Kilian T M, Klöting N, Blüher M, Beck-Sickinger A G
Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Universität Leipzig, Leipzig, Germany.
IFB AdiposityDiseases, Core Unit "Animal Models", Universität Leipzig, Leipzig, Germany.
Int J Obes (Lond). 2016 Apr;40(4):698-705. doi: 10.1038/ijo.2015.227. Epub 2015 Aug 26.
INTRODUCTION/OBJECTIVES: The protein delta homolog 1 (DLK1) has been reported to have an important role as inhibitor of adipogenesis. Understanding its mode of action can be a promising approach to cope with the formation of obesity. However, data on DLK1 signaling are not consistent, and especially its role as negative regulator of Notch receptors is discussed controversially.
DLK1 effects have been investigated in differentiated 3T3-L1 cells by Adipokine Profiler Array, enzyme-linked immunosorbent assay and quantitative real-time PCR (qRT-PCR). In vivo effects of DLK1 on adipogenesis have been studied by the DLK1 treatment of pregnant C57BL/6NTac mice and the phenotypical characterization of the offspring fed on chow or high-fat diet (HFD). Furthermore, gene expression of key adipogenesis genes in adipose tissue (AT) samples was observed by qRT-PCR.
In 3T3-L1 cells, DLK1 was found to be an inhibitor of Notch1 signaling. Gene expression of Notch1 and Hes1 was lowered by 53% and 65%, respectively, and the expression of protein target PAI-1 was decreased by 51%. The offspring of DLK1-treated pregnant mice were fed chow or HFD starting from week 4. At week 18, a larger proportion of visceral AT was determined on HFD after DLK1 treatment (P=0.011), whereas adipocyte size was reduced (P=0.007 for maximal size). This was affiliated to an upregulation of adipocyte differentiation. The underlying mechanism was found in an increased expression of the Notch1 receptor gene and protein in AT of the offsprings independently of the diet. However, feeding a chow diet resulted in a decreased expression of Notch1 target genes Hes1 and RBP-Jκ, whereas under HFD these genes were upregulated.
Treatment of mice with recombinant human DLK1 during pregnancy has significant effects on AT of the offspring. This can be associated with counter-regulatory changes in the Notch1 signaling cascade.
引言/目的：据报道，蛋白质δ同源物1（DLK1）作为脂肪生成的抑制剂发挥着重要作用。了解其作用模式可能是应对肥胖形成的一种有前景的方法。然而，关于DLK1信号传导的数据并不一致，尤其是其作为Notch受体负调节因子的作用存在争议。
通过脂肪因子分析阵列、酶联免疫吸附测定和定量实时聚合酶链反应（qRT-PCR），在分化的3T3-L1细胞中研究了DLK1的作用。通过对怀孕的C57BL/6NTac小鼠进行DLK1处理，并对以普通饲料或高脂饮食（HFD）喂养的后代进行表型特征分析，研究了DLK1对体内脂肪生成的影响。此外，通过qRT-PCR观察脂肪组织（AT）样本中关键脂肪生成基因的基因表达。
在3T3-L1细胞中，发现DLK1是Notch1信号传导的抑制剂。Notch1和Hes1的基因表达分别降低了53%和65%，蛋白质靶标PAI-1的表达降低了51%。从第4周开始，对经DLK1处理的怀孕小鼠的后代喂食普通饲料或HFD。在第18周时，DLK1处理后，HFD喂养的小鼠内脏AT的比例更大（P=0.011），而脂肪细胞大小减小（最大尺寸P=0.007）。这与脂肪细胞分化的上调有关。其潜在机制是后代的AT中Notch1受体基因和蛋白质的表达增加，且与饮食无关。然而，喂食普通饲料会导致Notch1靶基因Hes1和RBP-Jκ的表达降低，而在HFD喂养下这些基因会上调。
孕期用重组人DLK1治疗小鼠对后代的AT有显著影响。这可能与Notch1信号级联反应中的反调节变化有关。
