Abstract
Stress‐responsive adrenocortical function is the final physiological response to the cascade of events that occurs when the interaction between individuals and their environment takes place. Glucocorticoids are produced in response to perturbance of homeostasis and are necessary for the energy required to restore this homeostasis. Genetics contributes to the individual variation in basal and stimulated plasma glucocorticoid levels and also to adrenal gland mass that increases in response to prolonged adrenal stimulation. This review briefly describes regulation of the adrenocortical axis, summarizes the linkage studies carried out so far in humans and in model organisms, and discusses the potential candidate genes that might contribute to the variation. The significance of individual variations in the glucocorticoid stress‐responsiveness, with particular attention to their potential role in the recent explosion of obesity and the prevalence of metabolic syndrome X, is commented upon.
| Abbreviations | ||
| ACTH | = | adrenocorticotropin |
| AVP | = | arginine vasopressin |
| Chr | = | chromosome |
| CI | = | confidence interval |
| cM | = | centimorgan, a unit of recombinant frequency |
| CORT | = | corticosterone |
| CRH | = | corticotropin‐releasing hormone |
| CRHR1 | = | corticotropin‐releasing hormone receptor 1 |
| F2 | = | the offspring of a cross between two individuals from the first generation |
| GR | = | glucocorticoid receptor |
| HPA | = | hypothalamic‐pituitary‐adrenocortical |
| Mb | = | megabase = 1 million nucleotides |
| MSH | = | melanocyte‐stimulating hormone |
| POMC | = | proopiomelanocortin |
| QTL | = | quantitative trait loci |
| SNP | = | single nucleotide polymorphism |
Introduction
Individual differences in adrenocortical function have relevance to a series of pathologies and illnesses that are exaggerated or precipitated by stressful events, such as obesity Citation1, depressive episodes Citation2, Citation3, constitutive sensitivity to inflammatory and autoimmune reactions, Citation4, other disease states Citation5, or sensitization to drug addiction Citation6. Many of these illnesses show an increased prevalence in recent years Citation7, Citation8. This increase might be the consequence of increased environmental pressure, which is usually the prelude to evolutionary selection, thus raising the significance of individual differences in their physiological responses to stress. Early studies have noted the presence of these differences and that there is a heritable and an environmental component that contribute to the variance in adrenocortical functional measures both in humans and in mammals.
Since the pivotal work of Hans Selye Citation9, it has been recognized that stressors initiate a cascade of biochemical events in the brain and subsequently in the peripheral systems that allow the organism to respond to challenges and eventually reinstate homeostasis. Selye defined stress physiologically as the state in which both the sympathoadrenomedullary and adrenocortical systems are activated. His early experimental investigations showed that rats exposed to long‐lasting ‘physical and mental challenges’ have enlarged adrenals Citation10, and his subsequent work mainly focused on the importance of the hypothalamic‐pituitary‐adrenocortical (HPA) axis as represented by the release of glucocorticoids Citation11. The effects of acute and chronic exposures to stressors have been extensively investigated in animal models in order to characterize the factors contributing to stress vulnerability Citation12–19.
Key messages
Individual variations in the stress‐responsive adrenocortical function are due to polygenic inheritance and environmental influences.
Basal plasma glucocorticoid levels at the trough of the circadian rhythm are influenced by different positional candidate genes than those at the peak of the rhythm or in response to an acute stressor.
Adrenal weight variations are affected by intra‐adrenal genes, such as adrenal enzymes, and by effectors of the whole hypothalamic‐pituitary‐adrenocortical axis.
Most positional candidate genes that contribute to variation in the stress‐responsive adrenocortical function are associated with obesity or metabolic syndrome X.
Increase in chronic social stress may contribute to the high prevalence of obesity: a cumulative lifelong effect that is enhanced by increased human longevity.
The regulation of the hypothalamic‐pituitary‐adrenocortical axis
The neuroendocrine regulation of the HPA axis is initiated by stimulation of hypophysiotrophic neurons in the medial parvocellular division of the hypothalamic paraventricular nucleus. These neurons synthesize and secrete corticotropin‐releasing hormone (CRH), the primary secretagogue for adrenocorticotropin (ACTH), and arginine vasopressin (AVP), that modulates ACTH release Citation20. Axons from these neurons project to the median eminence where they release their contents into the hypophysial portal veins. CRH stimulates anterior pituitary corticotropes to synthesize proopiomelanocortin (POMC), a large molecule that is processed by convertases in the cell to ACTH that is stored in secretory vesicles. In response to CRH‐AVP stimulation, stored ACTH is released into the systemic circulation. Glucocorticoids are then synthesized and released into the circulation upon binding of ACTH to ACTH receptors in the adrenal cortex.
