Université de Lille, INSERM, CHU Lille, UMR-S1172, JPArc - Jean-Pierre Aubert Research Center Neurosciences and Cancer, Lille, France.
Neuroendocrinology. 2017;105(4):372-383. doi: 10.1159/000455048. Epub 2016 Dec 23.
Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin.
虽然禁食或能量亏缺对下丘脑神经肽回路的短期影响现在已经得到更好的理解，但长期能量亏缺和再喂养的影响仍有待阐明。我们发现，在长期能量亏缺后，尽管脂肪量、卵巢活动和进食行为得到恢复，小鼠在再喂养期间仍持续表现出低瘦素血症。我们旨在研究能量亏缺 10 周后和营养恢复 10 周后的下丘脑适应。为此，我们评估了瘦素受体和主要食欲肽和厌食肽及其受体的 mRNA 水平，这些受体受瘦素调节。评估了下丘脑炎症标志物，因为瘦素也可能参与这种现象。长期限时喂养和分离诱导下丘脑食欲肽的 mRNA 水平显著增加，而 Y1 和 Y5 受体 mRNA 下调。尽管黑皮质素受体 (MC3-R 和 MC4-R) 和 OXR1(OX 受体 1)的表达增加，但食欲素 (OX)、黑色素浓缩激素、促阿片黑素细胞皮质原、26RFa(26 个氨基酸 RF-酰胺肽)及其受体的 mRNA 水平没有变化。再喂养期诱导下丘脑瘦素受体 mRNA 过度表达。除 Y2、Y5、MC3-R 和 MC4-R 外，其他评估的 mRNA 水平均恢复正常，这些受体仍上调。即使白细胞介素-1β mRNA 水平与小胶质细胞活化标志物 Iba1（离子钙结合衔接分子 1）平行增加，神经炎症标志物也没有明显变化。在血浆瘦素水平低的再喂养小鼠中，通过重新校准下丘脑对瘦素的敏感性，可以维持瘦素调节功能和下丘脑基因表达的正常化。
