Obesity‐Related Stressors Repress Gonadotropin‐releasing Hormone Gene Expression via the Transcription Factor c‐Fos

Abstract

In obesity, endoplasmic reticulum (ER) stress is a well‐characterized mediator of hormonal dysfunction in multiple tissues, including liver, pancreas, and adipose tissue. In the brain, ER stress induced by excess nutrients and inflammatory cytokines disrupts insulin and leptin sensitivity in hypothalamic neurons controlling food intake. Obesity‐related cellular stressors may also disrupt hypothalamic control of the reproductive system, as obesity is a risk factor for infertility in both men and women. Thus, we sought to determine how ER stress and nutrient excess directly affect production of gonadotropin‐releasing hormone (GnRH) by hypothalamic neurons. GnRH controls pituitary gonadotropin release and subsequent gonadal function, and expression of the Gnrh1 gene is regulated by multiple transcription factors and signaling pathways. Using an immortalized mouse hypothalamic cell line (GT1‐7), we determined that ER stress induced by tunicamycin or thapsigargin repressed expression of the Gnrh1 gene as measured by qRT‐PCR. We also exposed cells to a saturated fatty acid (palmitic acid) to mimic excess nutrients in obesity and observed similar Gnrh1 repression. Both ER stress and palmitic acid promoted inflammation in GT1‐7 cells, as measured by NFκB and JNK activation and IL‐6 production. Repression of Gnrh1 by ER stress was partially rescued by PKC and JNK inhibitors. Because ER stress and palmitic acid upregulated expression of Fos, and because c‐Fos is a known repressor of Gnrh1, we asked whether inhibition of c‐Fos transcriptional activity could rescue Gnrh1 repression. The c‐Fos/AP‐1 inhibitor T5224 was able to completely reverse repression of Gnrh1 by ER stress and palmitic acid, indicating a pivotal role for c‐Fos induction in Gnrh1 repression by obesity‐related stressors. Thus, our work suggests that obesity‐related stressors can directly impact GnRH neurons, and that dysregulation of Gnrh1 expression may contribute to obesity‐related infertility.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.