After exposure to stressful stimuli, glucocorticoids are rapidly released from the adrenal glands to provide the energy necessary for the stress response. Through negative feedback control, cortisol levels return to basal values when the stressful stimulus is controlled by the individual. If not, as in situations of chronic stress, sustained high cortisol levels have deleterious effects on the organism Citation13, Citation21. Individual differences in the functioning of the adrenocortical axis are being investigated by measures that tap into the multiple facets of this regulation: basal state, the acute, and the chronic stress response.
Basal glucocorticoid secretion
Basal, unstimulated measures of adrenocortical function, such as plasma glucocorticoid levels, have a diurnal rhythm (reviewed in Citation20) as well as an endogenous pulsatility Citation22. During the trough of the diurnal rhythm, glucocorticoid levels are low and induced by autonomous CRH‐independent ACTH secretion from the pituitary Citation23. In contrast, the increased secretion of ACTH and glucocorticoids observed in the morning in humans and in the evening in nocturnal rodents is the result of increased ACTH and CRH secretion at the circadian peak Citation24. Thus, regulation of the basal glucocorticoid secretion at the diurnal peak might share characteristics with that of the acute stress response.
The other major regulator of this rhythm is the availability of food. The food‐entrained HPA rhythm may actually be stimulated, since hunger is a stressor, and hunger is a prerequisite for the food‐entrained rhythm. These two major oscillators allow the organism to mobilize resources for events that require energy, the beginning of the activity cycle and the acquisition of food. This physiological regulation evolved when daily activity revolved around acquiring food that was not in abundance. Thus, the availability of unlimited food supply put another evolutionary pressure onto the organism: the physiological rhythms of glucocorticoids are no longer in sync with the energy required to obtain food.
The acute stress response
The normal sequence of the HPA stress response is activation of hypothalamic CRH neurons, secretion of CRH, activation of the pituitary corticotropes with subsequent ACTH secretion Citation20. Peripheral glucocorticoids rise in response to the ACTH stimulation within minutes of the stimulus. Hypophysectomy leads to adrenal atrophy, and ACTH administration restores glucocorticoid secretion, thereby demonstrating the significance of ACTH in the glucocorticoid response to stress. However, non‐ACTH‐mediated regulation of the adrenal cortex response to stress is also implicated Citation25.
Physiological responses to an acute stressor also show a diurnal rhythm. Adrenal sensitivity to ACTH appears to involve a neural component that is under the control of the suprachiasmatic nuclei of the hypothalamus Citation26. In rats, adrenal sensitivity to ACTH appears to increase about 2.5‐fold at the acrophase compared to the nadir of the rhythm Citation23, Citation27–29. Adrenal sensitivity to ACTH stimulation is also increased by γ ‐melanocyte‐stimulating hormone (see below), and the glucocorticoid response to a stressor would depend on the availability of steroidogenic enzymes of the adrenal cortex. The amplitude and duration of the adrenocortical response to acute stress is influenced by factors such as the controllability and predictability of the stress, the intensity of the stressor, and the timing of the measurements in relation to both the circadian rhythm and to the initiation of the stressor Citation30. Thus, in a study that investigates the genetic contribution to adrenocortical responsiveness to a stressor, these environmental variables would very much need to be rigorously controlled.
Adrenal gland hypertrophy/hyperplasia: the chronic stress response
In severe forms of stress, the human body can increase its ACTH‐mediated cortisol production 5–10‐fold Citation31. This kind of chronic stimulation of the adrenal gland leads to upregulation of the steroidogenic cytochrome P450 enzymes and different structural changes in the adrenal gland, which include cellular hypertrophy and hyperplasia.
Chronic stress is known to increase adrenal weight Citation32, leading to both adrenal hyperplasia and hypertrophy Citation33. Following chronic stress in rats, hyperplasia occurs in the outer zona fasciculate, while the inner zona fasciculate and medulla go through hypertrophy Citation33. A primary role for ACTH in this chronic stress‐induced increase in adrenal weight has been ascertained Citation34. However, the role of a peptide derived from the amino‐terminal fragment of POMC as a potent adrenal mitogen has also been established (reviewed in Citation35).
