Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice
Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice
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DOI：
10.1210/en.2007-1673
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发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Kastin, Abba J.
中科院分区：
文献类型：
--
作者：
Pan, Weihong;Hsuchou, Hung;Kastin, Abba J.
Agoutilively yellow（A（vy））自发突变产生了一种不寻常的小鼠表型，即Agouti-colored被毛和成年型肥胖伴代谢综合征。Avy小鼠中持续产生agglutinin信号蛋白拮抗下丘脑中的黑皮质素受体。为了确定这种神经内分泌回路的破坏如何影响瘦素通过血脑屏障（BBB）的转运，我们测量了肥胖、高瘦素血症和肥胖增加后Avy和B6对照小鼠的瘦素流入。静脉推注后，I-125-瘦素通过血脑屏障显着更快的年轻（2个月大）B6小鼠比年轻的Avy小鼠或老年（8个月大）小鼠的任何一个菌株。原位脑灌注研究未观察到这种差异，表明原因是循环因素，如瘦素水平升高或可溶性受体。因此，Avy小鼠表现出外周瘦素抵抗。ObRa是瘦素在血脑屏障的主要转运受体，在年龄匹配（2个月大）的Avy和B6小鼠之间的脑微血管中的mRNA表达没有变化。在Avy微血管中观察到较高的ObRb mRNA，但意义不明。免疫荧光染色出乎意料地显示，许多ObR（+）细胞是星形胶质细胞，Avy小鼠下丘脑中的ObR（+）星形胶质细胞明显多于B6小鼠。虽然瘦素从循环中渗透较慢的Avy小鼠，增加的ObR表达的星形胶质细胞和增加的ObRb mRNA的微血管表明中枢神经系统的敏感性提高循环瘦素的可能性。
The agouti viable yellow (A(vy)) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in Avy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in Avy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, I-125-leptin crossed the BBB significantly faster in young ( 2 month old) B6 mice than in young Avy mice or in older ( 8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, Avy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched ( 2 month old) Avy and B6 mice. Higher ObRb mRNA was seen in the Avy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the Avy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the Avy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.