scholarly journals Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

2021 ◽  
Vol 118 (27) ◽  
pp. e2106868118
Author(s):  
Irene Cimino ◽  
Hanna Kim ◽  
Y. C. Loraine Tung ◽  
Kent Pedersen ◽  
Debra Rimmington ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Cytokine Response ◽  
Reduce Food Intake ◽  
Wild Type ◽  
Marked Rise ◽  
Blocking Antibody ◽  
Hypothalamic Pituitary Adrenal ◽  
Acute Increase ◽  
Corticosterone Response ◽  
Hpa Response

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

scholarly journals Hypothalamic-Pituitary-Adrenal Axis Activity of Newborn Mice Rapidly Desensitizes to Repeated Maternal Absence but Becomes Highly Responsive to Novelty

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6366-6377 ◽  
Author(s):  
L. Enthoven ◽  
M. S. Oitzl ◽  
N. Koning ◽  
M. van der Mark ◽  
E. R. de Kloet
Keyword(s):  
Glucocorticoid Receptor ◽  
Receptor Antagonist ◽  
Hpa Axis ◽  
Mineralocorticoid Receptor ◽  
Maternal Separation ◽  
Mineralocorticoid Receptor Antagonist ◽  
Newborn Mice ◽  
Hypothalamic Pituitary Adrenal ◽  
The Third ◽  
Corticosterone Response

In CD1 mice we investigated the hypothalamic-pituitary-adrenal (HPA) axis response to maternal separation for 8 h daily from postnatal d 3 to 5. At d 3 a slow separation-induced corticosterone response developed that peaked after 8 h, and the pups became responsive to stressors. On the second and third day, the response to 8 h separation rapidly attenuated, whereas the response to novelty did not, a pattern reflected by the hypothalamic c-fos mRNA response. If maternal separation and exposure to novelty were combined, then after the third such daily exposure, the sensitivity to the stressor was further enhanced. Meanwhile, basal corticosterone and ACTH levels were persistently suppressed 16 h after pups were reunited with their mothers. To explain the HPA axis desensitization after repeated separation, we found that circulating ghrelin levels increased and glucose levels decreased after all periods of maternal separation, ruling out a role of altered metabolism. Glucocorticoid feedback was not involved either because a glucocorticoid receptor antagonist amplified the corticosterone response after the first but became ineffective after the third separation. In contrast, a mineralocorticoid receptor antagonist decreased and increased corticosterone levels after the first and third period of separation, respectively. In conclusion, the newborn’s HPA axis readily desensitizes to repeated daily maternal separation, but continues to respond to novelty in a manner influenced by a central mineralocorticoid receptor- rather than glucocorticoid receptor-mediated mechanism.

scholarly journals Vitamin A regulates hypothalamic–pituitary–adrenal axis status in LOU/C rats

2013 ◽  
Vol 219 (1) ◽  
pp. 21-27 ◽  
Author(s):  
Nathalie Marissal-Arvy ◽  
Rachel Hamiani ◽  
Emmanuel Richard ◽  
Marie-Pierre Moisan ◽  
Véronique Pallet
Keyword(s):  
Vitamin A ◽  
Hpa Axis ◽  
Restraint Stress ◽  
Vitamin A Deficiency ◽  
Plasma Corticosterone ◽  
Hypothalamic Pituitary Adrenal ◽  
Corticosteroid Receptors ◽  
Vitamin A Status ◽  
Corticosterone Response ◽  
Hpa Axis Activity

