A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.
A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.
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DOI：
10.1002/cne.24327
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Simerly R
中科院分区：
文献类型：
--
作者：
Kamitakahara A;Bouyer K;Wang CH;Simerly R
在发育中的下丘脑中，脂肪衍生的激素瘦素刺激从下丘脑弓状核（ARH）到控制能量平衡的其他区域的轴突生长。这些预测显着减少瘦素缺陷（Lepob/ob）小鼠，这种表型在很大程度上是由新生儿瘦素治疗挽救。然而，成熟的Lepob/ob小鼠的治疗是无效的，这表明瘦素的营养作用仅限于发育的关键时期。为了在时间上描绘关闭这个关键时期的瘦素刺激的增长，我们治疗Lepob/ob小鼠与外源性瘦素在各种离散的时间段，并测量Agouti相关肽（AgRP）的密度含有从ARH的腹侧部分的背内侧核的下丘脑（DMHv），和室旁核（PVHmp）的内侧小细胞部分的投影。结果表明，瘦素失去其神经营养潜力或接近出生后第28天。瘦素暴露的持续时间似乎很重要，9天或11天的治疗比更短（5天）的治疗更有效。此外，瘦素治疗9天或更长时间足以恢复Lepob/ob雌性PVHmp和DMHv的AgRP神经支配，但仅恢复Lepob/ob雄性DMHv。总之，这些研究结果表明，瘦素的营养作用取决于瘦素暴露的时间和持续时间，显示目标和性别特异性，并且这些因素中的每一个对瘦素依赖性回路形成的调节可能对摄食行为、代谢和肥胖风险产生持久的后果。
In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lepob/ob) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lepob/ob mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lepob/ob mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11- day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lepob/ob females, but only to the DMHv in Lepob/ob males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk.
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