Aberrant Glucocorticoid Receptor Signaling Drives Hepatic Steatosis in Ovarian Insufficient Mice

Presentation Number: OR02-4
Date of Presentation: April 4th, 2017

Matthew Allan Quinn*1, Xiaojiang Xu2 and John A Cidlowski3
1National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, 2National Institute of Environmental Health Sciences (NIEHS/NIH), Research Triangle Park, NC, 3NIEHS/NIH, Research Triangle Park, NC


Menopause is characterized by decreased ovarian function resulting in a sequela of pathologies including the metabolic syndrome. Classically, the lack of ovarian hormones is thought to underlie the metabolic abnormalities associated with menopause. Here, using a surgical model of menopause in mice via ovariectomy we show in fact stress hormones, via the glucocorticoid receptor (GR), are the pathogenic driver of metabolic syndrome and hepatic steatosis during ovarian insufficiency. Targeting the GR pathway via adrenalectomy (ADX) or hepatocyte-specific deletion of GR rescued/blocked OVX-induced steatosis. Utilizing RNA-Seq we found a large cohort of GR-regulated genes to be hyper-sensitive to glucocorticoid treatment in OVX’d mice compared to ovary intact animals. Gene network and gene set enrichment analysis revealed the hepatic lipid metabolism pathway to be the most sensitive GR-regulated pathway to be altered in response to lack of ovarian hormones. Within the lipogenic pathway we identified perilipin-5 (PLIN5) as a novel GR-regulated hepatic lipid metabolism gene contributing to corticosteroid-driven steatosis in OVX’d mice. Utilizing hepatocyte-specific ER knockout mice we discerned this phenomenon occurs via an estrogen receptor alpha independent mechanism. We found hyperphosphorylation of the glucocorticoid receptor at serine 211 in response to hormone treatment in OVX’d mice versus ovary intact mice suggesting altered cell signaling pathways converging on GR could promote hypersensitivity to glucocorticoids observed in OVX’d mice. Thus, we provide evidence stress hormones, rather than lack of ovarian hormones, are the pathogenic driver of metabolic complications in response to menopause.


Nothing to Disclose: MAQ, XX, JAC