Hypothalamo-pituitary-adrenal Function Research Articles

Changes in DNA Methylation of Clock Genes in Obese Adolescents after a Short-Term Body Weight Reduction Program: A Possible Metabolic and Endocrine Chrono-Resynchronization

Circadian rhythms are generated by a series of genes, collectively named clock genes, which act as a self-sustained internal 24 h timing system in the body. Many physiological processes, including metabolism and the endocrine system, are regulated by clock genes in coordination with environmental cues. Loss of the circadian rhythms has been reported to contribute to widespread obesity, particularly in the pediatric population, which is increasingly exposed to chronodisruptors in industrialized society. The aim of the present study was to evaluate the DNA methylation status of seven clock genes, namely clock, arntl, per1-3 and cry1-2, in a cohort of chronobiologically characterized obese adolescents (n: 45: F/M: 28/17; age ± SD: 15.8 ± 1.4 yrs; BMI SDS: 2.94 [2.76; 3.12]) hospitalized for a 3-week multidisciplinary body weight reduction program (BWRP), as well as a series of cardiometabolic outcomes and markers of hypothalamo-pituitary-adrenal (HPA) function. At the end of the intervention, an improvement in body composition was observed (decreases in BMI SDS and fat mass), as well as glucometabolic homeostasis (decreases in glucose, insulin, HOMA-IR and Hb1Ac), lipid profiling (decreases in total cholesterol, LDL-C, triglycerides and NEFA) and cardiovascular function (decreases in systolic and diastolic blood pressures and heart rate). Moreover, the BWRP reduced systemic inflammatory status (i.e., decrease in C-reactive protein) and HPA activity (i.e., decreases in plasma ACTH/cortisol and 24 h urinary-free cortisol excretion). Post-BWRP changes in the methylation levels of clock, cry2 and per2 genes occurred in the entire population, together with hypermethylation of clock and per3 genes in males and in subjects with metabolic syndrome. In contrast to the pre-BWRP data, at the end of the intervention, cardiometabolic parameters, such as fat mass, systolic and diastolic blood pressures, triglycerides and HDL-C, were associated with the methylation status of some clock genes. Finally, BWRP induced changes in clock genes that were associated with markers of HPA function. In conclusion, when administered to a chronodisrupted pediatric obese population, a short-term BWRP is capable of producing beneficial cardiometabolic effects, as well as an epigenetic remodeling of specific clock genes, suggesting the occurrence of a post-BWRP metabolic and endocrine chronoresynchronization, which might represent a "biomolecular" predictor of successful antiobesity intervention.

Recovery of the Hypothalamo-Pituitary-Adrenal Axis After Transsphenoidal Adenomectomy for Non-ACTH-Secreting Macroadenomas.

Secondary adrenal insufficiency is a potential complication of transsphenoidal adenomectomy (TSA). Most centers test recovery of the hypothalamo-pituitary-adrenal (HPA) axis after TSA, but, to our knowledge, there are no data predicting likelihood of recovery or the frequency of later recovery of HPA function. To assess timing and predictors of HPA axis recovery after TSA. Single-center, retrospective analysis of consecutive pituitary surgeries performed between February 2015 and September 2018. Patients (N = 109) with short Synacthen test (SST) data before and at sequential time points after TSA. Recovery of HPA axis function at 6 weeks, and 3, 6, and 9 to12 months after TSA. Preoperative SST indicated adrenal insufficiency in 21.1% Among these patients, 34.8% recovered by 6 weeks after TSA. Among the 65.2% (n = 15) remaining, 13.3% and 20% recovered at 3 months and 9 to 12 months, respectively. Of the 29% of patients with adrenal insufficiency at the 6-week SST, 16%, 12%, and 6% subsequently recovered at 3, 6, and 9 to 12 months, respectively. Preoperative SST 30-minute cortisol, postoperative day 8 cortisol, and 6-week postoperative SST baseline cortisol levels above or below 430 nmol/L [15.5 μg/dL; AUC ROC, 0.86]; 160 nmol/L (5.8 μg/dL; AUC ROC, 0.75); and 180 nmol/L (6.5 μg/dL; AUC ROC, 0.88), were identified as cutoffs for predicting 6-week HPA recovery. No patients with all three cutoffs below the threshold recovered within 12 months after TSA, whereas 92% with all cutoffs above the threshold recovered HPA function within 6 weeks (OR, 12.200; 95% CI, 5.268 to 28.255). HPA axis recovery can occur as late as 9 to 12 months after TSA, demonstrating the need for periodic reassessment of patients who initially have SST-determined adrenal insufficiency after TSA. Pre- and postoperative SST values can guide which patients are likely to recover function and potentially avoid unnecessary lifelong glucocorticoid replacement.

Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function.

Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis. HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function. Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived. All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18μg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1μg) ACTH stimulation consistent with central adrenal insufficiency. STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.

Inhibiting influence of testosterone on stress responsiveness during adolescence

The maturation of the hypothalamo-pituitary-adrenal (HPA) axis is a key-component of the changes that occur during adolescence. In guinea pigs, HPA responsiveness during late adolescence depends strongly on the quantity and quality of social interactions: Males that lived in a large mixed-sex colony over the course of adolescence exhibit a lower stress response than males that were kept in pairs (one male/one female). Since colony-housed males have higher testosterone (T) levels than pair-housed males, and inhibiting effects of T on HPA function are well known, we tested the hypothesis that the decrease in stress responsiveness found in colony-housed males is due to their high T concentrations. We manipulated T levels in two experiments: 1) gonadectomy/sham-gonadectomy of colony-housed males (which usually have high T levels), 2) application of T undecanoate/vehicle to pair-housed males (which usually have low T levels). As expected, gonadectomized males showed a significantly increased stress response in comparison with sham-gonadectomized males, and T-injected males had a significantly lower stress response than vehicle-injected males. Both experiments thus confirm an inhibiting effect of T on HPA responsiveness during adolescence, which can mediate the influence of social interactions. The reduction in stress responsiveness is hypothesized to have a biologically adaptive value: A sudden increase in glucocorticoid concentrations can enhance aggressive behavior. Thus, pair-housed males might be adapted to aggressively defend their female (‘resource defense strategy’), whereas colony-housed males display little aggressive behavior and are capable of integrating themselves into a colony (‘queuing strategy’).

The development of endotoxin tolerance, and the role of hypothalamo-pituitary-adrenal function and glucocorticoids in Pekin ducks

Endotoxin tolerance represents a state of abated immunological responsiveness to pyrogens, which, in mammals, leads to the decline or abolition of the fever response. The development of endotoxin tolerance in birds is not well understood; consequently, the impact of repeated pathogenic exposure on the avian febrile response, and thus on the ability of birds to fight recurrent infection, is not known. We determined the effect of repeated injections of lipopolysaccharide (LPS) on the febrile response of Pekin ducks. We gave ducks five injections of LPS, spaced 1, 4 or 10 days apart, and recorded their core body temperature with abdominally implanted temperature data loggers. Once we established that Pekin ducks developed endotoxin tolerance, we investigated the effect of repeated injections of LPS on the central and peripheral segments of the hypothalamo-pituitary-adrenal (HPA) axis in an attempt to elucidate the role of glucocorticoids in the modulation of the febrile response during the tolerant period. When our ducks became tolerant to LPS, they had significantly higher basal levels of plasma corticosterone (CORT, the principal glucocorticoid in birds), and their HPA response to treatment with LPS was blunted. We propose that the augmented levels of basal plasma CORT resulted from sensitized HPA function, and this, in turn, contributed to the development of endotoxin tolerance. Regulation of the circulating level of CORT might be a possible target for the re-establishment of appropriate immune responses in birds.

Rearing conditions have long-term consequences for stress responsiveness in free-living great tits

In captivity, the adrenocortical stress response can be permanently altered by events that occur during early life. Free-living animals have rarely been examined in this regard. To examine whether early-life events impact the hypothalamo–pituitary–adrenal (HPA) axis in the natural setting, we evaluated the stress response of free-living interspecifically cross-fostered great tits ( Parus major). Cross-fostered birds may show a long-term potentiation of the adrenocortical stress response because species-specific nutritional requirements may not be met in the nest and/or cross-fostered birds may experience psychosocial stress while being raised by heterospecifics. Nevertheless, we hypothesized that in the natural setting, programmed changes in HPA function would be eclipsed by reactive responses to the immediate environment. Thus, we predicted that adult cross-fostered great tits and controls would show no differences in their adrenocortical stress response. Contrary to predictions, we found that stress responsiveness (i.e., the rate of the corticosterone increase associated with capture and handling) was significantly higher in cross-fostered great tits than in controls. Further, stress responsiveness was not significantly different between mature adults and first-year juveniles. Thus, data indicate significant effects of early rearing conditions on adrenocortical reactivity in the natural setting and also suggest that effects of rearing conditions in free-living animals can last into adulthood.

