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Plasma phosphoethanolamine (PEA) levels are significantly decreased in major depressive disorder (MDD) patients compared to healthy controls: Also, in chronic ACTH treatment mouse model of MDD, plasma and frontal cortex PEA were significantly decreased compared to vehicle treated controls: PEA has thus been proposed as a potential diagnostic biomarker for MDD. However, the neuroendocrine mechanism by which PEA changes in vivo, and its role in the pathobiology of MDD is not yet known. Previous in vitro studies reported that the endogenous LXR agonist 25-hydroxycholesterol, the intermediate precursor for the conversion of cholesterol to steroid hormones in the adrenal gland, caused increased PEA levels in cells. To understand PEA function in the neuroendocrine circuitry of MDD, in vivo effects of 25-hydroxylcholesterol on 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 while acute LXR agonism with 25-hydroxycholesterol decreased plasma PEA levels, chronic LXR agonism significantly increased plasma PEA levels in both male and female mice. Moreover, in the adrenal gland where LXR agonism mediates the synthesis of glucocorticoids from cholesterol, 25-hydroxycholesterol significantly increased adrenal PEA levels in female mice; with no change in PEA in male mice compared to vehicle treated controls. Furthermore, in the hypothalamus compared to vehicle controls, LXR agonism caused significant PEA level decrease in female mice by 20%; and by 80% increase in male mice. Additionally, metabolomics results showed significant changes in levels of several metabolites in key brain and peripheral tissues of 25-hydroxycholesterol treated mice. These results are suggestive of a neuroendocrine role for PEA in the pathobiology of MDD; and that by way of LXR signaling PEA may impact the hypothalamic-pituitary-adrenal axis in the control of stress response. 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.

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.

Prior studies have revealed that the sympathetic nervous system regulates the clinical and pathological manifestations of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model mediated by Th1 T cells. Although the regulatory role of catecholamines has been indicated in the previous works, it remained possible that other sympathetic neurotransmitters like neuropeptide Y (NPY) may also be involved in the regulation of EAE. Here we examined the effect of NPY and NPY receptor subtype-specific compounds on EAE, actively induced with myelin oligodendrocyte glycoprotein 35–55 in C57BL/6 mice. Our results revealed that exogenous NPY as well as NPY Y1 receptor agonists significantly inhibited the induction of EAE, whereas a Y5 receptor agonist or a combined treatment of NPY with a Y1 receptor antagonist did not inhibit signs of EAE. These results indicate that the suppression of EAE by NPY is mediated via Y1 receptors. Furthermore, treatment with the Y1 receptor antagonist induced a significantly earlier onset of EAE, indicating a protective role of endogenous NPY in the induction phase of EAE. We also revealed a significant inhibition of myelin oligodendrocyte glycoprotein 35–55-specific Th1 response as well as a Th2 bias of the autoimmune T cells in mice treated with the Y1 receptor agonist. Ex vivo analysis further demonstrated that autoimmune T cells are directly affected by NPY via Y1 receptors. Taken together, we conclude that NPY is a potent immunomodulator involved in the regulation of the Th1-mediated autoimmune disease EAE.

Aims: To evaluate effects of exposure to bisphenol A diglycidyl ether (BADGE) on urinary excretion of bisphenol A, and plasma gonadotrophic hormones and testosterone in male epoxy resin sprayers. Methods: Cross sectional study of 42 workers whose job was to spray epoxy resin hardening agents including BADGE and mixed organic solvents, and 42 matched control workers without BADGE use in the same machine plants. Results: Concentrations of urinary bisphenol A were higher in the epoxy resin sprayers (median 1.06 µmol/mol creatinine) compared with the controls (median 0.52 µmol/mol creatinine). Urinary metabolite concentrations of organic solvents used were all higher in the epoxy resin workers compared with the controls. Endocrinological examination showed different concentrations of follicle stimulating hormone (FSH) between the epoxy sprayers (median 5.3 mIU/ml) and the controls (median 7.6 mIU/ml). FSH showed a mild correlation with urinary bisphenol A, but not with the metabolites of organic solvents. Luteinising hormone and free testosterone concentrations did not differ between the two groups. Conclusion: BADGE may generate bisphenol A endogenously. Results suggest that bisphenol A may disrupt secretion of gonadotrophic hormones in men. The clinical significance of endocrine disrupting effects by bisphenol A should be further investigated in male workers exposed to bisphenol A.

Objective: The lateral hypothalamic area (LHa) is involved in various functions such as feeding, drinking, sexual and reward behavior, among others. Recently, we demonstrated that the LHa can regulate cellular immunity in the spleen. In experiments involving the LHa, it was noticed that the spleen shrinks noticeably after LHa destruction. To explore this phenomenon further, the effect of LHa lesioning on splenocyte apoptosis was investigated. Methods: Male Wistar-King-Aptekman rats underwent bilateral lesioning of their LHa and consequent spleen weights, splenocyte numbers and apoptosis were measured. For the detection of splenocyte apoptosis, both ELISA, which measures DNA fragmentation within the splenocytes, and flow cytometry, which measures the percentage of apoptotic lymphocytes in the spleen, were used. Results: In the LHa-lesioned rats, spleen weights and the number of splenocytes decreased significantly within 24 h. Additionally, in the spleen, lymphocyte apoptosis significantly increased compared to the control after 6 h. Conclusion: These results suggest that the LHa may play a role in immunoregulation by affecting lymphocytes in the spleen through apoptosis and may be relevant to the pathway of stress-induced apoptosis.

