Glucocorticoid Regulation Research Articles

Corticosterone pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis activity via multiple actions that vary with time, site of action and de novo protein synthesis

Glucocorticoid regulation of the hypothalamic-pituitary-adrenal (HPA) axis is believed to depend on multiple actions operative within discrete time domains. However, the underlying cellular and molecular mechanisms for those glucocorticoid actions remain undetermined. Moreover, there is absence of in vivo studies examining whether there are multiple glucocorticoid effects on HPA axis-related function within an intermediate feedback time frame (1-3 h after glucocorticoid elevation), and whether those effects depend on de novo protein synthesis. We examined in rats the effects of protein synthesis inhibition on HPA axis response to restraint (15 min) after 1 and 3 h phasic corticosterone (CORT) pretreatment. We measured HPA axis hormones (ACTH and CORT) and gene expression in the paraventricular nucleus (c-fos and crh genes), as well as gene expression in the anterior and intermediate pituitaries (c-fos and pomc genes). Both CORT pretreatment intervals produced inhibition of stress-induced ACTH secretion, but no inhibition was observed in the presence of protein synthesis inhibition. CORT pretreatment produced inhibitory effects on stress-induced gene expression that varied for each gene depending on the anatomical site, pretreatment time, and protein synthesis dependency. Taken together, the ACTH and gene expression patterns support the presence of multiple independent glucocorticoid actions initiated during the intermediate glucocorticoid negative feedback phase. Moreover, we conclude that those effects are exerted predominantly on the intrinsic anatomical elements of the HPA axis, and some of those effects depend on CORT induction of the expression of one or more regulatory gene products.

Breast Cancer-Resistance Protein (BCRP1) in the Fetal Mouse Brain: Development and Glucocorticoid Regulation

Breast cancer-resistance protein (BCRP1), encoded by Abcg2 mRNA, limits the penetration of a spectrum of compounds into the brain. The fetal brain is a primary target for many BCRP1 substrates; however, the developmental expression, function, and regulation of Abcg2/BCRP1 in the mouse fetal brain are unknown. Synthetic glucocorticoids (e.g., dexamethasone [DEX]) increase Abcg2/BCRP1 expression and function in vitro in endothelial cells derived from brain microvessels. A regulatory role of glucocorticoids on Abcg2/BCRP1 in the fetal brain is of importance given that approximately 10% of pregnant women are treated with synthetic glucocorticoid for threatened preterm labor. We hypothesized the following: 1) Abcg2 mRNA and BCRP1 protein expression increases with development (from Embryonic Day [E] 15.5 to E18.5), corresponding to decreased accumulation of BCRP1 substrate in the fetal brain. 2) Maternal treatment with DEX will up-regulate Abcg2 mRNA and BCRP1 protein expression in the fetal brain, resulting in decreased BCRP1 substrate accumulation. Pregnant FVB dams were euthanized on E15.5 or E18.5, and fetal brains were collected and analyzed for [(3)H]mitoxantrone (BCRP1-specific substrate) accumulation and Abcg2/BCRP1 expression. In another six groups (n = 4-5/group), pregnant mice were treated with DEX (0.1 or 1 mg/kg) or vehicle (saline) from either E9.5 to E15.5 (midgestation) or E12.5 to E18.5 (late gestation) and then injected with [(3)H]mitoxantrone. In conclusion, Abcg2 mRNA expression significantly decreases with advancing gestation, while BCRP1-mediated neuroprotection increases. Furthermore, there is a dose-, sex-, and age-dependent effect of DEX on Abcg2 mRNA in the fetal brain in vivo, indicating a complex regulatory role of glucocorticoid during development.

