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Baraboi ED, Smith P, Ferguson AV, Richard D. Lesions of area postrema and subfomical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist. Am J Physiol Regul Integr Comp Physiol 298: R1098-R1110, 2010. First published January 27, 2010; doi:10.1152/ajpregu.003226.2009.--The mechanism and route whereby glucagon-like peptide 1 (GLP-I) receptor agonists, such as GLP-I and exendin-4 (Ex-4), access the central nervous system (CNS) to exert their metabolic effects have yet to be clarified. The primary objective of the present study was to investigate the potential role of two circumventficular organs (CVOs), the area postrema (AP) and the subfornical organ (SFO), in mediating the metabolic and CNS-stimulating effects of Ex-4. We demonstrated that electrolytic ablation of the AP, SFO, or AP + SFO does not acutely prevent the anorectic effects of Ex-4. AP + SFO lesion chronically decreased food intake and body weight and also modulated the effect of Ex-4 on the neuronal activation of brain structures involved in the hypothalamic-pituitary-adrenal axis and glucose metabolism. The results of the study also showed that CVO lesions blunted Ex-4-induced expression of c-fos mRNA (a widely used neuronal activity marker) in 1) limbic structures (bed nucleus of the stria terminalis and central amygdala), 2) hypothalamus (paraventricular hypothalamic nucleus, supraoptic nucleus, and arcuate nucleus), and 3) hindbrain (lateral and lateral-external parabrachial nucleus, medial nucleus of the solitary tract, and ventrolateral medulla). In conclusion, although the present results do not support a role for the CVOs in the anorectic effect induced by a single injection of Ex-4, they suggest that the CVOs play important roles in mediating the actions of Ex-4 in the activation of CNS structures involved in homeostatic control. food intake; energy expenditure; hypothalamic-pituitary-adrenal axis; glucose metabolism; c-fos doi: 10.1152/ajpregu.00326.2009.

On a low-[Na.sup.+] diet (L[Na.sup.+]), urinary [Na.sup.+] loss is prevented by aldosterone-induced [Na.sup.+] reabsorption through epithelial [Na.sup.+] channels (ENaC) in the connecting tubules (CNT) and cortical collecting ducts (CCD). However, the mechanism whereby [K.sup.+] loss is minimized and [Na.sup.+] reabsorption is maximized in the face of a reduced lumen-to-bath [Na.sup.+] gradient is not fully understood. The large-conductance calcium-activated potassium channel (BK)[beta]1 subunit (gene: Kcnmb1), which has a role in [K.sup.+] secretion in the CNT, is absent in the CCD in mice on a control diet. We hypothesized that BK[alpha]/[beta]1 helps to maximize [Na.sup.+] reabsorption during [Na.sup.+] deficiency. With L[Na.sup.+], the [Na.sup.+] clearance of Kcnmb1-mutant mice ([Kcnmb1.sup.-/-]) was 45% greater and the plasma [Na.sup.+] concentration and osmolality were significantly reduced compared with wild-type mouse (WT) controls. On L[Na.sup.+], [Kcnmb1.sup.-/-] exhibited exacerbated volume depletion (higher Hct and weight loss) compared with WT. L[Na.sup.+], which did not affect the mean arterial blood pressure (MAP) of WT, significantly reduced MAP of [Kcnmb1.sup.-/-]. The plasma aldosterone concentration of [Kcnmb1.sup.-/-] on L[Na.sup.+] was significantly elevated compared with [Kcnmb1.sup.-/-] on a control diet but was not different from WT on L[Na.sup.+]. Immunohistochemical staining revealed that BK[alpha] and BK[beta]1, which were absent in the principal cells (PCs) of the CCD, were localized on the basolateral membrane (BSM) of PCs of WT on L[Na.sup.+]. Moreover, BK[alpha] was absent from the BSM of PCs of [Na.sup.+]-deficient [Kcnmb1.sup.-/-]. We conclude that part of the mechanism to maximize [Na.sup.+] reabsorption during [Na.sup.+] deficiency is the placement of BK[alpha]/[beta]1 channels in the BSM of CCD PCs. BK channel; maxi K; mineralocorticoids; adrenal cortex; potassium secretion