The aim of this study was to explore the involvement of retinoids in the hypoactivity and hyporeactivity to stress of the hypothalamic–pituitary–adrenal (HPA) axis in LOU/C rats. We measured the effects of vitamin A deficiency administered or not with retinoic acid (RA) on plasma corticosterone in standard conditions and in response to restraint stress and on hypothalamic and hippocampal expression of corticosteroid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in LOU/C rats. Interestingly, under control conditions, we measured a higher plasma concentration of retinol in LOU/C than in Wistar rats, which could contribute to the lower basal activity of the HPA axis in LOU/C rats. Vitamin A deficiency induced an increased HPA axis activity in LOU/C rats, normalized by RA administration. Compared with LOU/C control rats, vitamin A-deficient rats showed a delayed and heightened corticosterone response to restraint stress. The expression of corticosteroid receptors was strongly decreased by vitamin A deficiency in the hippocampus, which could contribute to a less efficient feedback by corticosterone on HPA axis tone. The expression of 11β-HSD1 was increased by vitamin A deficiency in the hypothalamus (+62.5%) as in the hippocampus (+104.7%), which could lead to a higher production of corticosterone locally and contribute to alteration of the hippocampus. RA supplementation treatment restored corticosterone concentrations and 11β-HSD1 expression to control levels. The high vitamin A status of LOU/C rats could contribute to their low HPA axis activity/reactivity and to a protective effect against 11β-HSD1-mediated deleterious action on cognitive performances during ageing.

scholarly journals Effect of vasopressin 1b receptor blockade on the hypothalamic–pituitary–adrenal response of chronically stressed rats to a heterotypic stressor

2008 ◽  
Vol 200 (3) ◽  
pp. 285-291 ◽  
Author(s):  
Francesca Spiga ◽  
Louise R Harrison ◽  
Cliona P MacSweeney ◽  
Fiona J Thomson ◽  
Mark Craighead ◽  
...  
Keyword(s):  
White Noise ◽  
Chronic Stress ◽  
Hpa Axis ◽  
Home Cage ◽  
Male Rats ◽  
Receptor Blockade ◽  
Hypothalamic Pituitary Adrenal ◽  
Corticosterone Secretion ◽  
Corticosterone Response ◽  
Adrenal Response

Exposure to chronic restraint (CR) modifies the hypothalamic–pituitary–adrenal (HPA) axis response to subsequent acute stressors with adaptation of the response to a homotypic and sensitization of the response to a heterotypic stressor. Since vasopressin (AVP) activity has been reported to change during chronic stress, we investigated whether this was an important factor in HPA facilitation. We therefore tested whether vasopressin 1b receptor (AVPR1B) blockade altered the ACTH and corticosterone response to heterotypic stressors following CR stress. Adult male rats were exposed to CR, single restraint, or were left undisturbed in the home cage. Twenty-four hours after the last restraint, rats were injected with either a AVPR1B antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in saline, 0.2/kg, s.c.) and then exposed to either restraint, lipopolysaccharide (LPS) or white noise. CR resulted in the adaptation of the ACTH and corticosterone response to restraint and this effect was not prevented by pretreatment with Org. Although we found no effect of CR on LPS-induced ACTH and corticosterone secretion, both repeated and single episodes of restraint induced the sensitization of the ACTH, but not corticosterone response to acute noise. Pretreatment with Org reduced the exaggerated ACTH response to noise after both single and repeated exposure to restraint.

Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia

2004 ◽  
Vol 286 (1) ◽  
pp. R123-R128 ◽  
Author(s):  
Scott B. Evans ◽  
Charles W. Wilkinson ◽  
Pam Gronbeck ◽  
Jennifer L. Bennett ◽  
Aryana Zavosh ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Control Level ◽  
Specific Role ◽  
Hypothalamic Pituitary Adrenal ◽  
Single Bout ◽  
Corticosterone Response