Expression of complement and pentraxin proteins in acute phase response elicited by tumor photodynamic therapy: The engagement of adrenal hormones

Treatment of solid tumors by photodynamic therapy (PDT) was recently shown to trigger a strong acute phase response. Using the mouse Lewis lung carcinoma (LLC) model, the present study examined complement and pentraxin proteins as PDT-induced acute phase reactants. The results show a distinct pattern of changes in the expression of genes encoding these proteins in the tumor, as well as host liver and spleen, following PDT mediated by photosensitizer Photofrin™. These changes were influenced by glucocorticoid hormones, as evidenced by transcriptional activation of glucocorticoid receptor and the upregulation of gene encoding this receptor. The expression of gene for glucocorticoid-induced zipper (GILZ) protein, whose activity is particularly susceptible to glucocorticoid regulation, was also changed in PDT-treated tumors. A direct demonstration that tumor PDT induces glucocorticoid hormone upregulation is provided by documenting elevated levels of serum corticosterone in mice bearing PDT-treated LLC tumors. Tumor response to PDT was negatively affected by blocking glucocorticoid receptor activity, which suggests that glucocorticoid hormones have a positive impact on the therapeutic outcome with this therapy.

Temporal variation in glucocorticoid levels during the resting phase is associated in opposite way with maternal and paternal melanic coloration

Sex-dependent selection can help maintain sexual dimorphism. When the magnitude of selection exerted on a heritable sex trait differs between the sexes, it may prevent each sex to reach its phenotypic optimum. As a consequence, the benefit of expressing a sex trait to a given value may differ between males and females favouring sex-specific adaptations associated with different values of a sex trait. The level of metabolites regulated by genes that are under sex-dependent selection may therefore covary with the degree of ornamentation differently in the two sexes. We investigated this prediction in the barn owl, a species in which females display on average larger black spots on the plumage than males, a heritable ornament. This melanin-based colour trait is strongly selected in females and weakly counter-selected in males indicating sex-dependent selection. In nestling barn owls, we found that daily variation in baseline corticosterone levels, a key hormone that mediates life history trade-offs, covaries with spot diameter displayed by their biological parents. When their mother displayed larger spots, nestlings had lower corticosterone levels in the morning and higher levels in the evening, whereas the opposite pattern was found with the size of paternal spots. Our study suggests a link between daily regulation of glucocorticoids and sex-dependent selection exerted on sexually dimorphic melanin-based ornaments.

Developmental expression of multidrug resistance phosphoglycoprotein (P-gp) in the mouse fetal brain and glucocorticoid regulation

The multidrug resistance gene ( Abcb1) protein product, phosphoglycoprotein (P-gp) is expressed on the luminal surface of capillary endothelial cells of the adult blood–brain barrier ( bbb). P-gp is critical for neuroprotection as it actively pumps substrates back into the capillary lumen. The fetal brain represents a primary target for many P-gp substrates; however, the developmental expression, function and regulation of Abcb1 in the fetal brain are not well understood. Approximately 10% of pregnant women undergo synthetic glucocorticoid therapy for the management of preterm labor (PTL), though the effects of synthetic glucocorticoid on P-gp in the fetal brain are not known. We hypothesize that in the fetal brain: 1) expression and function of Abcb1 will increase with advancing gestation; 2) synthetic glucocorticoids will up-regulate the expression of Abcb1 and 3) this increased expression will correspond to a decrease in brain accumulation of P-gp substrates. Pregnant FVB dams were euthanized on embryonic day (E) 15.5 or E18.5 and fetal brains were collected and analyzed for [ 3H]digoxin accumulation or P-gp expression. In another group, pregnant FVB dams were injected daily with either dexamethasone (DEX; 0.1 mg/kg or 1 mg/kg) or vehicle from E9.5-E15.5 (mid-gestation) or E12.5-E18.5 (late-gestation) and analyzed on E15.5 or E18.5. Abcb1a mRNA (P < 0.01) and P-gp protein increased near term, corresponding to decreased [ 3H]digoxin accumulation in the fetal brain (P < 0.001). DEX treatment during mid-gestation modified Abcb1 mRNA expression and P-gp function in a dose-, gestational age-, and sex-specific manner. In conclusion, P-gp mediated protection of the fetal brain increases with advancing gestation in an isoform-specific manner. Synthetic glucocorticoid exposure can modify expression and function of multidrug-resistance in the fetal brain, and this will likely have clinical implication given the extensive use of synthetic glucocorticoid in the management of PTL.

