Chronic stress has been found to be a major risk factor for various human pathologies. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated via, among others, the glucocorticoid receptor (GR). The activity of the GR is modulated by a variety of proteins, including the co-chaperone FK506 binding protein 51 (FKBP5). Although FKBP5 has been associated with risk for affective disorders and has been implicated in GR sensitivity, previous studies focused mainly on peripheral blood, while information about basal distribution and induction in the central nervous system are sparse.
In the present study, we describe the basal expression pattern of Fkbp5 mRNA in the brain of adult male mice and show the induction of Fkbp5 mRNA via dexamethasone treatment or different stress paradigms. We could show that Fkbp5 is often, but not exclusively, expressed in regions also known for GR expression, for example the hippocampus. Furthermore, we were able to induce Fkbp5 expression via dexamethasone in the CA1 and DG subregions of the hippocampus, the paraventricular nucleus (PVN) and the central amygdala (CeA). Increase of Fkbp5 mRNA was also found after restrained stress and 24 hours of food deprivation in the PVN and the CeA, while in the hippocampus only food deprivation caused an increase in Fkbp5 mRNA.
Interestingly, regions with a low basal expression showed higher increase in Fkbp5 mRNA following induction than regions with high basal expression, supporting the hypothesis that GR sensitivity is, at least partly, mediated via Fkbp5. In addition, this also supports the use of Fkbp5 gene expression as a marker for GR sensitivity. In summary, we were able to give an overview of the basal expression of fkbp5 mRNA as well as to extend the findings of induction of Fkbp5 and its regulatory influence on GR sensitivity from peripheral blood to the brain.
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"environment interactions. In this context, studies demonstrated that food deprivation (FD) induces Fkbp5 expression in the brain (Scharf et al. 2011, Yang et al. 2012). In the study by Scharf and colleagues, FD was used as a stressor, but intuitively, changes resulting from FD may also represent a response to the metabolic challenge. "
[Show abstract][Hide abstract]ABSTRACT: While it is known that stress promotes obesity, the effects of stress within an obesogenic context are largely unclear and molecular targets at the interface remain elusive. The FK506 binding protein 51 (FKBP51, gene: Fkbp5) has been identified as a target gene implicated in the development of stress-related psychiatric disorders, and is a possible candidate involved in stress and metabolic regulation. The aims of the current study were to investigate the interaction between chronic stress and an obesogenic context and to additionally examine whether FKBP51 is involved in this interaction. For this purpose, male C57BL/6 mice were exposed to 8-weeks of a high fat diet before being challenged to chronic social defeat stress. Here we demonstrate that chronic stress induces hypophagia and weight loss, ultimately improving features arising from an obesogenic context, including glucose tolerance and levels of insulin and leptin. We show that Fkbp5 expression is responsive to diet and stress in the hypothalamus and hippocampus, respectively. Furthermore, under basal conditions, higher levels of hypothalamic FKBP51 expression were related to increased body weight gain. Our data indicate that FKBP51 may represent a novel target in metabolic regulation.
Full-text · Article · Apr 2014 · Journal of Endocrinology
"It is possible that FKBP5 mRNA over-expression in the DLPFC may occur in schizophrenia and bipolar disorder cases due to hypercortisolemia, which has been described in these illnesses1011. FKBP5 gene expression is upregulated by glucocorticoids through GR in rodent and primate brain3637383940, and in squirrel monkeys, chronic hypercortisolemia is compensated for by over-expression of FKBP541. Therefore, it is possible that FKBP5 upregulation may have arisen in an attempt to ‘buffer’ chronically increased stress/cortisol in individuals in this cohort. "
[Show abstract][Hide abstract]ABSTRACT: Molecular abnormalities within the glucocorticoid receptor (GR) stress signaling pathway may confer, or reflect, susceptibility to stress in schizophrenia and bipolar disorder, but the extent of such abnormalities in the brain is not known. Using RNA-Seq and qPCR in two postmortem cohorts totaling 55 schizophrenia, 34 bipolar disorder and 55 control individuals, we identified increased FKBP5 and PTGES3 mRNA expression, and decreased BAG1 mRNA expression, in the prefrontal cortex in schizophrenia cases relative to controls (68.0% [p < 0.001], 26.0% [p < 0.01] and 12.1% [p < 0.05] respectively). We also observed increased FKBP5 and decreased BAG1 mRNA expression in bipolar disorder (47.5% [p < 0.05] and 14.9% [p < 0.005]). There were no diagnostic differences in steady-state FKBP51 protein levels, nor in HSPA1A, HSP90AA1, DNAJB1 or HSPB1 mRNA levels. GR, co-factor and chaperone mRNA levels were strongly correlated. These results reveal coordinated cortical dysregulation of FKBP5, PTGES3, BAG1 and GR genes within the glucocorticoid signaling pathway in psychotic illness.
Full-text · Article · Dec 2013 · Scientific Reports
"In the rodent brain, FKBP5 has the highest expression levels in the hippocampus, with much lower expression in other brain regions (Scharf et al. 2011). Upon stimulation with dexamethasone or exposure to stress (restraint stress or 24 h food deprivation), FKBP5 expression is dramatically increased in a number of brain regions (Scharf et al. 2011), with the largest changes observed in the amygdala and the paraventricular nucleus. In the hippocampus, the change in expression levels is less pronounced and follows only dexamethasone administration and the more severe stressor of food deprivation. "
[Show abstract][Hide abstract]ABSTRACT: Psychiatric phenotypes are multifactorial and polygenic, resulting from the complex interplay of genes and environmental factors that act cumulatively throughout an organism's lifetime. Adverse life events are strong predictors of risk for a number of psychiatric disorders and a number of studies have focused on GxEs occurring at genetic loci involved in the stress response. Such a locus that has received increasing attention is the gene encoding FK506 binding protein 51 (FKBP5), a heat shock protein 90 co-chaperone of the steroid receptor complex that among other functions regulates sensitivity of the glucocorticoid receptor. Interactions between FKBP5 gene variants and life stressors alter the risk for mood and anxiety disorders, but also for a number of other disease phenotypes. In this review, we will focus on molecular and system-wide mechanisms of this GxE with the aim of establishing a framework that explains GxE interactions. We will also discuss how an understanding of the biological effects of this GxE may lead to novel therapeutic approaches.
Full-text · Article · Nov 2013 · Genes Brain and Behavior