Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
Compr Physiol. 2021 Sep 23;11(4):2351-2369. doi: 10.1002/cphy.c200017.
Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:1-19, 2021.
瘦素作为研究食欲、肥胖和饥饿的核心主题已有 25 年的历史。由于瘦素的主要产生部位是外周，而最感兴趣的作用部位是下丘脑，因此瘦素如何进入中枢神经系统（CNS）并穿过血脑屏障（BBB）一直是人们关注的焦点。我们在这里回顾了正在进行的研究，这些研究解决了一些基本问题，如肥胖和其他情况下瘦素抵抗的部位、抵抗的原因及其相互关系、进入 CNS 的三个屏障部位、为什么最近使用超药理学剂量的研究不能解决这些问题，但能深入了解瘦素进入 CNS 的非饱和性、以及这在治疗性使用瘦素方面可能有何用处。本文还回顾了关于瘦素受体的短形式是否作为 BBB 瘦素转运体发挥作用的争议的现状，以及肥胖如何改变瘦素的转运。对这些和其他主题的回顾总结了对瘦素实际进化功能的新认识，以及对瘦素抵抗可能发挥的生理作用的新认识。 © 2021 美国生理学会。综合生理学 11:1-19, 2021。
