Elias C F, Kelly J F, Lee C E, Ahima R S, Drucker D J, Saper C B, Elmquist J K
Department of Neurology, Beth Israel Deaconess Medical Center and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02215, USA.
J Comp Neurol. 2000 Jul 24;423(2):261-81.
Leptin has profound effects on food intake, body weight, and neuroendocrine status. The lack of leptin results in hormonal and metabolic alterations and a dramatic increase in body weight. Leptin acts in the brain, especially in the hypothalamus; however, the central nervous system sites that respond to leptin have not been examined comprehensively. In this study, we explored systematically the distribution of leptin-activated neurons throughout the rat brain. Furthermore, we investigated the chemical identity of subsets of these leptin-activated cells. Fos-like immunoreactivity (Fos-IR) was investigated in the rat brain after two different doses of leptin (1.0 mg/kg and 5.0 mg/kg) at 2 hours and 6 hours after injections. The induction of Fos-IR was observed in hypothalamic nuclei, including the paraventricular nucleus (PVH), the retrochiasmatic area (RCA), the ventromedial nucleus (VMH), the dorsomedial nucleus (DMH), the arcuate nucleus (Arc), and the ventral premammillary nucleus (PMV). In addition, leptin-induced Fos-IR was found in several nuclei of the brainstem, including the superior lateral and external lateral subdivisions of the parabrachial nucleus (slPB and elPB, respectively), the supragenual nucleus, and the nucleus of the solitary tract (NTS). By using double-labeling immunohistochemistry or immunohistochemistry coupled with in situ hybridization, leptin-activated neurons were found that contained cocaine- and amphetamine-regulated transcript mRNA in several hypothalamic nuclei, including the RCA, Arc, DMH, and PMV. In the Arc and DMH, leptin-induced Fos-IR was observed in neurons that expressed neurotensin mRNA. Dynorphin neurons in the VMH and in the Arc also expressed Fos-IR. In the brainstem, we found that cholecystokinin neurons in the slPB and glucagon-like peptide-1 neurons in the NTS were activated by leptin. We also investigated the coexpression of Fos-IR and the long form of the leptin receptor (OBRb) mRNA. We found double-labeled neurons surrounding the median eminence and in the RCA, Arc, VMH, DMH, and PMV. However, in brainstem sites, very little OBRb mRNA was found; thus, there were very few double-labeled cells. These results suggest that leptin stimulates brain pathways containing neuropeptides that are involved in the regulation of energy balance, autonomic homeostasis, and neuroendocrine status.
瘦素对食物摄入、体重和神经内分泌状态有深远影响。瘦素缺乏会导致激素和代谢改变以及体重显著增加。瘦素作用于大脑，尤其是下丘脑；然而，对瘦素产生反应的中枢神经系统部位尚未得到全面研究。在本研究中，我们系统地探索了瘦素激活神经元在大鼠全脑的分布。此外，我们研究了这些瘦素激活细胞亚群的化学特性。在注射两种不同剂量（1.0 mg/kg和5.0 mg/kg）的瘦素后2小时和6小时，对大鼠脑内的Fos样免疫反应性（Fos-IR）进行了研究。在包括室旁核（PVH）、视交叉后区（RCA）、腹内侧核（VMH）、背内侧核（DMH）、弓状核（Arc）和腹侧乳头前核（PMV）在内的下丘脑核团中观察到Fos-IR的诱导。此外，在脑干的几个核团中发现了瘦素诱导的Fos-IR，包括臂旁核的上外侧和外侧亚区（分别为slPB和elPB）、膝上核和孤束核（NTS）。通过使用双标免疫组织化学或免疫组织化学与原位杂交相结合的方法，发现在包括RCA、Arc、DMH和PMV在内的几个下丘脑核团中，瘦素激活的神经元含有可卡因和苯丙胺调节转录物mRNA。在Arc和DMH中，在表达神经降压素mRNA的神经元中观察到瘦素诱导的Fos-IR。VMH和Arc中的强啡肽神经元也表达Fos-IR。在脑干中，我们发现slPB中的胆囊收缩素神经元和NTS中的胰高血糖素样肽-1神经元被瘦素激活。我们还研究了Fos-IR与瘦素受体长形式（OBRb）mRNA的共表达。我们在正中隆起周围以及RCA、Arc、VMH、DMH和PMV中发现了双标神经元。然而，在脑干部位，发现的OBRb mRNA很少；因此，双标细胞也很少。这些结果表明，瘦素刺激了包含参与能量平衡、自主稳态和神经内分泌状态调节的神经肽的脑通路。