The adrenalgland is of critical importance for a plethora of biological processes. We performed the first systematic analysis of adrenal gland growth using unbiased stereological methods in male and female mice from weaning to adulthood (weeks 3, 5, 7, 9, and 11) at the organ, compartment, and cellular levels. Adrenal weights increased from week 3 to week 7 in male and female mice, remained at this level in females, but decreased by 25% between week 7 and week 9 in males. Female adrenal glands displayed a higher weight at any stage investigated. The volume of the zona fasciculata was consistently higher in female vs. male mice. In both genders, the number of zona fasciculata cells reached a maximum at the age of 7 wk and decreased significantly until week 9. Serum corticosterone concentrations decreased from 3 to 11 wk of age both in male and female mice. However, the estimated total amounts of corticosterone in the circulation were similar in 3- and l l-wk-old mice. Furthermore, total circulating corticosterone was higher in females than in males at an age of 5 and 11 wk. In the zona glomerulosa and in the X-zone, time- and gender-dependent growth effects were observed. In conclusion, our results demonstrate that growth and function of the adrenal glands are markedly influenced by gender and age. These factors require careful consideration in studies aiming at the functional dissection of genetic and environmental factors affecting adrenal growth and function. adrenal gland; mouse; adrenal cortex; adrenal medulla; adrenal zones; dissector; stereology; corticosterone doi:10.1152/ajpendo.00705.2006.

Adrenal sexual dimorphism is thought to be important in explaining sex-related differences regarding prevalent diseases and the responses to stress and drugs. We report here that in CD1 mice there is marked sexual dimorphism affecting not only gland size and corticoid hormone secretion but also adrenal ornithine decarboxylase (ODC), polyamine, and catecholamine levels in which testosterone appears to be a major determinant. Our results show that adrenal weight, ODC activity, and corticosterone and aldosterone secretion were higher in female than in male mice and that orchidectomy brought these male parameters closer to the values found in females, mRNA levels of steroidogenic proteins SF-1, Dax-1, steroid 21-hydroxylase, and aldosterone synthase appeared to be slightly higher in female than in male adrenals. Immunocytochemical analysis of adrenal ODC revealed that immunoreactivity was higher in females than in males and was located mainly in the cortical cells, and especially in zona glomerulosa, whereas no sex differences in ODC mRNA levels were observed. These results suggest that sex-associated differences in the expression of ODC in the mouse adrenal gland appear to be related mainly to posttranscriptional mechanisms. Combination treatment of mice with [alpha]-difluoromethylornithine (a suicide inhibitor of ODC) and a polyamine-deficient diet produced a marked decrease in adrenal polyamine and catecholamine levels and a significant reduction in plasma corticosterone and aldosterone concentrations that were not associated with a decrease in the mRNA levels of steroidogenic proteins. All of these data suggest a relevant role for testosterone, ODC, and polyamines in the mouse adrenal function. mice; [alpha]-difluoromethylornithine; corticosterone; aldosterone; steroidogenesis

