Departments of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada.
Departments of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada; Medicine, Faculty of Medicine, University of Toronto, Ontario, Canada; Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Ontario, Canada.
Mol Cell Endocrinol. 2020 Dec 1;518:110991. doi: 10.1016/j.mce.2020.110991. Epub 2020 Aug 22.
The function of the gonadotropin-releasing hormone (GnRH) neuron is critical to maintain reproductive function and a significant decrease in GnRH can lead to disorders affecting fertility, including hypogonadotropic hypogonadism. Spexin (SPX) is a novel hypothalamic neuropeptide that exerts inhibitory effects on reproduction and feeding by acting through galanin receptor 2 (GALR2) and galanin receptor 3 (GALR3). Fatty acids can act as nutritional signals that regulate the hypothalamic-pituitary-gonadal (HPG) axis, and elevated levels of circulating saturated fatty acids associated with high fat diet (HFD)-feeding have been shown to induce neuroinflammation, endoplasmic reticulum stress and hormonal resistance in the hypothalamus, as well as alter neuropeptide expression. We previously demonstrated that palmitate, the most common saturated fatty acid in a HFD, elevates the expression of Spx, Galr2 and Galr3 mRNA in a model of appetite-regulating neuropeptide Y hypothalamic neurons. Here, we found that Spx, Galr2 and Galr3 mRNA were also significantly induced by palmitate in a model of reproductive GnRH neurons, mHypoA-GnRH/GFP. As a follow-up to our previous report, we examined the molecular pathways by which Spx and galanin receptor mRNA was regulated in this cell line. Furthermore, we performed inhibitor studies, which revealed that the effect of palmitate on Spx and Galr3 mRNA involved activation of the innate immune receptor TLR4, and we detected differential regulation of the three genes by the protein kinases PKC, JNK, ERK, and p38. However, the intracellular metabolism of palmitate to ceramide did not appear to be involved in the palmitate-mediated gene regulation. Overall, this suggests that SPX may play a role in reproduction at the level of the hypothalamus and the pathways by which Spx, Galr2 and Galr3 are altered by fatty acids could provide insight into the mechanisms underlying reproductive dysfunction in obesity.
促性腺激素释放激素（GnRH）神经元的功能对于维持生殖功能至关重要，而 GnRH 的显著减少可导致影响生育的疾病，包括促性腺激素低下性性腺功能减退症。Spexin（SPX）是一种新的下丘脑神经肽，通过作用于甘丙肽受体 2（GALR2）和甘丙肽受体 3（GALR3）对生殖和摄食产生抑制作用。脂肪酸可以作为调节下丘脑-垂体-性腺（HPG）轴的营养信号，并且与高脂肪饮食（HFD）喂养相关的循环饱和脂肪酸水平升高已被证明可诱导下丘脑的神经炎症、内质网应激和激素抵抗，以及改变神经肽表达。我们之前的研究表明，棕榈酸是 HFD 中最常见的饱和脂肪酸，可上调食欲调节神经肽 Y 下丘脑神经元模型中 Spx、Galr2 和 Galr3 mRNA 的表达。在这里，我们发现棕榈酸也可显著诱导生殖 GnRH 神经元模型 mHypoA-GnRH/GFP 中 Spx、Galr2 和 Galr3 mRNA 的表达。作为我们之前报告的后续，我们检查了 Spx 和甘丙肽受体 mRNA 在该细胞系中受调控的分子途径。此外，我们进行了抑制剂研究，结果表明棕榈酸对 Spx 和 Galr3 mRNA 的作用涉及先天免疫受体 TLR4 的激活，并且我们检测到三种基因受蛋白激酶 PKC、JNK、ERK 和 p38 的差异调节。然而，棕榈酸向神经酰胺的细胞内代谢似乎不参与棕榈酸介导的基因调控。总体而言，这表明 SPX 可能在下丘脑水平上在生殖中发挥作用，并且脂肪酸改变 Spx、Galr2 和 Galr3 的途径可能为肥胖症生殖功能障碍的机制提供深入了解。
