Faouzi Miro, Leshan Rebecca, Björnholm Marie, Hennessey Thomas, Jones Justin, Münzberg Heike
Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Endocrinology. 2007 Nov;148(11):5414-23. doi: 10.1210/en.2007-0655. Epub 2007 Aug 9.
Hypothalamic neurons expressing the long form of the leptin receptor (LRb) mediate important leptin actions. Although it has been suggested that leptin crosses the blood-brain barrier (BBB) via a specific transport system, we hypothesized the existence of a population of hypothalamic arcuate nucleus (ARC) neurons that senses leptin independently of this transport system. Indeed, endogenous circulating leptin results in detectable levels of baseline activated signal transducer and activator of transcription 3 (STAT3) phosphorylation in a population of ARC/LRb neurons, consistent with increased sensing of circulating leptin in these neurons compared with other LRb neurons. Furthermore, a population of ARC/LRb neurons that responds more rapidly and sensitively to circulating leptin compared with other hypothalamic LRb neurons detected by leptin activated phosphorylated STAT3. In addition, peripheral application of the BBB-impermeant retrograde tracer fluorogold revealed a population of ARC/LRb neurons that directly contact the circulation (e.g. via neuronal processes reaching outside the BBB). Taken together, these data suggest that a population of ARC/LRb neurons directly contacts the circulation and displays increased sensitivity to circulating leptin compared with neurons residing entirely behind the BBB elsewhere in the hypothalamus.
表达长型瘦素受体（LRb）的下丘脑神经元介导重要的瘦素作用。尽管有人提出瘦素通过特定转运系统穿过血脑屏障（BBB），但我们推测存在一群下丘脑弓状核（ARC）神经元，它们能独立于该转运系统感知瘦素。实际上，内源性循环瘦素会导致一群ARC/LRb神经元中信号转导子和转录激活子3（STAT3）磷酸化的基线激活水平可被检测到，这与这些神经元相比其他LRb神经元对循环瘦素的感知增加相一致。此外，与通过瘦素激活的磷酸化STAT3检测到的其他下丘脑LRb神经元相比，一群ARC/LRb神经元对循环瘦素的反应更快、更敏感。另外，外周应用不能透过血脑屏障的逆行示踪剂荧光金显示出一群直接接触循环系统的ARC/LRb神经元（例如通过延伸至血脑屏障外的神经突）。综上所述，这些数据表明，与完全位于下丘脑其他部位血脑屏障后的神经元相比，一群ARC/LRb神经元直接接触循环系统并对循环瘦素表现出更高的敏感性。
