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Deletion of pleiotrophin impairs glucose tolerance and liver metabolism in pregnant mice: Moonlighting role of glycerol kinase
The FASEB Journal ( IF 4.8 ) Pub Date : 2021-09-22 , DOI: 10.1096/fj.202101181r
Begoña Zapatería 1 , Julio Sevillano 1 , María Gracia Sánchez-Alonso 1 , María Limones 1 , Javier Pizarro-Delgado 1 , Agata Zuccaro 1 , Gonzalo Herradón 2 , Gema Medina-Gómez 3 , María Pilar Ramos-Álvarez 1
Affiliation  

Pleiotrophin is a pleiotropic cytokine that has been demonstrated to have a critical role in regulating energy metabolism, lipid turnover and plasticity of adipose tissue. Here, we hypothesize that this cytokine can be involved in regulatory processes of glucose and lipid homeostasis in the liver during pregnancy. Using 18-days pregnant Ptn-deficient mice, we evaluated the biochemical profile (circulating variables), tissue mRNA expression (qPCR) and protein levels of key enzymes and transcription factors involved in main metabolic pathways. Ptn deletion was associated with a reduction in body weight gain, hyperglycemia and glucose intolerance. Moreover, we observed an impairment in glucose synthesis and degradation during late pregnancy in Ptn−/− mice. Hepatic lipid content was significantly lower (73.6%) in Ptn−/− mice and was associated with a clear reduction in fatty acid, triacylglycerides and cholesterol synthesis. Ptn deletion was accompanying with a diabetogenic state in the mother and a decreased expression of key proteins involved in glucose and lipid uptake and metabolism. Moreover, Ptn−/− pregnant mice have a decreased expression of transcription factors, such as PPAR-α, regulating lipid uptake and glucose and lipid utilization. Furthermore, the augmented expression and nuclear translocation of glycerol kinase, and the decrease in NUR77 protein levels in the knock-out animals can further explain the alterations observed in hepatic glucose metabolism. Our results point out for the first time that pleiotrophin is an important player in maintaining hepatic metabolic homeostasis during late gestation, and further highlighted the moonlighting role of glycerol kinase in the regulation of maternal glucose homeostasis during pregnancy.

中文翻译:

多效蛋白的缺失会损害怀孕小鼠的葡萄糖耐量和肝脏代谢:甘油激酶的月光化作用

Pleiotrophin 是一种多效性细胞因子,已被证明在调节能量代谢、脂质周转和脂肪组织的可塑性方面具有关键作用。在这里,我们假设这种细胞因子可能参与怀孕期间肝脏中葡萄糖和脂质稳态的调节过程。使用怀孕 18 天的Ptn缺陷小鼠,我们评估了主要代谢途径中涉及的关键酶和转录因子的生化特征(循环变量)、组织 mRNA 表达 (qPCR) 和蛋白质水平。Ptn缺失与体重增加、高血糖和葡萄糖耐受不良的减少有关。此外,我们观察到Ptn -/-妊娠晚期葡萄糖合成和降解受损老鼠。Ptn -/-小鼠的肝脏脂质含量显着降低(73.6%),并且与脂肪酸、甘油三酯和胆固醇合成的明显减少有关。Ptn缺失伴随着母亲的糖尿病状态以及参与葡萄糖和脂质摄取和代谢的关键蛋白质的表达降低。此外,Ptn -/-怀孕小鼠的转录因子表达降低,如 PPAR-α,调节脂质摄取和葡萄糖和脂质利用。此外,甘油激酶的表达增加和核转位,以及敲除动物中 NUR77 蛋白水平的降低可以进一步解释在肝脏葡萄糖代谢中观察到的变化。我们的研究结果首次指出多效素是维持妊娠晚期肝脏代谢稳态的重要参与者,并进一步强调了甘油激酶在妊娠期母体葡萄糖稳态调节中的间接作用。
更新日期:2021-09-23
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