Centre for Neuroendocrinology, Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand.
J Neuroendocrinol. 2009 May;21(5):449-56. doi: 10.1111/j.1365-2826.2009.01862.x.
Hypothalamic leptin resistance during pregnancy is an important adaptation that facilitates the state of positive energy balance required for fat deposition in preparation for lactation. Within the arcuate nucleus, pro-opiomelanocortin (POMC) neurones and neuropeptide Y (NPY)/agouti-related gene protein (AgRP) neurones are first-order leptin responsive neurones involved in the regulation of energy balance. The present study aimed to investigate whether the regulation of these neuropeptides is disrupted during pregnancy in association with the development of leptin resistance. As measured by quantitative in situ hybridisation, POMC and AgRP mRNA levels were not significantly different during pregnancy, whereas NPY mRNA levels increased such that, by day 21 of pregnancy, levels were significantly higher than in nonpregnant, animals. These data suggest that these neurones were not responding normally to the elevated leptin found during pregnancy. To further characterise the melanocortin system during pregnancy, double-label immunohistochemistry was used to quantify leptin-induced phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in POMC neurones, using α-melanocyte-stimulating hormone (MSH) as a marker. The percentage of α-MSH neurones containing leptin-induced pSTAT3 did not significantly differ from nonpregnant animals, indicating that there was no change in the number of POMC neurones that respond to leptin during pregnancy. Treatment with α-MSH significantly reduced food intake in nonpregnant rats, but not in pregnant rats, indicating resistance to the satiety actions of α-MSH during pregnancy. The data suggest that multiple mechanisms contribute to leptin resistance during pregnancy. As well as a loss of responses in first-order leptin-responsive neurones in the arcuate nucleus, there is also a downstream disruption in the melanocortin system.
怀孕期间下丘脑瘦素抵抗是一种重要的适应机制，有助于促进正能量平衡状态，为泌乳期脂肪沉积做准备。在弓状核内，前阿黑皮素原（POMC）神经元和神经肽 Y（NPY）/刺鼠相关蛋白（AgRP）神经元是一级瘦素反应神经元，参与能量平衡的调节。本研究旨在探讨这些神经肽的调节是否在怀孕期间发生紊乱，与瘦素抵抗的发展有关。通过定量原位杂交测量，POMC 和 AgRP mRNA 水平在怀孕期间没有显著差异，而 NPY mRNA 水平增加，以至于在怀孕第 21 天，水平显著高于非怀孕动物。这些数据表明，这些神经元对怀孕期间升高的瘦素没有正常反应。为了进一步研究怀孕期间的黑素皮质素系统，使用双重免疫组织化学来定量 POMC 神经元中信号转导和转录激活因子 3（pSTAT3）的瘦素诱导磷酸化，使用 α-促黑素细胞激素（MSH）作为标记。含有瘦素诱导的 pSTAT3 的 α-MSH 神经元的百分比与非怀孕动物没有显著差异，表明在怀孕期间，对瘦素做出反应的 POMC 神经元数量没有变化。α-MSH 治疗显著减少了非怀孕大鼠的食物摄入量，但对怀孕大鼠没有影响，表明在怀孕期间，α-MSH 的饱食作用产生抵抗。数据表明，多种机制导致怀孕期间的瘦素抵抗。除了弓状核内一级瘦素反应神经元的反应丧失外，黑素皮质素系统也出现下游紊乱。
