SUN-LB082 Sexual Dimorphism of Phosphoethanolamine in HPA-Axis Response to LXR Agonist 25-Hydroxycholesterol: Neuroendocrine Implications for Major Depressive Disorder

Major depression is a chronic illness and a major component of disease burden, with high prevalence in women than in men. Plasma phosphoethanolamine (PEA) levels are significantly decreased in major depressive disorder (MDD) patients compared to healthy controls. Additionally, in the chronic ACTH treatment MDD mouse model, plasma and frontal cortex PEA were significantly decreased compared to vehicle treated controls. However, the reasons behind MDD prevalence in females, the neuroendocrine mechanisms by which PEA changes in vivo, and its role in the pathobiology of MDD is not yet understood. In cells, LXR agonist 25-hydroxycholesterol increased PEA levels: To understand the sexually dimorphic PEA function in the neuroendocrine circuitry of MDD, basal in vivo central and peripheral PEA levels, as well as post 25-hydroxylcholesterol treatment PEA levels in blood plasma, adrenal gland, and brain nuclei implicated in MDD were studied in mice. Both targeted and untargeted metabolomics analysis using capillary electrophoresis-mass spectrometry were applied to measure PEA and various metabolite levels in the respective tissues. Here we report that compared to vehicle control females, vehicle treated male mice had about 50% higher basal plasma PEA levels than females. In the brain areas implicated in MDD, male mice displayed significantly increased basal PEA levels compared to female basal levels by about 3 fold. Specifically, basal PEA levels in males were higher than females in the frontal cortex, striatum, hippocampus, hypothalamus, and the amygdala. Moreover, while acute LXR agonist, 25-hydroxycholesterol decreased plasma PEA levels, chronic LXR agonism significantly increased plasma PEA levels in both male and female mice. Hypothalamic PEA decreased by 20% in females and 80% in males after LXR agonist treatment. Moreover, basal adrenal PEA was 45% significantly higher in females than in males; and 25-hydroxycholesterol significantly increased female adrenal PEA by 35% over basal levels, with no change in males. Metabolomics analysis further revealed significant changes in levels of several metabolites in the plasma, brains, and adrenals of 25-hydroxycholesterol treated mice in a sexually dimorphic manner. These findings underscore the importance of the PEA-LXR system in explaining the sexual dimorphic differential coping strategy of the two sexes to stressful stimuli; and may serve as a novel potential diagnostic and therapeutic target for major depressive disorder. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.