Nilsson Ida, Lindfors Charlotte, Fetissov Sergueï O, Hökfelt Tomas, Johansen Jeanette E
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
J Comp Neurol. 2008 Mar 1;507(1):1128-40. doi: 10.1002/cne.21599.
Agouti-related protein (AgRP) is a key orexigenic neuropeptide expressed in the hypothalamic arcuate nucleus and a marker for neurons conveying hormonal signals of hunger to the brain. Mice homozygous for the anorexia (anx) mutation are characterized by decreased food intake, starvation, and death by 3-5 weeks of age. At this stage immunoreactivity for AgRP is increased in cell bodies but decreased in the nerve terminals. We studied when during early postnatal development the aberrant phenotype of the AgRP system becomes apparent in anx/anx mice and possible underlying mechanisms. AgRP and ionized calcium binding adapter molecule (Iba1), a marker for activated microglia, as well as Toll-like receptor 2 (TLR-2), were studied by immunohistochemistry at postnatal days P1, P5, P10, P12, P15 and P21 in anx/anx and wild-type mice. We found that the AgRP system in the anx/anx mouse develops similarly to the wild type until P12, when AgRP fibers in anx/anx mice cease to increase in density in the main projection areas. At P21, AgRP fiber density in anx/anx mice was significantly reduced vs. P15, in certain regions. At P21, many strongly AgRP-positive cell bodies were observed in the anx/anx arcuate nucleus vs. only few and weakly fluorescent ones in the wild type. The decrease in AgRP fiber density in anx/anx mice overlapped with an increase in Iba1 and TLR-2 immunoreactivities. Thus, the aberrant appearance of the AgRP system in the anx/anx mouse in the early postnatal development could involve a microglia-associated process and the innate immune system.
刺鼠相关蛋白（AgRP）是一种在下丘脑弓状核中表达的关键促食欲神经肽，是将饥饿激素信号传递至大脑的神经元的标志物。厌食（anx）突变纯合子小鼠的特征是食物摄入量减少、饥饿，并在3 - 5周龄时死亡。在此阶段，AgRP在细胞体中的免疫反应性增加，但在神经末梢中降低。我们研究了在出生后早期发育过程中，AgRP系统的异常表型在anx/anx小鼠中何时变得明显以及可能的潜在机制。通过免疫组织化学方法，在出生后第1天（P1）、第5天（P5）、第10天（P10）、第12天（P12）、第15天（P15）和第21天（P21）对anx/anx和野生型小鼠的AgRP、离子钙结合衔接分子（Iba1，一种活化小胶质细胞的标志物）以及Toll样受体2（TLR - 2）进行了研究。我们发现，anx/anx小鼠的AgRP系统在P12之前的发育与野生型相似，此时anx/anx小鼠的AgRP纤维在主要投射区域的密度停止增加。在P21时，与P15相比，anx/anx小鼠某些区域的AgRP纤维密度显著降低。在P21时，在anx/anx小鼠的弓状核中观察到许多强AgRP阳性细胞体，而野生型中只有少数且荧光较弱的细胞体。anx/anx小鼠中AgRP纤维密度的降低与Iba1和TLR - 2免疫反应性的增加相重叠。因此，出生后早期发育中anx/anx小鼠AgRP系统的异常出现可能涉及小胶质细胞相关过程和先天免疫系统。
