Reduction Of Glucocorticoid Receptor Research Articles

Associations between plasma metal/metalloid mixtures and the risk of central obesity: A prospective cohort study of Chinese adults

Central obesity has increased rapidly over the past decade and posed a substantial disease burden worldwide. Exposure to metals/metalloids has been acknowledged to be involved in the development of central obesity through regulation of cortisol, insulin resistance, and glucocorticoid receptor reduction. Despite the importance, it is lack of prospective study which comprehensively evaluate the relations between multiple metals exposure and central obesity. We explored the prospective associations of plasma metal concentrations with central obesity in a prospective study of the Dongfeng-Tongji cohort. The present study included 2127 participants with a 6.87-year mean follow-up duration. We measured 23 plasma metal/metalloid concentrations at baseline. The associations between metals and incident central obesity were examined utilizing the Cox proportional hazard regression in single and multiple metals models. Additionally, we applied elastic net (ENET), Bayesian kernel machine regression (BKMR), plasma metal score (PMS), and quantile-based g-computation (Qgcomp) models to explore the joint associations of metal mixtures with central obesity. After adjusting potential confounders, we found significant associations of plasma manganese (Mn) and thallium (Tl) concentrations with a higher risk of central obesity, whereas plasma rubidium (Rb) concentration was associated with a lower risk of central obesity both in single and multiple metals models (all FDR <0.05). The ENET and Qqcomp models verified similar metals (Mn, Rb, and Tl) as important predictors for central obesity. The results of both BKMR model and PMS suggested cumulative exposure to metal mixtures was associated with a higher risk of central obesity. Our findings suggested that co-exposure to metals was associated with a higher risk of central obesity. This study expands our knowledge that the management of metals/metalloids exposure may be beneficial for the prevention of new-onset central obesity, which may subsequently alleviate the disease burden of late-life health outcomes.

Cinnamaldehyde prevents intergenerational effect of paternal depression in mice via regulating GR/miR-190b/BDNF pathway.

Paternal stress exposure-induced high corticosterone (CORT) levels may contribute to depression in offspring. Clinical studies disclose the association of depressive symptoms in fathers with their adolescent offspring. However, there is limited information regarding the intervention for intergenerational inheritance of depression. In this study we evaluated the intervention of cinnamaldehyde, a major constituent of Chinese herb cinnamon bark, for intergenerational inheritance of depression in CORT- and CMS-induced mouse models of depression. Depressive-like behaviors were induced in male mice by injection of CORT (20 mg·kg-1·d-1, sc) for 6 weeks or by chronic mild stress (CMS) for 6 weeks. We showed that co-administration of cinnamaldehyde (10, 20, or 40 mg·kg-1·d-1, ig) for 6 weeks in F0 males prevented the depressive-like phenotypes of F1 male offspring. In addition, co-administration of cinnamaldehyde (20 mg·kg-1·d-1, ig) for 4 weeks significantly ameliorated depressive-like behaviors of chronic variable stress (CVS)-stimulated F1 offspring born to CMS mice. Notably, cinnamaldehyde had no reproductive toxicity, while positive drug fluoxetine showed remarkable reproductive toxicity. We revealed that CMS and CORT significantly reduced testis glucocorticoid receptor (GR) expression, and increased testis and sperm miR-190b expression in F0 depressive-like models. Moreover, pre-miR-190b expression was upregulated in testis of F0 males. The amount of GR on miR-190b promoter regions was decreased in testis of CORT-stimulated F0 males. Cinnamaldehyde administration reversed CORT-induced GR reduction in testis, miR-190b upregulation in testis and sperm, pre-miR-190b upregulation in testis, and the amount of GR on miR-190b promoter regions of F0 males. In miR-190b-transfected Neuro 2a (N2a) cells, we demonstrated that miR-190b might directly bind to the 3'-UTR of brain-derived neurotrophic factor (BDNF). In the hippocampus of F1 males of CORT- or CMS-induced depressive-like models, increased miR-190b expression was accompanied by reduced BDNF and GR, which were ameliorated by cinnamaldehyde. In conclusion, cinnamaldehyde is a potential intervening agent for intergenerational inheritance of depression, probably by regulating GR/miR-190b/BDNF pathway.

Possible role of arginase 1 positive microglia on depressive/anxiety-like behaviors in atopic dermatitis mouse model.