We have previously reported that repeated bouts of insulin-induced hypoglycemia (IIH) in the rat result in blunted activation of the paraventricular, arcuate, and dorsomedial hypothalamic (DMH) nuclei. Because DMH activation has been implicated in the sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to stressors, we hypothesized that its blunted activation may play a role in the impaired counterregulatory response that is also observed with repeated bouts of IIH. In the present study, we evaluated the role of normal DMH activation in the counterregulatory response to a single bout of IIH. Local infusion of lidocaine ( n = 8) to inactivate the DMH during a 2-h bout of IIH resulted in a significant overall decrease of the ACTH response and a delay of onset of the corticosterone response compared with vehicle-infused controls ( n = 9). We observed suppression of the ACTH response at time ( t) = 90 and 120 min (50 ± 12 and 63 ± 6%, respectively, of control levels) and early suppression of the corticosterone response at t = 30 min (59 ± 13% of the control level). The epinephrine, norepinephrine, and glucagon responses were not altered by DMH inactivation. Our finding suggests that DMH inactivation may play a specific role in decreasing the HPA axis response after repeated bouts of IIH.

scholarly journals Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic–pituitary–adrenal axis response to acute stress

2012 ◽  
Vol 216 (1) ◽  
pp. 99-109 ◽  
Author(s):  
M J F Newson ◽  
G R Pope ◽  
E M Roberts ◽  
S J Lolait ◽  
A-M O'Carroll
Keyword(s):  
Hpa Axis ◽  
Wild Type ◽  
Plasma Acth ◽  
Systemic Injection ◽  
Male And Female ◽  
Hypothalamic Pituitary Adrenal ◽  
Female Mice ◽  
Apelin Receptor ◽  
Stress Dependent ◽  
Gender Specific

The neuropeptide apelin is expressed in hypothalamic paraventricular and supraoptic nuclei and mediates its effects via activation of the apelin receptor (APJ). Evidence suggests a role for apelin and APJ in mediating the neuroendocrine response to stress. To understand the physiological role of APJ in regulation of the hypothalamic–pituitary–adrenal (HPA) axis, we measured ACTH and corticosterone (CORT) plasma levels in male and female mice lacking APJ (APJ knockout, APJ KO) and in wild-type controls, in response to a variety of acute stressors. Exposure to mild restraint, systemic injection of lipopolysaccharide (LPS), insulin-induced hypoglycaemia and forced swim (FS) stressors, elevated plasma ACTH and CORT levels in wild-type mice. Acute mild restraint significantly increased plasma ACTH and CORT to a similar level in APJ KO mice as in wild-type mice. However, an intact APJ was required for a conventional ACTH, but not CORT, response to LPS administration in male mice and to insulin-induced hypoglycaemia in male and female mice. In contrast, APJ KO mice displayed an impaired CORT response to acute FS stress, regardless of gender. These data indicate that APJ has a role in regulation of the HPA axis response to some acute stressors and has a gender-specific function in peripheral immune activation of the HPA axis.

scholarly journals The stimuli-specific role of vasopressin in the hypothalamus–pituitary–adrenal axis response to stress

2009 ◽  
Vol 202 (2) ◽  
pp. 263-278 ◽  
Author(s):  
Dóra Zelena ◽  
Ágnes Domokos ◽  
Subodh Kumar Jain ◽  
Ryan Jankord ◽  
Ludmila Filaretova
Keyword(s):  
Hpa Axis ◽  
Living Organism ◽  
Social Avoidance ◽  
Volume Load ◽  
Wide Range ◽  
Corticosterone Response ◽  
Context Specific ◽  
Aggressive Attack ◽  
Hpa Response

Adaptation to a constantly changing environment is fundamental to every living organism. The hypothalamic–pituitary–adrenocortical (HPA) axis is a key component of the adaptation process. The present study tests the hypothesis that vasopressin (AVP) is required for the HPA response to acute stimuli. To accomplish this, naturally AVP-deficient Brattleboro rats were exposed to a wide range of stimuli and their HPA response was compared with heterozygous littermattes. The circadian rhythmicity of plasma ACTH and corticosterone was not different between the two genotypes. The ACTH and corticosterone response to volume load, restraint or aggressive attack were decreased in AVP-deficient rats. The stress-induced increase in ACTH, but not corticosterone, was significantly impaired in AVP-deficient animals after novelty, elevated plus-maze, forced swim, hypoglycaemia, ulcerogenic cold immobilisation, lipopolysaccharide, hypertonic saline and egg white injection. The HPA response to social avoidance, ether inhalation and footshock was not different between the genotypes. In vitro, the hypophysis of AVP-deficient animals showed a reduction in stimulated ACTH production and their adrenal glands were hyporeactive to ACTH. A dissociation between the ACTH and corticosterone response was observed in several experiments and could not be explained by an earlier ACTH peak or enhanced adrenal sensitivity, suggesting the existence of paraadenohypophyseal neuroendocrine regulators. Loss of AVP affected the HPA response to a wide variety of stressors. Interestingly, the contribution of AVP to the HPA response was not specific for, nor limited to, a known stressor category. Thus, there is a context-specific requirement for AVP in stress-induced activation of the HPA axis.

