Disrupting hypothalamic glucocorticoid receptors causes HPA axis hyperactivity and excess adiposity
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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.
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Hyperactivity of the HPA axis due to changes in glucocorticoid receptors leads to abnormally elevated levels of cortisol.
“Hyperactivity of the axis due to changes in glucocorticoid receptors (GRs) lead to abnormally elevated levels of cortisol [39].”
From Chronic Stress-Associated Depressive Disorders: The Impact of HPA Axis Dysregulation and Neuroinflammation on the Hippocampus—A Mini Review (2025) · cites this paper as [39]
The Abstract and the section on increased HPA axis activity report that substantial loss of hypothalamic GR in mice caused HPA-axis hyperactivity and elevated basal and stress-induced corticosterone. The paper distinguishes rodent corticosterone from human cortisol; it does not show that GR changes caused elevated cortisol in humans. (LLM, conf=0.88)
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- Authors
- Laryea, G., Schütz, G., & Muglia, L. J.
- Affiliations
- Vanderbilt University (US)
- German Cancer Research Center (DE)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Muglia, Louis J.
- ORCID
- Muglia, Louis J.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2013-10-01
- Volume
- 27
- Issue
- 10
- Pages
- 1655-1665
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC4061381
- OpenAlex
- W2007415189
- Semantic Scholar
- d546e76bb82110db9ec2a2cf5e2edec7112e9060
- Cited by
- 106
- References
- 27
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 3 · 2018: 10 · 2017: 6 · 2016: 13 · 2015: 11 · 2014: 8
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- Cincinnati Children's Hospital Medical Center
- National Institutes of Health
- National Institute of Mental Health (T32MH064913, MH079010, R01MH079010)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- glucocorticoid receptor, hypothalamic-pituitary-adrenal axis, paraventricular nucleus, corticosterone, stress response, obesity, Cushing's syndrome, ACTH, corticotropin-releasing factor, dexamethasone suppression, anxiety-like behavior, despair-like behavior, Cre-loxP conditional knockout
- MeSH terms
- Animals, Corticosterone, Female, Hypothalamo-Hypophyseal System, Locomotion, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Obesity, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, Receptors, Glucocorticoid, Adiposity, Mice
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