The adrenal gland is an essential stress-responsive organ that is part of both the hypothalamic-pituitary-adrenal axis and the sympatho-adrenomedullary system. Chronic stress exposure commonly increases adrenal weight, but it is not known to what extent this growth is due to cellular hyperplasia or hypertrophy and whether it is subregion specific. Moreover, it is not clear whether increased production of adrenal glucocorticoid after chronic stress is due to increased sensitivity to adrenocorticotropic hormone (ACTH) vs. increased maximal output. The present studies use a 14-day chronic variable stress (CVS) paradigm in adult male rats to assess the effects of chronic stress on adrenal growth and corticosterone steroidogenesis. Exogenous ACTH administration (0-895 ng/100 g body wt) to dexamethasone-blocked rats demonstrated that CVS increased maximal plasma and adrenal corticosterone responses to ACTH without affecting sensitivity. This enhanced function was associated with increased adrenal weight, DNA and RNA content, and RNA/DNA ratio after CVS, suggesting that both cellular hyperplasia and hypertrophy occurred. Unbiased stereological counting of cells labeled for Ki67 (cell division marker) or 4,6-diamidino-2-phenylindole (nuclear marker), combined with zone specific markers, showed that CVS induced hyperplasia in the outer zona fasciculata, hypertrophy in the inner zona fasciculata and medulla, and reduced cell size in the zona glomerulosa. Collectively, these results demonstrate that increased adrenal weight after CVS is due to hyperplasia and hypertrophy that occur in specific adrenal subregions and is associated with increased maximal corticosterone responses to ACTH. These chronic stress-induced changes in adrenal growth and function may have implications for patients with stress-related disorders. Ki67; corticosterone; adrenocorticotropic hormone; adrenal cortex; adrenal medulla

The synthesis of adrenal steroids requires molecular oxygen. Because arterial hypoxemia is a common clinical condition, the purpose of the present study was to examine steroidogenesis in vitro under physiological changes in [O.sub.2] tension (P[O.sub.2]) in cells from human adrenal glands with aldosterone-secreting adenomas (ASA; n = 3) or with bilateral adrenal hyperplasia causing Cushing's syndrome (n = 4). A decrease in P[O.sub.2] from 150 mmHg (mild hyperoxia) to 80 mmHg had minimal effect on steroid production. A reduction to 40 mmHg (still well within the physiological range) significantly inhibited cAMP- and ACTH-stimulated aldosterone, cortisol, and dehydroepiandrosterone (DHEA) production from ASA. Furthermore, cortisol and DHEA production in cells from histologically normal tissue, adjacent to ASA and from bilateral adrenal hyperplasias, was also inhibited under a P[O.sub.2] of 40 mmHg. We conclude that physiological decreases in P[O.sub.2] to levels typical for adrenal venous P[O.sub.2] under mild hypoxia inhibit steroidogenesis. These studies may have implications for oxygen therapy in critically ill patients with functional adrenal insufficiency, as well as for therapeutic options in patients with adrenal neoplasms. oxygen; cortisol; dehydroepiandrosterone; adrenal cortex

Although starvation-induced biochemical and metabolic changes are perceived by the hypothalamus, the adrenal gland plays a key role in the integration of metabolic activity and energy balance, implicating feeding as a major synchronizer of rhythms in the hypothalamic-pituitary-adrenal (HPA) axis. Given that orexins are involved in regulating food intake and activating the HPA axis, we hypothesized that food deprivation, an acute challenge to the systems that regulate energy balance, should elicit changes in orexin receptor signaling at the hypothalamic and adrenal levels. Food deprivation induced orexin type 1 (OX1R) and 2 (OX2R) receptors at mRNA and protein levels in the hypothalamus, in addition to a fivefold increase in prepro-orexin mRNA. Cleaved peptides OR-A and OR-B are also elevated at the protein level. Interestingly, adrenal OX1R and OX2R levels were significantly reduced in food-deprived animals, whereas there was no expression of prepro-orexin in the adrenal gland in either state. Food deprivation exerted a differential effect on OXR-G protein coupling. In the hypothalamus of food deprived rats compared with controls, a significant increase in coupling of orexin receptors to [G.sub.q], [G.sub.s], and [G.sub.o] was demonstrated, whereas coupling to [G.sub.i] was relatively less. However, in the adrenal cortex of the food-deprived animal, there was decreased coupling of orexin receptors to [G.sub.s], [G.sub.o], and [G.sub.q] and increased coupling to [G.sub.i]. Subsequent second-messenger studies (cAMP/I[P.sub.3]) have supported these findings. Our data indicate that food deprivation has differential effects on orexin receptor expression and their signaling characteristics at the hypothalamic and adrenocortical levels. These findings suggest orexins as potential metabolic regulators within the HPA axis both centrally and peripherally.