Effects of chronic maternal stress on hypothalamo–pituitary–adrenal (HPA) function and behavior: No reversal by environmental enrichment

Maternal stress during pregnancy is linked to increased risk for impaired behavioral and emotional development and affective disorders in children. In animal models, acute periods of prenatal or postnatal stress have profound effects on HPA function and behavior in adult offspring. However, few animal studies have determined the impact of chronic exposure to stress throughout the perinatal period. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on HPA function, locomotor behavior and prepulse inhibition in adult guinea pig offspring, as well as to determine whether environmental enrichment (EE) could reverse the effects of CMS. Guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). Following weaning, offspring were housed in either standard conditions or EE. In both adult male and female offspring, there was no effect of CMS on basal or activated HPA function. CMS significantly increased locomotor activity in an open-field in male offspring, though no effect was observed in females. In female offspring, CMS disrupted PPI; however there was no effect on male PPI. EE had a number of effects on HPA function and behavior but in most cases these were independent of the influence of CMS. EE significantly elevated basal cortisol levels in male offspring at pnd70, whereas in female offspring, EE interacted with CMS to elevate basal cortisol levels from pnd35 to pnd70. In female offspring, EE decreased locomotor activity. In males, EE enhanced PPI; however in female offspring EE disrupted PPI. In conclusion, while CMS had minimal effects on HPA function, there were significant long-term sex-specific effects on behavior. EE did not reverse the effects observed as a result of CMS, but rather modified HPA function and behavior independently of CMS. Further, there was significant interaction of CMS with EE that resulted in elevation of basal HPA function in female offspring. These data, combined with previous studies from our laboratory, suggest that acute phases of maternal stress in late pregnancy may have greater long-term effects on HPA function and related behaviors than prolonged chronic maternal stress.

Sex‐ and age‐specific effects of nutrition in early gestation and early postnatal life on hypothalamo‐pituitary‐adrenal axis and sympathoadrenal function in adult sheep

The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n = 22; UC, n = 19) or were undernourished (CU, n = 17; UU, n = 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 microg kg(1)) plus arginine vasopressin (AVP) (0.1 microg kg(1)). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and sympathoadrenal function. With altered glucose tolerance previously reported in this model, this may have long-term detrimental effects on metabolic homeostasis and cardiovascular function.

Long-term consequences of early maternal deprivation in serotonergic activity and HPA function in adult rat

Increasing body of evidence indicates that early life stressful events may induce permanent alterations in neurodevelopment, which in turn, could lead to the development of psychopathologies in adulthood. In particular, maternal deprivation (MD) for 24 h in rats has been associated with several abnormalities in brain and behaviour during adulthood, relevant to the neurobiological substrate of anxiety disorders. The aim of the present study was to clarify the long-term effects of MD, on hypothalamo–pituitary–adrenal (HPA) axis activity and serotonergic (5-HT) function, in adulthood, subjects that have not been yet thoroughly investigated. For this purpose, Wistar rat pups were deprived from their mothers for a 24-h single period at postnatal day 9 (pnd 9) and were examined when aged 69–90 days. Plasma corticosterone and ACTH levels along with the animal's behaviour in an open field were used as indices of stress. Moreover, serotonergic activity was estimated in hypothalamus and hippocampus, key structures in the coordination of neuroendocrine and behavioural responses to stress. Interestingly, in adulthood, MD rats compared to controls, displayed decreased body weight, increased serotonergic activity and “anxiety” related behaviour, as well as elevated plasma corticosterone and ACTH levels. The findings of this study showed that MD results in long-term modifications in HPA axis and serotonergic activity indicating a clear relationship between early life stressful events and the development of anxiety-like disorders later in adulthood.

Dual Roles for Perivascular Macrophages in Immune-to-Brain Signaling

Cytokines produced during infection/inflammation activate adaptive central nervous system (CNS) responses, including acute stress responses mediated by the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms by which cytokines engage HPA control circuitry remain unclear, though stimulated release of prostanoids from neighboring vascular cells has been implicated in this regard. How specific vascular cell types, endothelial cells (ECs) versus perivascular cells (PVCs; a subset of brain-resident macrophages), participate in this response remains unsettled. We exploited the phagocytic activity of PVCs to deplete them in rats by central injection of a liposome-encapsulated proapoptotic drug. This manipulation abrogated CNS and hormonal indices of HPA activation under immune challenge conditions (interleukin-1) that activated prostanoid synthesis only in PVCs, while enhancing these responses to stimuli (lipopolysaccharide) that engaged prostanoid production by ECs as well. Thus, PVCs provide both prostanoid-mediated drive to the HPA axis and an anti-inflammatory action that constrains endothelial and overall CNS responses to inflammatory insults.

