Margetic S, Gazzola C, Pegg G G, Hill R A
Central Queensland University, School of Chemical and Biomedical Sciences, Queensland, Australia.
Int J Obes Relat Metab Disord. 2002 Nov;26(11):1407-33. doi: 10.1038/sj.ijo.0802142.
Following the discovery of leptin in 1994, the scientific and clinical communities have held great hope that manipulation of the leptin axis may lead to the successful treatment of obesity. This hope is not yet dashed; however the role of the leptin axis is now being shown to be ever more complex than was first envisaged. It is now well established that leptin interacts with pathways in the central nervous system and through direct peripheral mechanisms. In this review, we consider the tissues in which leptin is synthesized and the mechanisms which mediate leptin synthesis, the structure of leptin and the knowledge gained from cloning leptin genes in aiding our understanding of the role of leptin in the periphery. The discoveries of expression of leptin receptor isotypes in a wide range of tissues in the body have encouraged investigation of leptin interactions in the periphery. Many of these interactions appear to be direct, however many are also centrally mediated. Discovery of the relative importance of the centrally mediated and peripheral interactions of leptin under different physiological states and the variations between species is beginning to show the complexity of the leptin axis. Leptin appears to have a range of roles as a growth factor in a range of cell types: as be a mediator of energy expenditure; as a permissive factor for puberty; as a signal of metabolic status and modulation between the foetus and the maternal metabolism; and perhaps importantly in all of these interactions, to also interact with other hormonal mediators and regulators of energy status and metabolism such as insulin, glucagon, the insulin-like growth factors, growth hormone and glucocorticoids. Surely, more interactions are yet to be discovered. Leptin appears to act as an endocrine and a paracrine factor and perhaps also as an autocrine factor. Although the complexity of the leptin axis indicates that it is unlikely that effective treatments for obesity will be simply derived, our improving knowledge and understanding of these complex interactions may point the way to the underlying physiology which predisposes some individuals to apparently unregulated weight gain.
1994年瘦素被发现后，科学界和临床界一直满怀希望，认为对瘦素轴的调控可能会成功治疗肥胖症。这种希望尚未破灭；然而，现在已表明瘦素轴的作用比最初设想的要复杂得多。目前已经明确，瘦素通过中枢神经系统的通路以及直接的外周机制相互作用。在这篇综述中，我们探讨了合成瘦素的组织以及介导瘦素合成的机制、瘦素的结构，以及通过克隆瘦素基因所获得的知识，这些知识有助于我们理解瘦素在外周的作用。瘦素受体亚型在体内多种组织中的表达被发现，这促使人们对外周瘦素相互作用展开研究。其中许多相互作用似乎是直接的，但也有许多是由中枢介导的。不同生理状态下瘦素中枢介导和外周相互作用的相对重要性以及物种间的差异正在揭示瘦素轴的复杂性。瘦素似乎在一系列细胞类型中作为生长因子发挥多种作用：作为能量消耗的介质；作为青春期的许可因子；作为代谢状态的信号以及胎儿与母体代谢之间的调节因子；也许在所有这些相互作用中最重要的是，它还与其他能量状态和代谢的激素介质及调节因子相互作用，如胰岛素、胰高血糖素、胰岛素样生长因子、生长激素和糖皮质激素。当然，肯定还有更多的相互作用有待发现。瘦素似乎作为一种内分泌和旁分泌因子发挥作用，也许还作为自分泌因子。尽管瘦素轴的复杂性表明不太可能简单地得出有效的肥胖治疗方法，但我们对这些复杂相互作用的不断深入了解可能会为一些个体体重明显不受控制增加的潜在生理学机制指明方向。