O1 Photodynamic therapy induces systemic heat shock protein-70 response

Treatment of solid tumors by photodynamic therapy (PDT) was recently shown to trigger a strong acute phase response. Using the mouse Lewis lung carcinoma (LLC) model, the present study examined complement and pentraxin proteins as PDT-induced acute phase reactants. The results show a distinct pattern of changes in the expression of genes encoding these proteins in the tumor, as well as host liver and spleen, following PDT mediated by photosensitizer Photofrin™. These changes were influenced by glucocorticoid hormones, as evidenced by transcriptional activation of glucocorticoid receptor and the upregulation of gene encoding this receptor. The expression of gene for glucocorticoid-induced zipper (GILZ) protein, whose activity is particularly susceptible to glucocorticoid regulation, was also changed in PDT-treated tumors. A direct demonstration that tumor PDT induces glucocorticoid hormone upregulation is provided by documenting elevated levels of serum corticosterone in mice bearing PDT-treated LLC tumors. Tumor response to PDT was negatively affected by blocking glucocorticoid receptor activity, which suggests that glucocorticoid hormones have a positive impact on the therapeutic outcome with this therapy.

PL13 Biochemical backgrounds in the use of systemic photodynamic therapy in the treatment of various disseminated inflammatory diseases

Treatment of solid tumors by photodynamic therapy (PDT) was recently shown to trigger a strong acute phase response. Using the mouse Lewis lung carcinoma (LLC) model, the present study examined complement and pentraxin proteins as PDT-induced acute phase reactants. The results show a distinct pattern of changes in the expression of genes encoding these proteins in the tumor, as well as host liver and spleen, following PDT mediated by photosensitizer Photofrin™. These changes were influenced by glucocorticoid hormones, as evidenced by transcriptional activation of glucocorticoid receptor and the upregulation of gene encoding this receptor. The expression of gene for glucocorticoid-induced zipper (GILZ) protein, whose activity is particularly susceptible to glucocorticoid regulation, was also changed in PDT-treated tumors. A direct demonstration that tumor PDT induces glucocorticoid hormone upregulation is provided by documenting elevated levels of serum corticosterone in mice bearing PDT-treated LLC tumors. Tumor response to PDT was negatively affected by blocking glucocorticoid receptor activity, which suggests that glucocorticoid hormones have a positive impact on the therapeutic outcome with this therapy.

Glucocorticoid receptor in the rat epididymis: Expression, cellular distribution and regulation by steroid hormones

Glucocorticoids regulate several physiological functions, including reproduction, in mammals. Curiously, little is known about glucocorticoid-induced effects on the epididymis, an androgen-dependent tissue with vital role on sperm maturation. Here, RT-PCR, Western blot and immunohistochemical studies were performed to evaluate expression, cellular distribution and hormonal regulation of glucocorticoid receptor (GR) along rat epididymis. The rat orthologue of human GRα (mRNA and protein) was detected in caput, corpus and cauda epididymis and immunolocalized in the nucleus and cytoplasm of different epididymal cells (epithelial, smooth muscle and interstitial cells) and nerve fibers. Changes in plasma glucocorticoid and androgen levels differentially regulated GR expression in caput and cauda epididymis by homologous and heterologous mechanisms. In vivo treatment with dexamethasone significantly changed the expression of glucocorticoid-responsive genes and induced ligand-dependent GR nuclear translocation in epithelial cells from epididymis, indicating that GR is fully active in this tissue. Heterologous regulation of androgen receptor expression by glucocorticoids was also demonstrated in cauda epididymis. Our results demonstrate that the epididymis is under glucocorticoid regulation, opening new insights into the roles of this hormone in male fertility.