A single exposure to an acute stressor has lasting consequences for the hypothalamo–pituitary–adrenal response to stress in free-living birds

In vertebrates, activation of the hypothalamo–pituitary–adrenal (HPA) axis in response to unpredictable events results in elevated glucocorticoid secretion. Repeated exposure to stressors alters subsequent glucocorticoid secretion, either by inducing chronic stress or as a result of habituation. However, most studies of repeated stress focus on the impacts of multiple and frequent exposures to acute stressors, and few have been carried out in free-living animals. We investigated whether a single exposure to a novel stressor was sufficient to produce long-lasting alterations in HPA function in free-living eastern bluebirds ( Sialia sialis). We subjected adult females to a capture/restraint protocol in which we collected serial blood samples over an hour of restraint to be analyzed for corticosterone. We administered this protocol to three groups of females during the nestling phase of their first and/or second brood of the season: Repeaters (sampled during brood 1 and brood 2), Naïve-Brood 1 (sampled only during brood 1), and Naïve-Brood 2 (sampled only during brood 2). Repeaters had attenuated corticosterone responses to the second restraint bout compared to the first, and in brood 2, Repeaters had lower responses than Naïve-Brood 2 females. However, Naïve-Brood 1 and Naïve-Brood 2 birds did not differ in their responses to restraint. Thus, as little as one prior experience with an acute stressor was sufficient to alter subsequent HPA responsiveness, and this effect was not due to a natural change in HPA responsiveness as the breeding season progressed. These data may have important implications for understanding how acute stressors can alter a free-living animal’s ability to cope in the face of subsequent stressors, and for longitudinal field studies in which individuals are repeatedly sampled for glucocorticoid responsiveness.

Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic‐pituitary‐adrenal function

The perinatal environment is a powerful determinant of risk for developing disease in later life. Here, we have shown that maternal undernutrition causes dramatic changes in heart structure and hypothalamo-pituitary-adrenal (HPA) function across two generations. Pregnant guinea pigs were fed 70% of normal intake from gestational days 1-35 (early restriction; ER), or 36-70 (late restriction; LR). Female offspring (F(1)) were mated and fed ad libitum to create second generation (F(2)) offspring. Heart morphology, blood pressure, baroreceptor and HPA function were assessed in male F(1) and F(2) offspring. ER(F1) males exhibited elevated blood pressure, increased left ventricular (LV) wall thickness and LV mass. These LV effects were maintained in the ER(F2) offspring. Maternal undernutrition increased basal cortisol and altered HPA responsiveness to challenge in both generations; effects were greatest in LR groups. In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations.

Chronic maternal stress affects growth, behaviour and hypothalamo–pituitary–adrenal function in juvenile offspring

Maternal stress during pregnancy, particularly that combined with low socioeconomic status (SES), has been linked to an increased risk for impaired behavioural and emotional development and affective disorders in children. In animal models, acute periods of prenatal stress have profound effects on hypothalamo-pituitary-adrenal (HPA) function and behaviour. However, few studies have determined the impact of chronic exposure to stress in animal models. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on growth, locomotor behaviour and HPA axis function in juvenile guinea pig offspring. Pregnant guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). CMS mothers displayed increased basal salivary cortisol levels in the later stages of pregnancy compared to control mothers ( p < 0.05). The male offspring of CMS mothers had a lower bodyweight, which was maintained to weaning ( p < 0.01). In open-field testing, CMS male offspring showed a decrease in activity compared to controls ( p < 0.05). There was no effect of CMS on bodyweight or activity in female offspring. In contrast, both male and female offspring born to CMS mothers displayed increased ( p < 0.05) basal salivary cortisol at pnd25, but a blunted adrenocortical response to exposure to the novel open-field enclosure. In conclusion, CMS leads to modification of growth trajectory, locomotor activity and adrenocortical responses to stress in juvenile offspring. Further, males appear considerably more vulnerable to these effects than females.

