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，并且GnRH的显着下降会导致影响生育力的疾病，包括促性腺激素性性腺功能减退症。Spexin（SPX）是一种新型的下丘脑神经肽，它通过甘丙肽受体2（GALR2）和甘丙肽受体3（GALR3）发挥作用，对繁殖和喂养产生抑制作用。脂肪酸可以作为调节下丘脑-垂体-性腺（HPG）轴的营养信号，并且与高脂饮食（HFD）喂养相关的循环饱和脂肪酸水平升高已显示出诱导神经炎症，内质网应激和激素的作用。下丘脑抵抗力，以及改变神经肽表达。之前我们证明了棕榈酸酯食欲调节神经肽Y下丘脑神经元模型中的Spx，Garr2和Galr3 mRNA。在这里，我们发现在生殖GnRH神经元mHypoA-GnRH / GFP模型中，棕榈酸酯也显着诱导了Spx，Garr2和Galr3 mRNA。作为我们先前报告的后续，我们研究了在该细胞系中调节Spx和甘丙肽受体mRNA的分子途径。此外，我们进行了抑制剂研究，结果表明棕榈酸酯对Spx和Galr3的作用mRNA涉及先天免疫受体TLR4的激活，我们检测到了蛋白激酶PKC，JNK，ERK和p38对这三个基因的差异调节。但是，棕榈酸酯转化为神经酰胺的细胞内代谢似乎并不参与棕榈酸酯介导的基因调控。总的来说，这表明SPX可能在下丘脑水平上在生殖中起作用，而Spx，Garr2和Galr3被脂肪酸改变的途径可以提供对肥胖生殖功能障碍的潜在机制的了解。