The Hypothalamic-Pituitary-Adrenal Axis, Obesity, and Chronic Stress Exposure: Sleep and the HPA Axis in Obesity.
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SUBMITTER: Lucassen EA
PROVIDER: S-EPMC3498460 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
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The Hypothalamic-Pituitary-Adrenal Axis, Obesity, and Chronic Stress Exposure: Sleep and the HPA Axis in Obesity.
Lucassen Eliane A EA Cizza Giovanni G
Current obesity reports 20121201 4
Obesity, exposure to stress and inadequate sleep are prevalent phenomena in modern society. In this review we focus on their relationships and critically evaluate causality. In obese individuals, one of the main stress systems, the hypothalamic-pituitary-adrenal axis, is altered, and concentrations of cortisol are elevated in adipose tissue due to elevated local activity of 11β-hydroxysteroid dehydrogenase (HSD) type 1. Short sleep and decreased sleep quality are also associated with obesity. In ...[more]
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Project description:Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar ("matching") adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.
| S-EPMC5395581 | biostudies-literature
Project description:Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in metyrapone effects on delta power sleep, and no significant metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress-related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties.
| S-EPMC6170159 | biostudies-literature
Project description:INTRODUCTION:Exposure to stress, mediated through the hypothalamic-pituitary-adrenal (HPA) axis, elicits sex differences in endocrine, neurological, and behavioral responses. However, the sex-specific factors that confer resilience or vulnerability to stress and stress-associated psychiatric disorders remain largely unknown. The evident sex differences in stress-related disease prevalence suggest the underlying differences in the neurobiological underpinnings of HPA axis regulation. METHOD:Here, we used a chronic unpredictable stress (CUS) model to investigate the behavioral and biochemical responses of the HPA axis in C57BL/6 mice. Animals were tested in the open field and forced swim test to examine anxiety-like and depressive-like behaviors. Plasma corticosterone levels were measured after behavior and CUS, and glucocorticoid receptor (GR) expression and cytosolic and nuclear fractions of binding protein FKBP51 expression were taken to measure function and regulation of the stress response. RESULTS:Our results indicate increased depressive-like behavior in males and females which correlated with increased corticosterone levels following CUS. However, females displayed more anxiety-like behaviors with and without CUS. Interestingly, we found trends toward dysregulation of GR protein expression in CUS females, and an increase in the GR inhibitory protein, FKBP51, in the cytosol of CUS males but not females. CONCLUSION:These results suggest biochemical alterations to the HPA axis regulation which may elicit a glucocorticoid resistance in females after chronic stress and may contribute to the sex-biased vulnerability to stress-related psychiatric disorders.
| S-EPMC7177572 | biostudies-literature
Project description:BackgroundSexual assault is implicated in several adverse psychological and physical health outcomes, including posttraumatic stress disorder (PTSD) and depression. Neurobiological research has shown variations related to the hypothalamic-pituitary-adrenal (HPA) axis, immune alterations, metabolic function, and brain circuitry. Although these mechanisms have been extensively studied, the results have demonstrated different outcomes in PTSD.MethodsWe compared the plasma adrenocorticotropin (ACTH) and salivary cortisol levels of fifty-eight women with PTSD developed after sexual assault to those of forty-four female controls with no history of trauma. We also evaluated the psychiatric diagnosis and symptom severity of PTSD and depression. The participants' clinical conditions were associated with their hormonal levels to assess whether symptom severity was related to hormonal imbalance.ResultsA large percentage of sexually assaulted women had PTSD and comorbid depression. The ACTH levels were higher in the PTSD group than the control group and increased as PTSD severity increased, considering depressive symptoms, measured by the Beck Depression Inventory (BDI) (p < 0.0001), as well as PTSD symptoms, measured by subscale D of the Clinician-Administered PTSD Scale (CAPS-5) (p = 0.045) and the CAPS-5 total scale (p = 0.026). Cortisol levels measured at 10 pm were higher for the PTSD group than the control group (p = 0.045, p = 0.037, respectively), and the cortisol awakening response showed elevated cortisol levels for the PTSD group.ConclusionsThese results show a correlation between symptom severity and HPA axis imbalance in patients with PTSD. Elevated ACTH and an elevated cortisol response in patients with comorbid depressive symptoms were the opposite of the expected response for patients with PTSD only. This association leads to the hypothesis that the neurobiological alterations of PTSD are related to the type of symptoms presented and their severity. These manifestations likely influence the disease course, prognosis and response to treatment. These outcomes highlight the need to discuss particular neurobiological alterations in patients with PTSD developed after sexual assault, mainly those with severe depressive symptoms.