Relation between hypothalamic-pituitary-adrenal axis activity and insulin resistance in woman with polycystic ovary syndrome

Forty women with polycystic ovary syndrome( PCOS) were enrolled. Basal plasma and urine cortisol, pituitary hormones, homeostasis model assessment for insulin resistance, and plasma cortisol in 0. 25 mg dexamethasone inhibition test were determined. In over-weight or obese PCOS patients, cortisol levels before and after inhibition test were increased (P<0. 05 or P<0. 01 ). The results suggest that the feed-back regulation of glucocorticoids to hypothalamas-pituitary is impaired and the change in hypothalamic-pituitary-adrenal axis is associated with insulin resistance. Key words: Polycystic ovary syndrome; Insulin resistance; Hypothalamic-pituitary-adrenal axis; Cortisol

618. Disruption of Glucocorticoid Regulation in Therapeutic Human T Cells with Zinc Finger Nucleases

618. Disruption of Glucocorticoid Regulation in Therapeutic Human T Cells with Zinc Finger Nucleases

Glucocorticoid regulation of the vitamin D receptor

Many studies indicate calcitriol has potent anti-tumor activity in different types of cancers. However, high levels of vitamin D can produce hypercalcemia in some patients. Glucocorticoids are used to ameliorate hypercalcemia and to enhance calcitriol anti-tumor activity. Calcitriol in combination with the glucocorticoid dexamethasone (Dex) increased vitamin D receptor (VDR) protein levels and ligand binding in squamous cell carcinoma VII (SCC). In this study we found that both calcitriol and Dex induce VDR- and glucocorticoid receptor (GR)-mediated transcription respectively, indicating both hormone receptors are active in SCC. Pre-treatment with Dex increases VDR-mediated transcription at the human CYP24A1 promoter. Whereas, pre-treatment with other steroid hormones, including dihydrotestosterone and R1881, has no effect on VDR-mediated transcription. Real-time PCR indicates treatment with Dex increases Vdr transcripts in a time-dependent manner, suggesting Dex may directly regulate expression of Vdr. Numerous putative glucocorticoid response elements (GREs) were found in the Vdr gene. Chromatin immuno-precipitation (ChIP) assay demonstrated GR binding at several putative GREs located within the mouse Vdr gene. However, none of the putative GREs studied increase GR-mediated transcription in luciferase reporter assays. In an attempt to identify the response element responsible for Vdr transcript regulation, future studies will continue to analyze newly identified GREs more distal from the Vdr gene promoter.

Glucocorticoid Regulation of Clock Gene Expression in the Mammalian Limbic Forebrain

Glucocorticoids regulate a wide variety of functions, including synaptic plasticity, hypothalamic-pituitary-adrenal axis activation, conditional fear learning, metabolism, and sensitization to drugs of abuse. The diurnal secretion of glucocorticoids, driven by the mammalian master clock located in the suprachiasmatic nucleus of the hypothalamus, has been shown to induce and entrain clock gene expression in peripheral tissues. However, little attention has been given to the form and function of centrally located subordinate oscillators, and the synchronizing factors that influence them. Here we review findings that implicate glucocorticoids in the circadian regulation of clock genes in select oscillators in the limbic forebrain and propose mechanisms whereby glucocorticoids can feed back on rhythms downstream from the master clock and possibly alter the functional output of these nuclei.

Glucocorticoid regulation of the circadian clock modulates glucose homeostasis

Circadian clock genes are regulated by glucocorticoids; however, whether this regulation is a direct or secondary effect and the physiological consequences of this regulation were unknown. Here, we identified glucocorticoid response elements (GREs) at multiple clock genes and showed that 3 were directly regulated by the glucocorticoid receptor. We determined that a GRE within the core clock gene Per2 was continuously occupied during rhythmic expression and essential for glucocorticoid regulation of that gene in vivo. We further demonstrated that mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. We conclude that Per2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.