Byline: Ioanna Dimopoulou (1,3), Stylianos Tsagarakis (2), Evangelia Douka (1), Maria Zervou (1), Andreas T. Kouyialis (1), Urania Dafni (1), Nikolaos Thalassinos (2), Charis Roussos (1) Keywords: Head trauma; Stroke; Critical illness; Cortisol; Low-dose corticotropin stimulation test; Outcome prediction Abstract: Objective To investigate adrenal responses to the low-dose corticotropin (ACTH) stimulation test in acute traumatic or non-traumatic brain injury (BI) and to assess its value in predicting outcome. Design Prospective study. Setting Intensive care unit (ICU) in a university hospital. Patients and participants Seventy-five patients with acute BI, with a median age of 45 years were investigated. BI was due to trauma (n=51), ischemic stroke (n=17), subarachnoid hemorrhage (n=4) or intracerebral hemorrhage (n=3). Interventions Blood was taken on day 16 (median) after admission to the ICU to determine baseline cortisol and ACTH. Thereafter, a low-dose stimulation test (LDST) was performed: 1 Aug of tetracosactrin was injected and 30 min later a second blood specimen was obtained to measure stimulated cortisol. Patients having a stimulated cortisol below 500 nmol/l were defined as non-responders to the LDST. Measurements and results Median baseline and stimulated cortisol were 491 nmol/l and 690 nmol/l, respectively. The median increment in cortisol was 154 nmol/l (range 5--579 nmol/l). Mean ACTH was 46+-21 pg/ml. Ten (13%) patients were non-responders to the LDST these had a higher mortality rate compared to patients with adequate cortisol production (70 vs 32%, p=0.034). Logistic regression analysis revealed that APACHE II (p Conclusions Adrenal hypo-responsiveness in the setting of acute traumatic or non-traumatic BI is not an independent outcome predictor in the presence of high APACHE II, low GCS and older age. Author Affiliation: (1) Department of Critical Care Medicine, Evangelismos Hospital, Medical School, National and Kapodistrian University of Athens, 10675, Athens, Greece (2) Department of Endocrinology, Diabetes & Metabolism, Evangelismos Hospital , Medical School, National and Kapodistrian University of Athens, 10675, Athens, Greece (3) 2 Pesmazoglou Street, 14 561, Kifissia, Athens, Greece Article History: Registration Date: 25/03/2004 Received Date: 12/07/2003 Accepted Date: 23/03/2004 Online Date: 21/04/2004

Byline: I. V. Ermakova (1) Abstract: The glucocorticoid function of adrenals was studied in 23 first-year schoolboys that were subdivided into health groups I and II. The character and time organization of the infradian dynamics of the cortisol were studied during the period of acute adaptation to the beginning of schooling and throughout the school year. The schoolboys of health group II were different from those of group I by both the higher level of the week mesor and its dynamics during the entire school year. By the end of the first half of the year, the structure of cortisol infradian rhythms was changed in the first-year schoolboys of group II: the slow rhythms of cortisol secretion with the period of five to seven days became predominant, and the fact that the absolute values of their amplitudes were significantly increased suggested a tension in the functions of the adrenal cortex. Author Affiliation: (1) Institute of Developmental Physiology, Russian Academy of Education, Moscow, Russia Article History: Registration Date: 12/10/2004