| S-EPMC8010966 | biostudies-literature
Project description:Chronic stress is often associated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which can greatly increase risk for a number of stress-related diseases, including neuropsychiatric disorders. Despite a striking sex-bias in the prevalence of many of these disorders, few preclinical studies have examined female subjects. Hence, the present study aimed to explore the effects of chronic stress on the basal and acute stress-induced activity of the HPA axis in the female C57BL/6 mouse. We used a chronic variable stress (CVS) paradigm in these studies, which successfully induces physiological and behavioral changes that are similar to those reported for some patients with mood disorders. Using this model, we found pronounced, time-dependent effects of chronic stress on the HPA axis. CVS-treated females exhibited adrenal hypertrophy, yet their pattern of glucocorticoid secretion in the morning resembled that of controls. CVS-treated and control females had similar morning basal corticosterone (CORT) levels, which were both significantly elevated following a restraint stressor. Although morning basal gene expression of the key HPA-controlling neuropeptides corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OT) was unaltered within the paraventricular nucleus (PVN) by CVS, CVS altered the PVN OT and AVP mRNA responses to acute restraint. In control females, acute stress decreased AVP, but not OT mRNA; whereas, in CVS females, it decreased OT, but not, AVP mRNA. Unlike the morning pattern of HPA activity, in the evening, CVS-treated females showed increased basal CORT with hypoactive responses of CORT and PVN c-Fos immunoreactivity to restraint stress. Furthermore, CVS elevated evening PVN CRH and OT mRNAs in the PVN, but it did not influence anxiety- or depressive-like behavior after a light/dark box or tail suspension test. Taken together, these findings indicate that CVS is an effective model for HPA axis dysregulation in the female mouse and may be relevant for stress-related diseases.
| S-EPMC6693655 | biostudies-literature
Project description:OBJECTIVES:The association of obstructive sleep apnea (OSA) with hypothalamic pituitary adrenal (HPA) axis activation has not been fully understood from results of previous studies using hormonal assessments. We aimed to investigate the relationship between adrenal size, a potential marker reflecting HPA axis activity, and sleep parameters related to OSA. METHODS:We retrospectively reviewed data on 284 consecutive adult patients aged 20 to 80 y who had undergone polysomnography and abdominal computed tomography (CT). OSA was defined as none/mild (apnea-hypopnea index [AHI] <15, n = 75), moderate (AHI 15 to 30, n = 80), and severe OSA (AHI ?30, n = 129). Widths of adrenal body and limbs were measured by abdominal CT. RESULTS:Adrenal size was greater in participants with severe OSA than in those with none/mild or moderate OSA (adrenal body width: 6.03 mm, none/mild OSA; 6.09 mm, moderate OSA; 6.78 mm, severe OSA; p <0.001; adrenal limb width: 3.75 mm, none/mild OSA; 3.95 mm, moderate OSA; 4.26 mm, severe OSA, p <0.001). Multivariate regression analysis showed that not the 3% oxygen desaturation index and time of SpO2 <90% but a higher arousal index was the only determinant factor for increased adrenal limb width (? = 0.27, p <0.001) after adjusting for other variables that could affect adrenal size. Neither the arousal index nor hypoxic parameters were associated with adrenal body width. CONCLUSIONS:Results indicated that adrenal glands may enlarge in response to longstanding sleep fragmentation, suggesting the involvement of OSA in HPA axis augmentation.
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Project description:Pituitary corticotroph somatostatin receptor subtype 5 (SSTR5) signals to inhibit adrenocorticotrophin (ACTH) secretion. As ACTH deficiency results in attenuated adrenal cortisol production and an impaired stress response, we sought to clarify the role of SSTR5 in modifying the hypothalamic/pituitary/adrenal (HPA) axis. We generated Tg HP5 mice overexpressing SSTR5 in pituitary corticotrophs that produce the ACTH precursor proopiomelanocortin (POMC). Basal ACTH and corticosterone were similar in HP5 and WT mice, while HP5 mice showed attenuated ACTH and corticosterone responses to corticotrophin releasing hormone (CRH). HP5 mice exhibited attenuated corticosterone responses upon a restraint stress test and inflammatory stress following LPS injection, as well as increased anxiety-like and depressive-like behavior on open field and forced swim tests. Pituitary corticotroph CRH receptor subtype 1 (CRHR1) mRNA expression and ACTH responses to CRH were also attenuated in HP5 mice. In AtT20 cells stably overexpressing SSTR5, CRHR1 expression and cAMP response to CRH were reduced, whereas both were increased after SSTR5 KO. In elucidating mechanisms for these observations, we show that SSTR5-induced miR-449c suppresses both CRHR1 expression and function. We conclude that corticotroph SSTR5 attenuates HPA axis responses via CRHR1 downregulation, suggesting a role for SSTR5 in the pathogenesis of secondary adrenal insufficiency.
