LKB1 alleviates high glucose- and high fat-induced inflammation and the expression of GnRH and sexual precocity-related genes, in mouse hypothalamic cells by activating the AMPK/FOXO1 signaling pathway

Abstract

Precocious puberty (PP) is a developmental disorder. Hypothalamic cells can produce gonadotropin-releasing hormone (GnRH), the final output of neuroendocrine regulation that occurs during puberty. The aim of the present study was to investigate the role of live kinase B1 (LKB1), also known as serine/threonine kinase, in the progression of PP and identify the underlying mechanisms. First, the levels of LKB1 in peripheral blood and peripheral blood mononuclear cells of children with PP were detected by reverse transcription-quantitative (RT-q) PCR or western blotting. After the GT1-7 mouse hypothalamus cell line was treated with high glucose (HG) and high fat (HF), the expression of LKB1 and GnRH was tested. LKB1 was overexpressed by transfection with a pcDNA3.1 plasmid and the levels of inflammatory factors, GnRH, PP-related factors and proteins in the AMP-activated protein kinase (AMPK)/forkhead box protein O1 (FOXO1) pathway were determined using RT-qPCR or western blot analysis. Subsequently, Compound C, an inhibitor of AMPK/FOXO1 signaling, was used to clarify whether the effects of LKB1 on PP were mediated by the regulation of this pathway. Results indicated that children with PP exhibited a lower LKB1 expression. In addition, HG and HF culture resulted in an enhanced GnRH expression and a reduced LKB1 expression in GT1-7 cells. LKB1 overexpression inhibited the contents of TNF-α, IL-6 and GnRH in in GT1-7 cells exposed to HG and HF and reduced the expression of PP-related proteins, including estrogen receptor-β, cluster of differentiation 36 and G-protein-coupled receptor. In addition, the expression of phosphorylated (p)-AMPK and p-FOXO1 was markedly downregulated following LKBI overexpression. Furthermore, compound C intervention partially diminished the inhibitory effects of LKB1-mediated upregulation on the levels of inflammation and PP-related factors. In conclusion, these results demonstrated that LKB1 alleviated HG- and HF-induced inflammation, as well as the expression of GnRH and sexual precocity-related genes, in GT1-7 cells by activating the AMPK/FOXO1 signaling pathway.