In rats splenic natural killer (NK) cell activity was found to be significantly higher following chronic uncontrollable electrical stimulation of the lateral hypothalamus in fully conscious rats, compared to sham-operated rats. In a pre-test study, all rats had demonstrated that the electrode site had self-stimulating properties, which supports the possibility that the experience of reward may be implicated in NK cell activity augmentation.

Electrical stimulation of the lateral hypothalamus (LH) in rats increased splenic natural killer (NK) cell activity, whereas electrical ablation of the LH decreased it. However, the percentage of NK cells, as detected by the anti-NKR-P1 monoclonal antibody, in the spleen did not change significantly. These results suggest that the LH does not modulate the splenic NK cell activity by increasing the NK cell number but by increasing the intrinsic NK cell activity itself.

Natural killer cell (NK) activity in WKA and SD rats was found to be significantly higher following electrical stimulation of the lateral hypothalamus (LH) compared to sham operated. There was no such difference between sham operated rats and those receiving electrical stimulation in the frontal cortex as a control. Operations were performed under sodium pentobarbital anesthetic, and NK activity against YAC-1 target cells was measured 20 h later using 51Cr release assay. The LH area stimulated is a potent reward center and that stimulation of this point increased NK activity opens the possibility that pleasure might play a role in cellular immunity.

Publisher Summary This chapter summarizes the effect of the LH and reward behavior on the augmentation of cellular immunity. In addition to NK cell population and function, T-cell populations and Th1 functions are modulated centrally by the LH and by reward stimulation. LH does not modulate splenic NK cell activity by increasing NK cell numbers, but rather by increasing NK cell activity. Chronic stimulation of the LH caused significant augmentation of NK cell activity. Rats responding to LH stimulation with feeding showed a slightly greater effect than those responding with a locomotor reaction. The observed effects were anatomically specific. The involvement of the LH in reward phenomena was shown to be associated with NK cell augmentation as well. T-cell and Th1 cell functions are sensitive to stress. However, there are no data that illustrate the correlation of reward center with T cells and with their function. Results strongly suggest that excitation of the LH is linked with reward behavior and that pleasure increases type 1 T-cell functions. Ablation of the LH decreased Th1 activity and augmented Th2 activity. The direction of the effects of LH treatment on T-cell function coincides nicely with the effects on NK cells. It might now be safely said that reward links with increased Th1 activity and that, together with NK cell activity, reward or pleasure plays an important role in anticancer, antiviral, and cellular immunity via T-cell cytokine production.

Energy expenditure abnormalities have been observed in anorexia nervosa (AN). The uncoupling proteins (UCPs) have been implicated as having a role in energy metabolism and thermogenesis, and an association between a marker flanking the UCP-2/UCP-3 gene cluster and AN has been reported. Also known are insertion/deletion and -866G/A polymorphisms in the UCP-2 gene, and the -55C/T polymorphism in the UCP-3 gene. Differences in these alleles are reportedly related to changes in energy expenditure, body mass index, fat tissue accumulation and obesity. Therefore, this case-control association analysis was done to determine whether any of these UCP-2/3 gene polymorphisms are related to a predisposition to AN. In analysis of a cohort of 106 female Japanese AN sufferers and 126 normal female controls, we found no between-group differences in the polymorphism frequencies of these groups. The hypothesis that differences in the UCP-2/3 gene influence the susceptibility to AN was not supported.

To examine the relationship between altered cellular immune status and clustered features of the metabolic syndrome, we measured body mass index (BMI), serum concentrations of high-density lipoprotein-cholesterol, triglycerides, fasting plasma glucose, and blood pressure levels as well as differential leukocyte counts and lymphocyte sub-populations among 439 apparently healthy Japanese men aged 35-60 years. The components of the metabolic syndrome were defined based on the following criteria: BMI/=25.0 kg/m(2), fasting plasma glucose/=6.11 mmol/l, systolic blood pressure/=130 mmHg and/or diastolic blood pressure/=85 mmHg, high-density lipoprotein (HDL)-cholesterol1.03 mmol/l, and fasting triglyceride/=1.69 mmol/l. Counts of total leukocyte, total lymphocyte, CD3 + T cell, CD4 + T cell, and CD4 + CD45RO + T cell significantly correlated with the number of components of the metabolic syndrome (0, 1, 2, and 3+) after adjustment for age and smoking status. These findings were more evident among smokers than among non-smokers. The counts of total leukocytes, total lymphocytes and more specifically memory (CD4 + CD45RO + T) cells were elevated with clustered features of the metabolic syndrome in middle-aged men, which suggest the involvement of altered cellular immune status in the pathogenesis of atherosclerosis.