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Project description:In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latter, rather than the pain, might explain the HPA results. A population study ascertained pain and psychological status in subjects aged 25 to 65 years. Random samples were selected from the following three groups: satisfying criteria for chronic widespread pain; free of chronic widespread pain but with strong evidence of somatisation ('at risk'); and a reference group. HPA axis function was assessed from measuring early morning and evening salivary cortisol levels, and serum cortisol after physical (pain pressure threshold exam) and chemical (overnight 0.25 mg dexamethasone suppression test) stressors. The relationship between HPA function with pain and the various psychosocial scales assessed was modelled using appropriate regression analyses, adjusted for age and gender. In all 131 persons with chronic widespread pain (participation rate 74%), 267 'at risk' (58%) and 56 controls (70%) were studied. Those in the chronic widespread pain and 'at risk' groups were, respectively, 3.1 (95% CI (1.3, 7.3)) and 1.8 (0.8, 4.0) times more likely to have a saliva cortisol score in the lowest third. None of the psychosocial factors measured were, however, associated with saliva cortisol scores. Further, those in the chronic widespread pain (1.9 (0.8, 4.7)) and 'at risk' (1.6 (0.7, 3.6)) groups were also more likely to have the highest serum cortisol scores. High post-stress serum cortisol was related to high levels of psychological distress (p = 0.05, 95% CI (0.02, 0.08)). After adjusting for levels of psychological distress, the association between chronic widespread pain and post-stress cortisol scores remained, albeit slightly attenuated. This is the first population study to demonstrate that those with established, and those psychologically at risk of, chronic widespread pain demonstrate abnormalities of HPA axis function, which are more marked in the former group. Although some aspects of the altered function are related to the psychosocial factors measured, we conclude that the occurrence of HPA abnormality in persons with chronic widespread pain is not fully explained by the accompanying psychological stress.
| S-EPMC1257426 | biostudies-literature
Project description:Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college-attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat-related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self-reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear.
| S-EPMC5685810 | biostudies-literature
Project description:BackgroundEach year, almost 35% of children are exposed to maternal depression and more grow up in persistent poverty, increasing the risk for stress-related disease and other socio-developmental deficits later in life. These impacts are likely related to chronic stress via the hypothalamic-pituitary-adrenal (HPA) axis. However, there is little evidence relating early windows of child HPA axis activity to multiple exposures.MethodsWe investigated chronic measures of hair-derived HPA axis hormones (cortisol and dehydroepiandrosterone (DHEA)) in 104 one-year old infants from rural Pakistan and longitudinal measures of maternal depression, intimate partner violence (IPV), socio-economic status (SES), and the home environment.ResultsEstimates from adjusted linear mixed effects models did not reveal consistent significant associations between infant cortisol and maternal depression or home adversities. By contrast, infants exposed to maternal depression during pregnancy had lower DHEA levels (ß= -0.18 95% confidence interval [CI]: -0.34, -0.02) as did those whose mothers experienced multiple types of IPV (ß=-4.14 95% CI: -7.42, -0.79) within one year postpartum. Higher SES had a significant positive association with infant DHEA levels (ß= 0.77 95% CI: 0.08, 1.47). Depression severity and chronicity at one year postpartum had near significant associations with infant DHEA. Measures of home environment had no observable impacts on infant HPA axis activity.LimitationsLimitations include the modest sample size and aggregation of hair samples for analysis.ConclusionResults point to possible early HPA axis dysregulation driven by changes in DHEA activity, but not cortisol at one year of age. Findings contribute to growing research examining intergenerational transmissions of maternal depression, IPV, and household environment on infant stress-response systems.
| S-EPMC7792907 | biostudies-literature