Low early morning plasma cortisol in posttraumatic stress disorder is associated with co-morbid depression but not with enhanced glucocorticoid feedback inhibition

Co-morbid major depressive disorder (MDD) in individuals with posttraumatic stress disorder (PTSD) confers a more severe clinical course and is associated with distinct biologic abnormalities. Although dysregulation in the hypothalamic pituitary adrenal (HPA) axis has been well established in PTSD, the impact of commonly co-occuring MDD has received scant attention. Overnight (7p.m. to 7a.m.) plasma cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulphate (DHEA-S) were measured at 30 min intervals in 9 participants with PTSD with MDD (PTSD+MDD), 9 with PTSD without MDD (PTSD-MDD) and 16 non-traumatized healthy controls. A low-dose dexamethasone suppression test was administered to evaluate feedback sensitivity to glucocorticoids. Linear mixed models with body mass index (BMI) and age as covariates and Bonferroni corrected post hoc tests assessed group differences. Compared to healthy controls, subjects with PTSD+MDD, but not those subjects with PTSD-MDD, exhibited lower basal plasma cortisol levels between 1:30 a.m. and 3:30 a.m. and at 4:30 a.m. and 6:30 a.m. (effect size d=0.75). Despite similar plasma ACTH levels between the three groups, the ACTH/cortisol ratio was higher in PTSD+MDD patients compared to controls. We obtained similar results when the patient and control groups were re-studied 1 week later, and when men and current smokers were excluded. Basal plasma DHEA-S levels, and cortisol and ACTH response to a low-dose dexamethasone suppression test were similar in all three groups. Lower early morning plasma cortisol levels and a high ACTH/cortisol ratio in subjects with PTSD and co-morbid MDD may not be due to enhanced peripheral sensitivity to glucocorticoids. A central abnormality in glucocorticoid regulation could explain HPA axis dysfunction in this subgroup.

Hippocampus, glucocorticoids and neurocognitive functions in patients with first-episode major depressive disorders

The aim of this study was to determine whether there was any relationship between hippocampal volume, and glucocorticoid regulation, and cognitive dysfunctions in drug-naïve major depressive disorder (MDD) patients during their first episode. Twenty drug-free female MDD patients in their first episode and 15 healthy females as control subjects were included in the study. All subjects underwent 3.0 Tesla (T) magnetic resonance imaging (MRI), comprehensive neuropsychological testing and dexamethasone suppression tests (DST). The volumes of the right and left hippocampus of the patients were found to be significantly smaller than those of the controls. Patients were found to have significantly lower scores on measures of attention, working memory, psychomotor speed, executive functions, and visual and verbal memory fields. The performance of the patients only in the recollection memory and memory of reward-associated rules were positively correlated with hippocampal volumes. The volumes of the left and right hippocampus did not correlate with basal or post-dexamethasone cortisol levels. Our findings indicate that depressed patients have smaller hippocampi even in the earlier phase of their illness. Further research efforts are needed to explain the mechanisms that are responsible for the small hippocampus in depressed patients.

Correction for Zhang et al., Glucocorticoid regulation of preproglucagon transcription and RNA stability during stress

Correction for Zhang et al., Glucocorticoid regulation of preproglucagon transcription and RNA stability during stress

11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents

Background: The main components of metabolic syndrome (obesity, insulin resistance, hypertension and dyslipidemia) have become prevalent worldwide, and excess glucocorticoid levels have been implicated in patients with these symptoms. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme involved in glucocorticoid regulation through catalysis of the conversion of inactive cortisone to its active form cortisol. Numerous rodent studies have demonstrated the potential use of 11β-HSD1 inhibitors as treatment for the components of metabolic syndrome and limited clinical data in humans have shown 11β-HSD1 inhibition to improve glucose levels, insulin sensitivity and lipid profiles. Many organizations have been active in the 11β-HSD1 academic and patent literature, and two previous articles from this journal have reviewed disclosures through August 2007. Objective: To summarize the recent patent literature and progress in defining the utility of small molecule 11β-HSD1 inhibitors. Methods: This review covers the recent 11β-HSD1 patent literature and clinical activity ranging from late 2007 through the end of 2008. Results/conclusion: The exploration of 11β-HSD1 inhibitors continues, as a number of structural classes have been reported by several pharmaceutical companies over the past 16 months. Current clinical trials will ultimately shed light on the feasibility of 11β-HSD1 inhibitors as pharmaceutical agents for the various components of metabolic syndrome.