Human pathologies that are known to result in altered adrenal gland weights are numerous. Many of these pathologies are stress‐related, and the measurement of the adrenal hypertrophy occurs postmortem, such as in suicide victims Citation36, or by computed tomography and magnetic resonance imaging, which techniques do not lend themselves to genetic linkage studies. Of the pathologies that lead to adrenal gland hyper‐ or hypoplasia, only those whose identified genetic locus could contribute to stress‐related individual differences in adrenal weight are listed here (Table ). Some of these genes are also positional candidate genes that may underlie the variation in post‐stress plasma corticosterone levels and adrenal weight (Table ).
Table I. Syndromes affecting adrenal weight.
Table II. Positional candidate genes for adrenocortical phenotypes.
Individual differences
Individual variation and intraindividual stability of baseline cortisol levels and cortisol response to some stimuli have been described previously Citation37, Citation38. This individual variation is age‐ and sex‐dependent Citation39–41. Family and twin studies have also demonstrated that individual variations in adrenocortical functions are regulated, at least in part, by genetics Citation42, Citation43. Heritability of basal plasma cortisol levels is between 0.4–0.6 in several studies Citation44. The heritability of stimulated HPA function in humans do not result in consistent data (reviewed in Citation45). This may be due, at least in part, to the differences in challenge paradigms ranging from CRH and ACTH challenges to social stress tests, and the variations in the end point measurements. Significant heritabilities were found for cortisol response to stimulation with human CRH Citation38 and for cortisol response to endurance training Citation38, Citation46, and most of the studies supported the assumption that genetic factors do contribute to variability in stimulated cortisol responses.
Animal studies clearly illustrate that the stress‐responsive adrenocortical function significantly depends on the susceptible genotype. Strain differences in corticosterone responses to stress in rats and mice have been observed in many studies Citation47–50. To date, quantitative trait loci (QTL) have been detected for several physiological responses to various stressors Citation51. However, only a handful of studies, each in a different species, have investigated QTL for plasma corticosterone response to stress Citation52–54.
Identification of the underlying genetic components of basal and stress‐induced glucocorticoid levels is difficult because adrenocortical function is so dependent on the environment. For example, genes that contribute to variation in basal glucocorticoid secretion at the peak of glucocorticoid circadian rhythm might differ from those regulating basal glucocorticoid secretions at the trough, but might be shared with the acute glucocorticoid stress response genes. Mapping the genetic determinants of basal morning serum cortisol levels, at the peak of the circadian rhythm, two significant QTL have been identified in women, on chromosomes 11 and 14, at markers D11S1981 and D14S74, respectively Citation55. In the same Hutterite founder population, significant QTL were found for fasting serum cortisol levels at D1S3723 and at D11S1981 Citation56. Another genome scan found evidence that an insulin‐like growth factor II polymorphism, mapped 20 cM distal to D11S1981, was linked to morning serum cortisol Citation57.
QTL for basal glucocorticoid levels in rodents and in pigs have also been identified Citation56, Citation58, Citation59. In a male F2 population of Fisher 344 and Lewis intercross, QTL influencing corticosterone, the main glucocorticoid in rodents, levels close to the peak of diurnal rhythm were identified on chromosomes 4 and 10 Citation59. In the male and female F2 populations of the reciprocal intercross of Fisher 344 and Wistar Kyoto rats, genome scans identified a complex genetic architecture for corticosterone levels at the trough of the diurnal rhythm, including sex and maternal lineage effects as well as pairwise interactions Citation60. In the same study, three significant and two suggestive QTL for corticosterone levels after a 10‐min restraint stress, along with two pairs of interacting loci, were identified. Among these, the stress‐responsive corticosterone 1 (Srcrt‐1) at chromosome 2, Srcrt‐3 at chromosome 4, and the highly significant Srcrt‐4 at chromosome 6 seem to harbor obvious positional candidate genes (Table ). A significant genotype‐fecal corticosterone association is found at D1Mit105 in heterogeneous mice Citation58, a region that is orthologous to that containing the locus D1S3723 in humans Citation56. A significant linkage to the long arm of the porcine chromosome 7 has been identified for both basal and stress‐induced cortisol levels in pigs Citation53. This region is orthologous to the telomeric part of the long arm of human chromosome 14, a region implicated in the regulation of morning cortisol in women Citation55, and to Srcrt‐4 in rats Citation60.
Genetic variation in adrenal weight has been established in many species (summarized in Citation61). In addition, adrenal gland weight is significantly affected by environmental influences. The usual heritability or QTL studies do not distinguish between these, since they measure adrenal weight at the time of tissue harvest and therefore at the end of a series of phenotypic tests. If those tests are numerous and stressful, adrenal weights will reflect, in addition to the genetic influence on resting adrenal mass, adrenal hyperplasia/hypertrophy as the genetically influenced adrenocortical response to chronic stress. In a recent report, Valdar and colleagues Citation62 established the percent variance in adrenal weight that is due to genetic variation and to common environment as 27% and 36%, respectively.
