Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Department of Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA.
Metabolism. 2024 Dec;161:156056. doi: 10.1016/j.metabol.2024.156056. Epub 2024 Oct 30.
Since its discovery and over the past thirty years, extensive research has significantly expanded our understanding of leptin and its diverse roles in human physiology, pathophysiology and therapeutics. A prototypical adipokine initially identified for its critical function in appetite regulation and energy homeostasis, leptin has been revealed to also exert profound effects on the hypothalamic-pituitary-gonadal, thyroid, adrenal and growth hormone axis, differentially between animals and humans, as well as in regulating immune function. Beyond these roles, leptin plays a pivotal role in significantly affecting bone health by promoting bone formation and regulating bone metabolism both directly and indirectly through its neuroendocrine actions. The diverse actions of leptin are particularly notable in leptin-deficient animal models and in conditions characterized by low circulating leptin levels, such as lipodystrophies and relative energy deficiency. Conversely, the effectiveness of leptin is attenuated in leptin-sufficient states, such as obesity and other high-adiposity conditions associated with hyperleptinemia and leptin tolerance. This review attempts to consolidate 30 years of leptin research with an emphasis on its physiology and pathophysiology in humans, including its promising therapeutic potential. We discuss preclinical and human studies describing the pathophysiology of energy deficiency across organ systems and the significant role of leptin in regulating neuroendocrine, immune, reproductive and bone health. We finally present past proof of concept clinical trials of leptin administration in leptin-deficient subjects that have demonstrated positive neuroendocrine, reproductive, and bone health outcomes, setting the stage for future phase IIb and III randomized clinical trials in these conditions.
自发现以来，经过过去三十年的广泛研究，人们对瘦素及其在人类生理学、病理生理学和治疗学中的多种作用有了更深入的了解。瘦素最初作为一种典型的脂肪因子被发现，对食欲调节和能量平衡具有关键作用，现已被揭示对下丘脑-垂体-性腺、甲状腺、肾上腺和生长激素轴也具有深远影响，在动物和人类之间存在差异，同时还调节免疫功能。除了这些作用，瘦素通过其神经内分泌作用直接和间接促进骨形成和调节骨代谢，对骨骼健康起着至关重要的作用。瘦素的这些多样化作用在瘦素缺乏的动物模型和循环瘦素水平低的情况下尤为显著，如脂肪营养不良和相对能量不足。相反，在瘦素充足的状态下，如肥胖和其他与高瘦素血症和瘦素耐受相关的高脂肪含量情况下，瘦素的效果会减弱。本综述试图整合 30 年来的瘦素研究，重点关注其在人类中的生理学和病理生理学，包括其在治疗中的潜在应用。我们讨论了描述跨器官系统能量不足的生理病理学的临床前和人体研究，以及瘦素在调节神经内分泌、免疫、生殖和骨骼健康方面的重要作用。最后，我们介绍了过去针对瘦素缺乏受试者进行瘦素给药的概念验证临床试验，这些试验证明了对神经内分泌、生殖和骨骼健康的积极影响，为这些情况下的未来 IIb 期和 III 期随机临床试验奠定了基础。
