Postnatal undernutrition delays a key step in the maturation of hypothalamic feeding circuits.
Postnatal undernutrition delays a key step in the maturation of hypothalamic feeding circuits.
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DOI：
10.1016/j.molmet.2016.01.003
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发表时间：
2016-03
影响因子：
8.1
通讯作者：
Zeltser LM
中科院分区：
文献类型：
--
作者：
Juan De Solis A;Baquero AF;Bennett CM;Grove KL;Zeltser LM
在发育过程中暴露于营养不良（UN）的人类和动物在食物供应充足时往往会经历加速的“追赶”生长。关于调节早期生长率的机制知之甚少。我们以前曾报道，瘦素和突触前输入食欲神经肽Y/银蛋白/GABA（NAG）神经元在下丘脑弓状核的行动几乎完全兴奋在哺乳期，因为神经元和体液抑制系统不发展，直到断奶后。此外，我们确定了一个关键的步骤，调节成熟的NAG神经元的电生理反应在断奶-开始的基因编码ATP依赖性钾（KATP）通道亚基。我们探讨了UN促进随后的追赶性生长的可能性，部分原因是通过延迟负反馈系统成熟到驱动食物摄入的神经元回路。我们使用大窝仔（LL）大小模型来研究出生后联合国的影响，其次是追赶增长。我们评估了成熟的突触前和突触后抑制系统的NAG神经元使用的电生理和分子标准相结合，结合瘦素的能力，抑制禁食诱导的摄食过多。相对于对照组，LL后代的KATP通道亚基表达和功能的开始、瘦素对NAG神经元的作用的开关、NAG神经元的抑制性输入的向内生长以及对进食回路的稳态反馈的发展被延迟。功能性KATP通道的发展和建立瘦素介导的抑制食物摄入的围断奶期紧密相连，直到LL后代的生长和肥胖赶上控制才开始。我们的数据支持的想法，启动KATP通道亚基表达NAG神经元作为一个分子的看门人的成熟的稳态喂养电路。营养不足延迟NAG神经元突触前和突触后抑制信号传导。当UN后代达到对照组的体重时，KATP通道表达开始。瘦素抑制进食的能力的开始与KATP通道表达一致。KATP通道可能作为看门人的成熟电路延迟UN。
Humans and animals exposed to undernutrition (UN) during development often experience accelerated “catch-up” growth when food supplies are plentiful. Little is known about the mechanisms regulating early growth rates. We previously reported that actions of leptin and presynaptic inputs to orexigenic NPY/AgRP/GABA (NAG) neurons in the arcuate nucleus of the hypothalamus are almost exclusively excitatory during the lactation period, since neuronal and humoral inhibitory systems do not develop until after weaning. Moreover, we identified a critical step that regulates the maturation of electrophysiological responses of NAG neurons at weaning – the onset of genes encoding ATP-dependent potassium (KATP) channel subunits. We explored the possibility that UN promotes subsequent catch-up growth, in part, by delaying the maturation of negative feedback systems to neuronal circuits driving food intake. We used the large litter (LL) size model to study the impacts of postnatal UN followed by catch-up growth. We evaluated the maturation of presynaptic and postsynaptic inhibitory systems in NAG neurons using a combination of electrophysiological and molecular criteria, in conjunction with leptin's ability to suppress fasting-induced hyperphagia. The onset of KATP channel subunit expression and function, the switch in leptin's effect on NAG neurons, the ingrowth of inhibitory inputs to NAG neurons, and the development of homeostatic feedback to feeding circuits were delayed in LL offspring relative to controls. The development of functional KATP channels and the establishment of leptin-mediated suppression of food intake in the peri-weaning period were tightly linked and were not initiated until growth and adiposity of LL offspring caught up to controls. Our data support the idea that initiation of KATP channel subunit expression in NAG neurons serves as a molecular gatekeeper for the maturation of homeostatic feeding circuits. Undernutrition delays pre- and post-synaptic inhibitory signaling in NAG neurons. KATP channel expression is initiated when UN offspring reach the weight of controls. Onset of leptin's ability to suppress feeding coincides with KATP channel expression. KATP channels may act as gatekeepers for the maturation of circuits delayed by UN.