Thus far, there have only been two QTL studies using adrenal weight as a phenotype. One found no significant QTL Citation63. In contrast, four highly significant and two suggestive loci were identified for adrenal weight, with no interacting loci in the rat cross of F344 and WKY Citation60. Despite the large sex difference in this phenotype, no sex‐ or lineage‐dependent QTL were identified. The most significant QTL were found on chromosomes 2, 4, and 7 at markers D2Rat220, D4Rat128, and D7Rat24, named the stress‐responsive adrenal (Sradr)‐2, Sradr‐3, and Sradr‐5 loci, respectively.
Positional candidate genes
Positional candidate genes are mapped into the confidence interval of a previously identified linkage and are usually known to have physiological significance for the specific phenotype. The following is a discussion of some positional candidate genes (listed in Table ) and their potential relevance to adrenocortical function. It is interesting to note that many of the major players involved in the response of the HPA axis to stress (CRH, CRHR1, AVP, POMC) are missing from this list, or have only been implicated in a single study. Are these major genes too important for the survival of the organism to be altered? A recent report by Garlow et al. Citation64, finding that QTL for transcript abundance of CRH, CRHR1, CRH‐binding protein, and AVP are not linked to their respective structural genes, seems to support this assumption. A further significance of these findings is the implication that the regulation of the stress‐responsive HPA axis is more complex than previously envisioned.
The morning cortisol QTL on chromosome 11 is located approximately 300 kb from the ABCC8 (ATP‐binding cassette, subfamily C, member 8) gene, which encodes sulphonylurea receptor 1. This is an interesting candidate since sulphonylureas are a class of drugs widely used as oral hypoglycemics to promote insulin secretion in the treatment of noninsulin‐dependent diabetes mellitus, and there is an increasing body of evidence describing the role of cortisol in the metabolic syndrome X Citation1, Citation20. Although ABCC8 did not show association with type 2 diabetes, a recent genome‐wide study confirmed KCJ11, (potassium channel, inwardly rectifying subfamily J, member 11), a gene mapped next to ABCC8, to be robustly associated with type 2 diabetes Citation65.
The female‐specific association of morning cortisol on chromosome 14 is located 300 kb from SNW1, which encodes a ski‐interacting protein that binds to the ligand binging domains of nuclear receptors, including glucocorticoid receptor (GR), to enhance glucocorticoid‐induced gene expression. It is of interest that this gene is mapped into the Srcrt‐4 locus of corticosterone stress response in a rat QTL study Citation60.
Regulator of G protein signaling 4 (RGS4) has been implicated as a candidate schizophrenia susceptibility gene. It negatively modulates signal transduction at G‐protein‐coupled receptors, and its expression is associated with cortical dopamine signaling Citation66. Although no obvious connection could be made between this gene and fasting cortisol levels in humans or fecal corticosterone levels in mice, the position of this gene within these QTL is intriguing.
Corticosteroid‐binding globulin (transcortin, CBG) is mapped to the close vicinity of the locus on human chromosome 14, within the confidence interval of the Srcrt‐4 locus in a WKY, F344 rat cross and the QTL associated with cortisol variability in pig (Table ). CBG functions as a steroid transport protein and binds about 90% of glucocorticoids in peripheral blood. It is a member of the serpin superfamily of serine protease inhibitors, and there is evidence that it has intrinsic biological activity in addition to being the binding protein for corticosterone (CORT) and cortisol Citation67.
An Arg307Gly mutation has been identified in pig Citation68 that increases CBG capacity and decreases its affinity for cortisol. A CBG point mutation, G>A resulting in a Met to Ile substitution at residue 276, was also identified in the WKY rat CBG sequence Citation60, which has been shown to be responsible for the reduction in its steroid binding affinity Citation69. Although WKY males have lower, and females have higher total (free and bound) CORT responses to stress compared to F344 Citation60, the CBG point mutation‐induced reduction in binding affinity could lead to increased levels of free glucocorticoids in WKYs compared to strains with normal CORT binding.