scholarly journals Agouti-Related Protein Stimulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis and Enhances the HPA Response to Interleukin-1 in the Primate

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 1736-1741 ◽  
Author(s):  
Ennian Xiao ◽  
Linna Xia-Zhang ◽  
Nicolas R. Vulliémoz ◽  
Michel Ferin ◽  
Sharon L. Wardlaw
Keyword(s):  
Inflammatory Cytokines ◽  
Hpa Axis ◽  
Physiological Role ◽  
Related Protein ◽  
Hypothalamic Pituitary Adrenal ◽  
Neuroendocrine Responses ◽  
Agouti Related Protein ◽  
Hpa Response ◽  
Over Time ◽  
Significant Stimulatory Effect

α-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that α-MSH attenuates the stimulatory effect of IL-1 on the hypothalamic-pituitary-adrenal (HPA) axis and plays a physiological role in limiting the HPA response to IL-1. Recently an α-MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of α-MSH at specific melanocortin receptors. It is unknown whether AGRP can also modulate neuroendocrine responses to inflammatory cytokines. We have therefore examined the effects of AGRP on the HPA axis and on prolactin (PRL) at baseline and in response to stimulation by IL-1β in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (icv) infusion of 20 μg (n = 6) and 50 μg (n = 4) of human AGRP (83–132)-NH2 were compared with icv saline infusion. There was a significant stimulatory effect of 20 μg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 μg AGRP vs. saline; the AUC for ACTH increased by 166% (P = 0.028); the AUC for PRL increased by 108% (P = 0.046). There was a significant stimulatory effect of 50 μg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 μg AGRP increased by 98%; the AUC for cortisol increased by 37%; the AUC for PRL increased by 161%. The effects of AGRP on ACTH, cortisol, and PRL release were prevented by α-MSH infusion. In the second study, animals received icv either 50 ng of human IL-1β or 20 μg of AGRP followed by 50 ng IL-1β. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1β. The peak ACTH response to IL-1β alone was 124 ± 55 pg/ml vs. 430 ± 198 pg/ml after IL-1β plus AGRP; the peak cortisol response was 70 ± 8.2 μg/dl vs. 77 ± 6.2 μg/dl, but this was not significantly different. In conclusion, AGRP stimulated ACTH, cortisol, and PRL release in the monkey and enhanced the ACTH response to IL-1β. These studies suggest that, in addition to its known orexigenic effects, AGRP may play a role in neuroendocrine regulation and specifically that AGRP may interact with α-MSH to modulate neuroendocrine responses to inflammation.

scholarly journals Neonatal Gonadectomy and Adult Testosterone Replacement Suggest an Involvement of Limbic Arginine Vasopressin and Androgen Receptors in the Organization of the Hypothalamic-Pituitary-Adrenal Axis

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3581-3591 ◽  
Author(s):  
Brenda Bingham ◽  
Victor Viau
Keyword(s):  
Androgen Receptor ◽  
Hpa Axis ◽  
Paraventricular Nucleus ◽  
Arginine Vasopressin ◽  
Androgen Receptors ◽  
Male Rats ◽  
Testosterone Replacement ◽  
Testosterone Treatment ◽  
Hypothalamic Pituitary Adrenal ◽  
Hpa Response