Atopic dermatitis (AD) and mood disorder comorbidities are typical, but the exact mechanism underlying their interplay has not been clarified. In this study, we aimed to identify the possible mechanisms of anxiety/depressive-like behaviors observed in AD, focusing on microglia. AD was induced by Dermatophagoides farinae body extract (Dfb) in NC/Nga mice and anxiety/depressive-like behaviors were analyzed by behavioral assessments such as open field test (OFT), tail suspension test (TST), sucrose preference test (SPT), and social interaction. As clinical symptoms of AD induced, anxiety/depressive-like behaviors were increased in the OFT and TST and serum glucocorticoid was elevated. AD mice showed an increased mRNA expression of interleukin-4 (IL-4) in lymph nodes but decreased arginase 1 (Arg1) mRNA expression without a change of IL-4 in the hippocampus. In addition, AD mice showed microglia with a shortened branch of de-ramified form and astrocytes with longer processes and decreased branching in the hippocampus, especially in the dentate gyrus (DG). The immunofluorescence study of the DG confirmed that Arg1 reduction was associated with microglia, but not astrocytes. Furthermore, glucocorticoid receptor reduction, increased 5-HT1AR, reduced phosphorylated cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) expression were identified in the hippocampus of AD mice. Notably, an immunofluorescence study confirmed that pCREB was decreased in the DG of AD mice. Collectively, our data suggest that the reduced Arg1 positive microglia might contribute to anxiety/depressive-like behaviors via pCREB/BDNF reduction in AD.

Pubertal probiotics mitigate lipopolysaccharide-induced programming of the hypothalamic-pituitary-adrenal axis in male mice only

Puberty is a period of rapid cortical and neuronal development. Stress exposure during puberty programs the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to future stressors. However, programming can result in an enduring maladaptation of the HPA axis activity and can be associated with long-term anxiety- and depression-like behaviours. Probiotic treatment mitigates the effect of stress on mental health, suggesting that the gut microbiome may mediate the programming of the HPA axis. However, the mechanism underlying this effect remains elusive. Thus, we investigated the effect of probiotic exposure on lipopolysaccharide (LPS)-induced programming of the HPA axis and glucocorticoid receptor (GR) expression in the paraventricular (PVN), basolateral amygdala (BLA), piriform cortex (PIR), and medial prefrontal cortex (mPFC). Male and female mice were exposed to either probiotics or control skim milk and were treated with either saline or LPS during puberty. Prior to euthanasia in adulthood, mice were restrained for 30 min. The results showed that pubertal LPS treatment permanently decreased GR expression in the PVN in milk fed control males. However, pubertal probiotic treatment blocked the LPS-induced decrease in GR expression in males. Given that this effect is limited to males, further research is required to better understand sex differences in the interactions between the gut microbiome and the programming of the HPA axis during puberty. Nevertheless, our findings suggest that the gut microbiome influences the neurophysiology of the HPA axis and mediates its programming in pubertal males. The prevention of GR reduction in the male PVN and PIR using probiotics illustrates the complexity of the gut-brain communication and compels continued investigation.

Huntingtin-Associated Protein 1 in Mouse Hypothalamus Stabilizes Glucocorticoid Receptor in Stress Response.

Huntingtin-associated protein 1 (Hap1) was initially identified as a brain-enriched protein that binds to the Huntington’s disease protein, huntingtin. Unlike huntingtin that is ubiquitously expressed in the brain, Hap1 is enriched in the brain with the highest expression level in the hypothalamus. The selective enrichment of Hap1 in the hypothalamus suggests that Hap1 may play a specific role in hypothalamic function that can regulate metabolism and stress response. Here we report that Hap1 is colocalized and interacts with the glucocorticoid receptor (GR) in mouse hypothalamic neurons. Genetic depletion of Hap1 reduced the expression level of GR in the hypothalamus. Dexamethasone, a GR agonist, treatment or fasting of mice induced stress, resulting in increased expression of Hap1 in the hypothalamus. However, when Hap1 was absent, these treatments promoted GR reduction in the hypothalamus. In cultured cells, loss of Hap1 shortened the half-life of GR. These findings suggest that Hap1 stabilizes GR in the cytoplasm and that Hap1 dysfunction or deficiency may alter animal’s stress response.

Mineralocorticoid Antagonist Improves Glucocorticoid Receptor Signaling and Dexamethasone Analgesia in an Animal Model of Low Back Pain.

