Disrupting Hypothalamic Glucocorticoid Receptors Causes HPA Axis Hyperactivity and Excess Adiposity

Abstract

The glucocorticoid receptor (GR) regulates hypothalamic-pituitary-adrenal (HPA) axis activity during the stress response. The paraventricular nucleus (PVN) is a major site of negative feedback to coordinate the degree of the HPA axis activity with the magnitude of the exposed stressor. To define the function of endogenous PVN GR, we used Cre-loxP technology to disrupt different GR exons in Sim1-expressing neurons of the hypothalamus. GR exon 2-deleted mice (Sim1Cre-GRe2Δ) demonstrated 43% loss of PVN GR compared with an 87% GR loss in exon 3-deleted mice (Sim1Cre-GRe3Δ). Sim1Cre-GRe3Δ mice display stunted growth at birth but develop obesity in adulthood and display impaired stress-induced glucose release. We observed elevated basal and stress-induced corticosterone levels in Sim1Cre-GRe3Δ mice, compared with control and Sim1Cre-GRe2Δ mice, and impaired dexamethasone suppression, indicating an inability to negatively regulate corticosterone secretion. Sim1Cre-GRe3Δ mice also showed increased CRH mRNA in the PVN, increased basal plasma ACTH levels, and reduced locomotor behavior. We observed no differences in Sim1Cre-GRe2Δ mice compared with control mice in any measure. Our behavioral data suggest that GR deletion in Sim1-expressing neurons has no effect on anxiety or despair-like behavior under basal conditions. We conclude that loss of PVN GR results in severe HPA axis hyperactivity and Cushing's syndrome-like phenotype but does not affect anxiety and despair-like behaviors.

Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation

“…Sim1Cre-GRe2Δ mice show a 43% loss of PVN GR expression. However, there were no observed differences in HPA axis responsiveness, as measured by cort, ACTH or CRH concentrations, under basal or stressed conditions in Sim1Cre-GRe2Δ and control mice (Laryea et al, 2013).…”

“…In a separate study, Sim1Cre BAC transgenic mice (Balthasar et al, 2005) were mated to mice with loxp sites flanking the exon 1C-2 region of the GR allele (Boyle et al, 2005;Brewer et al, 2003) containing promoter elements, translation start site, and the transcriptional activation domain (Sim1Cre-GRe2Δ) (Laryea et al, 2013). Sim1Cre-GRe2Δ mice show a 43% loss of PVN GR expression.…”

“…In contrast, mice with GR exon 3 deletion in the PVN (Sim1Cre-GRe3Δ) (Tronche et al, 1999) demonstrate an 87% reduction in PVN GR expression and display stunted growth at birth, adult obesity and impaired stress-induced glucose release (Laryea et al, 2013). Sim1Cre-GRe3Δ mice display elevated cort concentrations under basal and stressful conditions, and an impaired response to the dexamethasone (GR agonist) suppression test, which interrogates the integrity of feedback inhibition on the HPA axis, indicating an inability to suppress cort regulation in response to high circulating cort concentrations.…”

Hypothalamic‐Pituitary‐Adrenal Axis—Feedback Control

“…In contrast, knockout of PVN GR resulted in increased ACTH and corticosterone during the circadian peak and in response to restraint (182,271). In these rats, there was also no suppression by dexamethasone suggesting that pituitary feedback can be overwhelmed or compensated for by changes in hypothalamic drive in the intact animal.…”

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

“…Because stress responses are regulated by the hypothalamic paraventicular nucleus (Laryea et al, 2013), and MT2 receptors are present in this area (Lacoste et al, 2015), we may speculate that melatonin could correct HPA axis disruption by acting on these receptors.…”