Differential expression of determinants of glucocorticoid sensitivity in androgen-dependent and androgen-independent human prostate cancer cell lines

Glucocorticoids (GCs) are widely used for the treatment of hormone refractory prostate cancer. However, few data are available on the expression and regulation of glucocorticoid and mineralocorticoid receptors (GR and MR) and 11β-hydroxysteroid dehydrogenase (11β-HSD) 1 and -2 activities in prostate cancer cells. Here we show that GR is expressed in both the androgen-independent PC-3 cell line and, at very low levels, in the androgen-dependent LNCaP cells, and MR is expressed in both cell lines. IL-1β increased GR expression in both cell lines. In LNCaP cells IL-1β also increased MR expression. Significant 11β-HSD oxidase activity and 11β-HSD2 protein were found in LNCaP cells, but not in PC3 cells, and no ketoreductase activity was detected in either cell lines. GR function was assessed by measuring the inhibitory effect of dexamethasone on constitutive and IL-1β-inducible IL-6 and osteoprotegerin (OPG) production. In PC-3 cells, IL-1β stimulated IL-6 and OPG release, and dexamethasone dose-dependently inhibited IL-1β-inducible IL-6 release, and constitutive and IL-1β-inducible OPG release. In LNCaP cells, IL-1β stimulated only OPG release. While dexamethasone was ineffective, cortisol dose-dependently inhibited IL-1β-inducible OPG release. Eplerenone (Epl), a selective mineralocorticoid antagonist, reverted this effect. We conclude that different patterns of expression of receptors and 11β-HSD activity were associated with different responsiveness to GCs in terms of regulated gene expression. GR and MR expression may vary as a function not only of the malignant phenotype, but also of local conditions such as the degree of inflammation. Inhibition of IL-6 and OPG release by GCs may contribute to the antitumor efficacy in prostate cancer.

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

ObjectiveCorticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis.Patients and designTwenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-α (determining most of the cortisol effect), GR-P (increasing GR-α effect) and GR-β (inhibitor of GR-α) were measured quantitatively.Main resultsNeutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-α and GR-P splice variants on day 0 compared to after recovery. GR-α and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-β mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = −0.60, P = 0.009).ConclusionsChildren with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock.

Glucocorticoid regulation of preproglucagon transcription and RNA stability during stress

Stress elicits a synchronized response of the endocrine, sympathetic, and central nervous systems to preserve homeostasis and well-being. Glucagon-like peptide-1 (GLP-1), a primary posttranslational product of the preproglucagon (PPG) gene, activates both physical and psychological stress responses. The current study examined mechanisms regulating expression of PPG gene products in the hindbrain. Our results indicate that PPG mRNA decreases rapidly after exposure to acute stressors of multiple modalities. Reduced mRNA levels are accompanied by reduced GLP-1 immunoreactivity in the paraventricular nucleus of hypothalamus, suggesting release at PPG terminals. Stress-induced decrements in PPG mRNA were attenuated in adrenalectomized-corticosterone-replaced rats, suggesting that mRNA down-regulation is due at least in part to glucocorticoid secretion. In contrast, acute stress increased levels of PPG heteronuclear RNA (hnRNA) in a glucocorticoid-dependent manner, suggesting that decreases in PPG mRNA are due to increased degradation rather than reduced transcription. Glucocorticoid administration to unstressed rats is sufficient to cause decrements in PPG mRNA and increments in PPG hnRNA. These findings suggest that glucocorticoids deplete the pool of transcribed PPG mRNA and concurrently stimulate PPG gene transcription, with the latter allowing a mechanism for replenishment of PPG mRNA after stress cessation. The combination of rapid PPG mRNA depletion and initiation of PPG transcription within 30 min is consistent with a rapid action of glucocorticoids on GLP-1 bioavailability, resulting in a transient reduction in the capacity for neuropeptidergic excitation of stress responses.