Low back pain, a leading cause of disability, is commonly treated by epidural steroid injections that target the anti-inflammatory glucocorticoid receptor (GR). However, their efficacy has been controversial. All currently used epidural steroids also activate the pro-inflammatory mineralocorticoid receptor (MR) with significant potency. Local inflammation of the dorsal root ganglia (DRG), a rat model of low back pain, was used. This model causes static and dynamic mechanical allodynia, cold allodynia and guarding behavior (a measure of spontaneous pain), and activates the MR, with pro-nociceptive effects. In this study, effects of local Dexamethasone (DEX; a glucocorticoid used in epidural injections), and eplerenone (EPL; a second generation, more selective MR antagonist) applied to the DRG at the time of inflammation were examined. Mechanical and spontaneous pain behaviors were more effectively reduced by the combination of DEX and EPL than by either alone. The combination of steroids was particularly more effective than DEX alone or the model alone (3-fold improvement for mechanical allodynia) at later times (day 14). Immunohistochemical analysis of the GR in the DRG showed that the receptor was expressed in neurons of all size classes, and in non-neuronal cells including satellite glia. The GR immunoreactivity was downregulated by DRG inflammation (48%) starting on day 1, consistent with the reduction of GR (57%) observed by Western blot, when compared to control animals. On day 14, the combination of DEX and EPL resulted in rescue of GR immunoreactivity that was not seen with DEX alone, and was more effective in reducing a marker for satellite glia activation/neuroinflammation. The results suggest that EPL may enhance the effectiveness of clinically used epidural steroid injections, in part by enhancing the availability of the GR. Thus, the glucocorticoid-mineralocorticoid interactions may limit the effectiveness of epidural steroids through the regulation of the GR in the DRG.

Hypothalamic Nuclear Glucocorticoid Receptors: Acute Stress and Rapid Actions.

Stress, be it physical or psychological, causes the activation of a neuroendocrine cascade that involves both central and peripheral mechanisms. In the simplest terms, central release of CRH from the paraventricular nucleus of thehypothalamus (PVN)andsubsequent releaseofACTH from the pituitary result in the peripheral release of glucocorticoids (cortisol in primates and corticosterone in many rodent species) from the adrenal gland (1). Glucocorticoids then act via negative feedback both centrally and peripherally through the glucocorticoid receptor (GR) to inhibit the further release of CRH from the PVN and ACTH from the pituitary (2). This process is a delicate balance that helps restore homeostasis, but perturbation of these responses can lead to neurobehavioral and physiological dysfunctions, including mood disorders and obesity (3–5). Hence, understanding the basic mechanisms that mediate this neuroendocrine loop has broad implications for both health and disease. Two companion papers in this issue by Solomon et al (6) and Nahar et al (7) have helped to further reveal the mechanisms through which glucocorticoids influence hypothalamic-pituitary-adrenal (HPA) function. Both reports use a powerful mouse model in which Sim1-cre recombinase transgenic mice are bred with homozygous floxed GR mice. Sim1 is a transcription factor specifically expressed in the PVN, supraoptic nucleus, and periventricular nucleus (8) and is responsible for the proper maturation of neurosecretory cells in the PVN (9). As Solomon et al report, theoffspring fromthis cross showsignificantly reduced GR levels in the PVN while leaving GR levels intact in the pituitary and other brain regions important in glucocorticoid-dependent negative feedback (6), thus resulting in a relatively anatomically restricted GR reduction. Using these PVN GR knockdown (KD) mice, Solomon et al (6) find sex-specific and stressor-dependent effects on HPA reactivity. In particular, they show GR KD mice respond to a brief 30-minute session of restraint stress with significantly increased and prolonged ACTH and corticosterone responses compared with their littermate controls, suggesting reduced negative feedback on the HPA axis (6). Notably, however, these effects of GR KD were observed only in males because female GR KD mice show reduced restraint-induced ACTH and no differences in stress-induced corticosterone responsiveness. In response to chronic variable stress, neither male nor female GR KD mice show any differences in HPA reactivity. Hence, the authors conclude that there are significant sex differences in the role that PVN GR plays in response to acute stress and that changes in HPA reactivity after chronic stress in male and female mice are independent of GR in the PVN (6). Complimenting this line of research, the report by Nahar et al (7) investigated rapid nongenomic actions of glucocorticoids in modulating excitatory and inhibitory transmission in the mouse hypothalamus. They show that hypothalamic magnocellular neurons respond to dexamethasone (DEX), a synthetic glucocorticoid, with a rapid suppression of excitatory postsynaptic inputs (ie, glutamatergic synapses). The authors further demonstrate that this effect of DEX is mediated by postsynaptic membrane associated receptors and G protein signaling (7), similar to their seminal work in rats (10–12). The authors also show that DEX leads to a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs [ie, -aminobutyric acid

Autocrine down-regulation of glucocorticoid receptors by interleukin-11 in human osteoblast-like cell lines.