Objectives: Insomnia is associated with physical and mental disorders. We examined the effect of insomnia on immune functions, focusing on the T helper 1 (Th1)/ T helper 2 (Th2) balance, by a cross-sectional design. Methods: We provided a self-administered questionnaire to evaluate sleep habits, smoking and medical disorders to 578 men without any toxic exposure (20–64 years old), and measured natural killer (NK) cell activity in 324 men and production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) after stimulation with phytohemagglutinin in 254 men. According to the criteria of DSM-IV, in which insomnia is classified into primary and secondary insomnia, we assessed the effect of insomnia on immune functions, controlling for age and smoking in groups with and without medical disorders. Results: The prevalence of insomnia in the present study was 9.2%. In the absence of medical disorders, insomniac men had a significantly lower IFN-γ and ratio of IFN-γ to IL-4 than noninsomniac men. Men with insufficient sleep or difficulty initiating sleep (DIS) had a significantly lower IFN-γ to IL-4 ratio than those not suffering from insufficient sleep or DIS. In the presence of medical disorders, insomniac men had significantly higher IL-4 than noninsomniac men. Men with difficulty maintaining sleep (DMS) had a significantly lower IFN-γ to IL-4 ratio than men without DMS. NK cell activity was independent of insomnia. Conclusions: The present results showed a link between insomnia unrelated to medical disorders and a shift in the Th1/Th2 balance toward Th2 dominance, indicating that the relationship between sleep quality and the etiology of immune-related diseases should be reconsidered.

Objectives: Recent studies have shown that apoptosis is involved in stress responses. The present study examined if stressors increase in vitro apoptosis of peripheral blood T lymphocytes in a dose-dependent manner. Methods: Daily subjective stress was quantitatively analyzed in 40 nonsmoking men with a daily hassles questionnaire. Apoptosis of T lymphocytes was measured by flowcytometry using Annexin V/PI double staining method after 0, 12, and 24 h of culture in the presence or absence of dexamethasone (DEX). Using a cross-sectional design, the current study examined the relationship between stress and in vitro apoptosis of T cells. Results: Results showed that apoptosis of T lymphocytes in vitro has a significant correlation with stress and age. Stress was positively correlated with percentage of apoptosis in T cells after 12 h of culture, irrespective of DEX treatment. Age was positively correlated with the percentage of T cell apoptosis after 0 and 12 h of coculture with DEX. Conclusions: These results indicate that age-related apoptosis and stress-related apoptosis of T cells are modulated through different mechanisms. This is the first study to show that in vitro lymphocyte apoptosis is influenced by daily stress in a dose-dependent manner.

Elevated plasma tumor necrosis factor-alpha (TNFalpha) levels and enhanced spontaneous TNFalpha release from peripheral blood mononuclear cells in patients with anorexia nervosa (AN) have been reported. TNFalpha activates the hypothalamic-pituitary-adrenal axis and reduces food intake, which is characteristic of eating disorders. Recently, three novel polymorphisms in the 5'-flanking region of the TNFalpha gene were reported at positions -1031 (T --> C substitution), -863 (C --> A) and -857 (C --> T). Differences in these alleles are reportedly related to altered TNFalpha-transcriptional promoter activity. Therefore, we performed a case-control association analysis to determine whether any of those three polymorphisms in the TNFalpha promoter region were involved in a predisposition to AN. The results of our analysis of a cohort of 79 female Japanese AN sufferers and 127 normal female control subjects provide no support for the hypothesis that -1031T/C, -863 C/A and -857C/T polymorphisms in the TNFalpha gene promoter region influence the susceptibility to AN.

Though immune outcome is known to be determined by which helper T cell response predominates, no local mechanism has yet been established which can explain how the neuronal system may control this. It is possible that the nervous system releases neuropeptides at specific local sites of infection or challenge, which triggers lymphocytes at those points to release specific cytokine profiles. These may then influence the direction of the Th1/Th2 response and therefore immune outcome. The aim of this study was to evaluate whether and if so how neuropeptides influence cytokine production by lymphocytes, especially T cells. We investigated the effects of neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP) on the production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) by stimulating nonadherent splenocytes and helper T cell clones with antigens in vitro in the presence or absence of these peptides. NPY greatly enhanced IL-4 production and inhibited IFN-gamma. CGRP inhibited IFN-gamma production markedly in a dose-dependent manner, but had no effects on IL-4 production. SP and VIP had no effects on IFN-gamma production, but SP enhanced and VIP suppressed IL-4 production slightly but consistently. Therefore neuropeptides can influence cytokine production. This opens the door to speculations that these specific cytokine profiles might play a part in influencing the direction of the consequent Th1/Th2 cascade and immune outcome and possibly the pathogenesis of immune-related diseases.