Testosterone exposure during critical periods of development exerts major organizing effects on the hypothalamic-pituitary-adrenal (HPA) axis. Here we examined how neonatal gonadectomy (GDX) with or without testosterone treatment during the first week of life alters the HPA response to adult testosterone replacement in 65-d-old male rats. As adults, neonatal GDX rats showed higher levels of plasma corticosterone and Fos activation in medial parvocellular part of the paraventricular nucleus of the hypothalamus under basal conditions and during 30 min of restraint exposure. These responses were normalized with testosterone treatment on postnatal d 1–5 but were not restored with adult testosterone replacement. As adults, neonatal GDX rats also showed a decrease in the number of androgen receptor and arginine vasopressin-positive cells in the bed nucleus of the stria terminalis and in the medial nucleus of the amygdala, and both of these responses were reversed with postnatal testosterone treatment. In stressed and unstressed animals, the number of androgen receptors and arginine vasopressin-expressing neurons in both of these nuclei correlated negatively with corticosterone concentrations in plasma and Fos levels in the paraventricular nucleus. Taken together, our findings suggest that testosterone exposure during the neonatal period primes the adult HPA response to testosterone by altering androgen receptor levels and function within afferent mediators of basal and stress-related input to the HPA axis.

scholarly journals Impaired adaptation to repeated restraint and decreased response to cold in urocortin 1 knockout mice

2007 ◽  
Vol 293 (1) ◽  
pp. E259-E263 ◽  
Author(s):  
Alena A. Zalutskaya ◽  
Maya Arai ◽  
George S. Bounoutas ◽  
Abdul B. Abou-Samra
Keyword(s):  
Hpa Axis ◽  
Physiological Role ◽  
Corticotropin Releasing Factor ◽  
Cold Environment ◽  
Wild Type ◽  
Partial Adaptation ◽  
Urocortin 1 ◽  
Corticosterone Response ◽  
Males And Females

Urocortin 1 (UCN1) is a corticotropin-releasing factor (CRF)-like peptide whose role in stress is not well characterized. To study the physiological role of UCN1 in the response of the hypothalamic-pituitary-adrenal (HPA) axis to stress, we generated UCN1-knockout (KO) mice and examined their adaptation to repeated restraint and to cold environment. Wild-type (WT) and UCN1-KO animals were restrained hourly for 15 min from 9 AM to 2 PM, and blood samples were obtained for corticosterone measurement. WT animals adapted to repeated restraint with a decreased corticosterone response; the restraint-stimulated corticosterone levels fell from 215 ± 31 ng/ml in naïve animals to 142 ± 50 ng/ml in mice subjected to repeated restraint ( P < 0.01) and from 552 ± 98 to 314 ± 58 ng/ml ( P < 0.001) in males and females, respectively. Male UCN1-KO mice did not show any adaptation to repeated restraint; instead, restraint-stimulated corticosterone levels were increased from 274 ± 80 ng/ml in naïve animals to 480 ± 75 ng/ml in mice subjected to repeated restraint ( P < 0.001). Female UCN1-KO mice showed only a partial adaptation to repeated restraint, with a decrease in the restraint-stimulated corticosterone response from 631 ± 102 ng/ml in naïve animals to 467 ± 78 ng/ml in mice subjected to repeated restraint ( P < 0.01). In addition, UCN1-KO mice showed no corticosterone response to 2-h cold environment. These data demonstrate an important role for UCN1 in the HPA axis adaptation to repeated restraint and in the corticosterone response to a cold environment.

Effects of alprazolam on cholecystokinin-tetrapeptide (CCK-4) induced panic and hypothalamic-pituitary-adrenal (HPA) axis activity

2004 ◽  
Vol 36 (05) ◽  
Author(s):  
D Eser ◽  
P Zwanzger ◽  
S Aicher ◽  
C Schüle ◽  
TC Baghai ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Hypothalamic Pituitary Adrenal ◽  
Hpa Axis Activity
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