Erythropoietin Inhibits Basal and Stimulated Corticotropin-Releasing Hormone Release from the Rat Hypothalamus via a Nontranscriptional Mechanism

Brain hypoxia-ischemia induces a local increase in the levels of erythropoietin (EPO) and vascular endothelial growth factor (VEGF); this condition is also associated with acute activation of the hypothalamo-pituitary-adrenal (HPA) axis, suggesting that increased levels of EPO and VEGF in the hypothalamus may play a role in the control of HPA function. Thus, in this study we used rat hypothalamic explants to investigate whether EPO and VEGF can directly modulate CRH release; the latter was assessed by RIA measurement of the peptide in the incubation medium and hypothalamic tissue. EPO and VEGF effects were studied in short-term (1-3 h) experiments under basal conditions or after stimulation with 56 mM KCl or 10 microM veratridine. We observed that EPO (1-10 nm) significantly reduced CRH release and, in parallel, increased intrahypothalamic CRH content. VEGF tended to reduce CRH release without reaching statistical significance. Moreover, EPO, but not VEGF, inhibited KCl- and veratridine-stimulated CRH release and counteracted the parallel decrease in intrahypothalamic CRH induced by the two secretagogues. EPO effects were not mediated by modification of CRH gene expression, either in the absence or the presence of KCl or veratridine; in this paradigm, KCl and veratridine per se did not modify CRH gene expression. Our findings suggest that EPO contributes to the regulation of the HPA axis activation; in pathological conditions such as brain ischemia, this growth factor may control the HPA axis function, preventing possible detrimental effects of HPA overactivation.

Prenatal Glucocorticoid Exposure Alters Hypothalamic‐Pituitary‐Adrenal Function in Juvenile Guinea Pigs

The neurodevelopmental consequences of prenatal glucocorticoid exposure are not well-understood, particularly in species that give birth to neuroanatomically mature offspring. In the present study, we hypothesised that repeated prenatal glucocorticoid administration would alter hypothalamo-pituitary-adrenal (HPA) function in juvenile guinea pig offspring. Pregnant guinea pigs were injected with betamethasone (1 mg/kg) or vehicle on gestational days 40, 41, 50, 51, 60 and 61 (six doses). Prenatal glucocorticoid exposure abolished the pituitary-adrenal response to maternal separation in juvenile males, but had no effect in female offspring. Indeed, female offspring (vehicle and betamethasone) did not mount a significant HPA response to separation at 10 days of age. Although there were no effects of prenatal glucocorticoid exposure on hippocampal or hypothalamic corticosteroid receptor expression or corticotrophin-releasing factor (CRF) mRNA, there were significant effects in the pituitary and adrenal; again males were more affected than females. Prenatal glucocorticoid exposure increased pituitary pro-opiomelanocortin and CRF receptor mRNA, and markedly decreased adrenocortical CYP17 mRNA. In conclusion, repeated prenatal glucocorticoid exposure has profound influences on HPA function and regulation in the juvenile guinea pig, and this involves altered regulation at the level of the pituitary and adrenal cortex. Furthermore, juvenile males appear to be more vulnerable to the effects of prenatal glucocorticoid exposure than females.

Diverse basal and stress-related phenotypes of Sprague Dawley rats from three vendors

Based on observed phenotypic differences in growth and ACTH responses to stress in Sprague Dawley rats obtained from different vendors, we ran head-to-head comparisons on rats obtained from three different vendors, Harlan, Charles River, and Simonsen, with respect to baseline phenotypic differences and a metabolic feedback hypothesis of hypothalamo-pituitary-adrenal (HPA) regulation. Charles River and Harlan rats gained weight faster than Simonsen rats, but chow intake standardized for body weight was not increased, consistent with their greater caloric efficiency. Weight gain was inversely related with mean daily temperatures, without differences in activity levels. Half of the animals given lard and 32% sucrose solutions in addition to chow increased caloric intake and core temperature, decreased caloric efficiency, and increased fat depots, leptin, and in Simonsen rats, insulin. A 5-day regimen of once-daily 2-h restraint decreased feeding and caloric efficiency. Rats from two vendors with the availability of sucrose and lard, Charles River and Simonsen, showed blunted HPA responses to restraint compared to chow controls, whereas the Harlans exhibited no adrenocortorticotropin (ACTH) response and an amplified adrenocortical response on the high-energy diet compared to chow controls. Substantial phenotypic differences exist between Sprague Dawley rats from different vendors with respect to metabolism and HPA function. The metabolic feedback hypothesis was supported in two of the three vendors' rats.

