量稳态中的作用现状的这一方面及其他方面进行了综述。