It has recently been suggested that interleukin (IL)-11 plays a role in the pathogenesis of glucocorticoid (GC)-induced osteoporosis. IL-11 belongs to the gp130 cytokine family, which includes also IL-6. We have previously investigated GC-IL-6 interplay, showing that GC inhibits IL-6 release and IL-6 up-regulates GC receptor (GR) numbers in the human osteoblast-like cell lines Saos-2 and MG-63, which constitutively have an opposite pattern of expression for GR, IL-11, IL-6, alkaline phosphatase and osteoprotegerin (OPG). The aim of this study was to investigate GC-IL-11 interplay in the same two cell lines. First, cells were incubated with cortisol (0.01-1 microM) for 20 h in the presence and in the absence of a known IL-11 secretagogue (IL-1beta); cell media were assayed for IL-11 by ELISA. Secondly, cells were incubated with IL-11 (0.1-100 ng/ml) or specific anti-IL-11 monoclonal antibody for 20 h, and then assayed for GR by a radioligand binding assay. Similar to IL-6, both constitutive and IL-1beta-inducible IL-11 release were dose-dependently inhibited by cortisol (P<0.01); at variance with IL-6, exogenous IL-11 dose-dependently decreased GR numbers in MG-63 cells (P<0.05), while anti-IL-11 antibody significantly increased GR numbers in both cell lines (P<0.05). IL-11-induced reduction of GR in MG-63 cells was confirmed by Western blot analysis. While exerting opposite effects on GR numbers, neither IL-6 nor IL-11 significantly modified GC-dependent inhibition of OPG release. Our data indicate that even physiological concentrations of cortisol negatively modulate IL-11 secretion and demonstrate, for the first time, an inhibitory effect of the cytokine on GR. Thus, the concept of autocrine-paracrine loops that modulate GC action and involve gp130 cytokines is corroborated. These loops could have clinical relevance for the dynamics of bone loss in patients given GC and having high concentrations of these cytokines in the bone microenvironment.

Lack of Decrease in Hypothalamic and Hippocampal Glucocorticoid Receptor mRNA during Starvation

We have shown in a previous study that high corticosterone levels during repeated immobilization stress result in a reduction of glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus (PVN) and the hippocampus. The reduction of GR presumably accounts for loss of or decrease in glucocorticoid-negative feedback, and thus hyperfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis persists during chronic stress. Starvation is a stress state in which the counterregulatory responses against the loss of food occur in the central nervous system. We explored the impact of starvation on the HPA axis, GR and mineralocorticoid receptor (MR) mRNAs in the hippocampus, the PVN, and the anterior pituitary (AP) of rats. Rats were starved for 4 days and sacrificed in the morning. Starved rats showed high levels of plasma corticosterone, whereas neither plasma corticotropin (ACTH), AP proopiomelanocortin (POMC) mRNA nor AP type-1 corticotropin-releasing hormone (CRH) receptor mRNA was altered in the starved rats. In the presence of high corticosterone, starvation resulted in a decrease in both CRH mRNA and type-1 CRH receptor mRNA in the PVN. Consistently, the starved rats did not show any changes in GR mRNA in the hippocampus (CA1-2, CA3, and dentate gyrus), the PVN or the AP despite the elevation of plasma corticosterone. A significant decrease in MR mRNA was seen in the dentate gyrus and the AP, but not in CA1–2, CA3 or PVN. The lack of reduction of GR may be one of the organism’s counterregulatory responses during starvation, which allows an intact glucocorticoid negative feedback, thereby resulting in decreased anorectic neuropeptide levels, namely CRH, in the PVN. The results also indicate that GR mRNA in the hippocampus and other brain regions is not solely regulated by circulating glucocorticoids. The mechanism underlying the regulation of GR mRNA in the central nervous system remains to be clarified.

Long-term effects of neonatal maternal deprivation and ACTH on hippocampal mineralocorticoid and glucocorticoid receptors

In the brain, corticosteroids bind to two types of receptors, the classical glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The effects of different manipulations taking place during early ontogeny on GR and MR binding properties were examined in the adult hippocampus. Infant rats at postnatal day (pnd) 3 were deprived of maternal contact for 24 h and injected with saline or ACTH 1–24 at the end of the deprivation period. They were then returned to their dams and weaned on pnd 21. At pnd 48, they were sacrifiedd (24 h post adrenalectomy) and the hippocampal MR and GR measured using an in vitro cytosol binding assay. In the male rats, deprivation and deprivation + ACTH resulted in a reduction of GRs. MRs were also significantly down regulated in the deprived males. In the female rats, saline injections in deprived female rats resulted in increased GR capacity and ACTH injections led to a further up-regulation of the GRs. None of the early manipulations influenced the regulation of the MRs in females. The binding affinity for corticosteriod receptors was also altered by some of early manipulations. These results in adult (7-week-old) rats indicate that the receptor systems for corticosteroids in the brain are sensitive to brief manipulations occurring early in development. These changes in receptor capacity and/or affinity may affect corticosteroid-mediated processes in the adult rat.