Hydroxyurea induces vasopressin release and cytokine gene expression in the rat hypothalamus

We previously showed that the cytostatic drug hydroxyurea (HU) activates the hypothalamo–pituitary–adrenal (HPA) axis in intact rats, whereas it is lethal in rats with impaired HPA function. In these animals, HU toxicity is mediated by increased circulating levels of proinflammatory cytokines, whose secretion cannot be counteracted by glucocorticoids, suggesting that HPA activation blunts HU toxicity. Here we investigated the mechanisms through which HU activates the HPA axis, looking at the direct effects of the drug on the isolated hypothalamus. We found that HU significantly increases the release of arginine vasopressin but not that of corticotrophin-releasing hormone in short-term incubation experiments. The levels of arginine vasopressin are also increased in the hypothalamus and systemic circulation 2 h after the in vivo administration of the drug. Furthermore, HU increased significantly the expression of interleukin-6 and, to a lesser extent, interleukin-1β in the hypothalamus. Interestingly, experiments with HU on primary cultures of rat microglia and astrocytes suggested that the increase in cytokine gene expression observed in hypothalamic explants is not accounted for by glial cells. Since both vasopressin and cytokines can activate the HPA axis, our present findings provide a reasonable explanation of the HPA activation elicited by HU in vivo in the rat.

Fetal programming of hypothalamo‐pituitary‐adrenal function: prenatal stress and glucocorticoids

Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behaviour. Both of these manipulations lead to increased fetal exposure to glucocorticoids. Glucocorticoids are essential for many aspects of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function. Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner. Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behaviour, brain and organ morphology, as well as altered regulation of other endocrine systems. It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome. Permanent changes in endocrine function will ultimately impact on health in both human and animal populations.

Effects of a single footshock followed by situational reminders on HPA axis and behaviour in the aversive context in male and female rats

Gender is an important factor in the vulnerability to develop psychopathologies. At the biological level, stress-related pathologies such as depression or post-traumatic stress disorder (PTSD) are associated with profound disturbances of the hypothalamo-pituitary-adrenal (HPA) axis. The aim of the present study was to assess sex-differences in the long-term effect of an intense stressful procedure on HPA function and behaviour in the aversive context in rats. Female and male rats experienced an aversive procedure consisting in an electric footshock (2mA, 10s) in a dark chamber followed by 3 weekly situational reminders (SR, 2min in the white chamber close to the footshock chamber). Our results indicate that 41 days after the end of the aversive procedure, female rats showed an increase of the corticosterone negative feedback in response to restraint stress, whereas such effect was not observed in males. Despite this change in the hormonal response, glucocorticoid receptors mRNA expression in the hippocampus was not affected in shocked females. In contrast, a significant increase of the mineralocorticoid receptors mRNA was observed in the CA2 of the hippocampus in shocked males. Finally, CRH mRNA levels in the paraventricular nucleus of the hypothalamus (PVN) were decreased in both female and male animals exposed to the aversive procedure. Behavioural observation revealed that shocked males and shocked females showed a high level of avoidance. However, the latency to visit the shock box was lower in females, which spent also more time in this area than males. In conclusion, our results suggest that gender might be a key factor impacting the direction of the effects induced by an intense stress. Interestingly, only females exhibited an increased negative feedback of the HPA axis response to stress, which could parallel endocrine changes of PTSD.

Increased Cortisol Bioavailability, Abdominal Obesity, and the Metabolic Syndrome in Obese Women

This study was conducted to obtain a detailed profile of hypothalamo-pituitary-adrenal (HPA) axis activity and reactivity and its differential relationships with body fat distribution and total fat mass in premenopausal obese women. Cortisol responses to stimulation (awakening, food intake, exercise) and suppression (0.25 mg dexamethasone), cortisol metabolism, and tissue sensitivity to glucocorticoids were studied in 53 premenopausal obese women grouped according to their waist-to hip ratio: women with abdominal body fat distribution (A-BFD; n = 31) and women with peripheral fat distribution (P-BFD; n = 22). Comparatively, A-BFD women had 1) lower awakening salivary cortisol levels; 2) increased salivary responsiveness to a standardized lunch; 3) similar pituitary sensitivity to dexamethasone but decreased sensitivity of monocytes to dexamethasone; 4) similar 24-hour urinary free cortisol but increased 24-hour urinary ratio of cortisone-to-cortisol; and 5) no difference in corticosteroid binding protein parameters. Although abdominal obesity is not very different from generalized obesity in terms of HPA function, subtle variations in HPA axis activity and reactivity are evidenced in A-BFD premenopausal obese women.