Decreased steroid binding of CBG leads to free glucocorticoid excess, which can exaggerate or precipitate many diseases. For example, genetic CBG deficiency appears to be associated with obesity Citation70 and hyperinsulinemia is associated with reduced CBG concentration Citation71. The G>A point mutation of CBG described above for the WKY rats, has also been found in a model of autoimmune diabetes mellitus Citation69. CBG secretion is inhibited by insulin Citation72, and CBG levels are inversely proportional to the degree of insulin resistance Citation73. Thus, CBG may be involved in the relationship between cortisol‐driven obesity in animals Citation74 and humans Citation75.
Neuropeptide Y (NPY) maps into both QTL for basal levels of CORT at the peak of the diurnal rhythm and the acute CORT stress response (Table ). NPY is widely distributed in the brain and peripheral nervous systems, and functional polymorphisms in NPY are implicated in stress‐responsiveness, alcohol dependence, and anxiety and depressive disorders Citation76–80. Furthermore, a significant effect of the preproNPY Leu7Pro genotype has been found in the association of NPY concentrations with cortisol concentrations Citation81, and the allele has also been associated with increased risk of type II diabetes Citation82. Corticotropin‐releasing hormone receptor‐2 gene (Crhr2) is mapped within the same chromosomal region, a gene with splice variants Citation83 that have been implicated in stress responsiveness and anxiety in murine gene knockout experiments Citation84. Interestingly, Crhr2 is expressed in the mouse adrenal cortex Citation85, and it is well known that CRH may influence adrenocortical steroidogenesis independently of pituitary function (for review see Citation86).
Glucocorticoid receptor (GR) is an obvious candidate gene, and several polymorphisms have been identified that are associated with different aspects of the adrenocortical activity. A polymorphism in the 5′untranslated region has been associated with enhanced basal cortisol activity Citation87. Another single nucleotide polymorphism (SNP) (N363S), a point mutation in exon 2 of GR Citation88, is associated with increased salivary cortisol response to psychosocial stress Citation45. Recent studies demonstrate that the N363S SNP regulates a novel set of genes and support a potential role for this glucocorticoid receptor polymorphism in human diseases Citation89. Additionally, epigenetic mechanisms have also been implicated that lead to permanently altered methylation status of GR Citation90.
Aldosterone synthase (CYP11B2) and 11β‐hydroxylase (CYP11B1) enzymes catalyze the 11‐beta‐hydroxylation of 11‐deoxycorticosterone (DOC). The latter enzyme is responsible for the conversion of 11‐deoxycortisol to cortisol and probably most of the conversion to corticosterone as well. Polymorphism in CYP11B2 affects only the DOC and 11‐deoxycortisol responses to ACTH stimulation Citation91. It has subsequently been shown that a linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms likely accounts for the heritability of 11‐deoxycortisol excretion Citation92. CYP11B2 activity has also been associated with obesity, hypertension, and the metabolic syndrome X Citation93.
Conclusion
Glucocorticoids are the end products of a complex adaptive system that prepares the organism to handle stress. Thereby, those who can sufficiently respond to acute or chronic stressors will have selective advantage over those who cannot provide the immediate energy for an appropriate response. Thus, one would expect that those who respond to stress with a higher glucocorticoid output would have an evolutionary benefit over those who respond with lower levels.
Selection pressure, until a few generations ago, was exerted for survival from infection and famine. Infection has been curtailed by hygiene and antibiotics, and famine by the ready availability of food in Western societies. Consequently, human life expectancy has increased substantially in recent years. With this life expectancy increase, and with the selection pressure that applies only until the end of reproductive period of human life, famine resilience may turn into an obesity risk factor in a large part of human life. Although the higher glucocorticoid response to stress provides immediate benefit for the organism, the increased social pressure and speed of life can perpetuate this response leading to continuously elevated levels of glucocorticoids during the prolonged lifetime. Since elevated glucocorticoids seem to play a role in the vulnerability to the metabolic syndrome X or obesity, humans are facing an apparent longevity paradox: the longer we are exposed to the ‘stress of life’ the more likely we will become obese, and the more obese we are the shorter is our life expectancy Citation94.
Thus, can reduction of stress‐induced glucocorticoid levels decrease obesity or the prevalence of the metabolic syndrome X, or is increased food consumption actually a replacement for elevated glucocorticoid levels to which the organism is accustomed? Whether these hypotheses can be turned into potential treatments of obesity or the metabolic syndrome X is unknown. However, the surprising overlap between candidate genes, those that contribute to individual variation in the stress‐responsive adrenocortical function and those that contribute to obesity or to other aspects of the metabolic syndrome X, suggests a promising future for this area of research.
Acknowledgements
This work was supported in part by grant NIH MH060789, and the Davee Foundation.
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