Abstract: Utilization of the daily rhythm of ACTH secretion was assessed as a measure of the adequacy of replacement therapy in primary chronic adrenal failure (PCAF Addison's disease) with glucocorticoids (GC) by assaying plasma ACTH by radioimmunoassay every 4 h for one day in three groups of patients. Patients of group 1 had PCAF (n = 14) and received replacement therapy consisting of prednisolone (5 mg at 09:00 and 2.5 mg at 14:00) and group 2 patients received dexamethasone (0.5 mg at 23:00) in combination with prednisolone (2.5 mg at 14:00). All patients with PCAF also received 0.005--0.01 mg/day of 9[alpha]-fluorocortisol. The control group consisted of 14 healthy volunteers. Both types of replacement therapy resulted in high levels of variability in ACTH levels as compared with that in normal subjects. The areas under the curve (AUC) of the ACTH concentration over one day were not significantly different between groups 1 and 2 or between group 2 and controls. The AUC of ACTH in group 1 was significantly larger than that in controls. The mean ACTH concentration in group 1 at 07:00 and 11:00 was significantly greater than those in the other two groups. The daily rhythm of ACTH was generally closer to normal in patients given dexamethasone. Since our own clinical experience shows that at least two thirds of patients are initially given dexamethasone and that this had to be withdrawn because of the development of overdosage syndrome (weight gain, increased appetite, insomnia), it appears that there is a lack of concordance between the clinical data and the daily rhythm of ACTH secretion. When assessing the adequacy of replacement therapy in PCAF, it is important to note that the appearance of a normal rhythm of ACTH secretion over one day does not exclude the possibility of GC overdosage, with the effect that interpretation of the results of this type of measurement must take the clinical picture into account. Article History: Registration Date: 08/10/2004

A bidirectional activity is characteristics of the endoplasmic reticulum Ca2+ -ATPase of bovine adrenal cortex, which is based on the ADP and ATP concentrations and Ca2+ gradient across the microsomal membrane. The ratio of ADP/ATP affect the pumping process of the Ca2+ -ATPase. The release of Ca2+ from preloaded microsomes is enhanced due to the rise in ADP/ATP ratio when exogenous ADP is introduced.

Analysis of the association of steroid production with tissue renin in the adrenal cortex in transgenic rats under dietary sodium restriction conditions reveals that sodium restriction induces an increase in adrenal renin levels and aldosterone biosynthesis in the adrenal cortex. Sodium restriction also enhances adrenal renin mRNA levels but not the renal renin and plasma renin functions. Sodium restriction causes an increase in circulating and renal renin levels in the Sprague-Dawley (SD) rats but does not enhance the mineralocorticoid generation in SD rats.

Studies on adrenal blood flow in anesthetized dogs reveal that alpha-1-receptor stimulation may be involved in the phenylephrine-induced adrenal cortial and medullary blood flow. The beta-adrenergic receptor-mediated increase in catecholamine secretion does not alter adrenal medullary vasculature which however dilates in response to phenylephrine addition. The alpha 2-adrenergic receptor stimulation does not alter secretion and vascular tone.

Renin-angiotensin system (RAS) and angiotensin II (ANG II) expressions were assessed in many tissues in the initial and continuing phases of hypertension in 2K-1C rats to examine the function of tissue RAS in the evolution and sustenance of hypertension. When 2K-1C hypertension development, which is modulated in a tissue-specific way, takes place, there is a distinguishing formation of expression of tissue RAS gene in rats. Circulating ANG II could influence brain ANG II, but the latter will not be affected by the brain renin angiotensin system. ANG II, through negative feedback through its own receptor, could control brain renin.

Analysis of forskolin-resistant mutants of a Y1 mouse adrenocortical tumor cell line showed that it is completely insensitive to corticotropin, fully responsive to NaF and contains decreased levels of GTP-binding protein G protein. The functional activities of the G protein beta-gamma subunits in both mutant and wild type Y1 cell membranes were investigated. The results showed that the mutant G proteins contain altered beta-gamma subunits which are functionally deficient in facilitating pertusis toxin-mediated ADP ribosylation of G(sub t-alpha), as well as rhodopsin-catalyzed guanine nucleotide exchange on G(sub t-alpha).

A direct relationship exists between sodium (Na) nutrition and morphology of the mammalian adrenal cortex, but little research on the relationship between soil Na levels and herbivore populat Consequently, we assessed the effect of Na on wild cottontail rabbits (Sylvilagus floridanus) inhabi poor soils in southcentral Indiana by characterizing their adrenal mass and histology prior to, and provision of supplemental Na. Data and tissues were collected at annual (1985-87) hunter check stati during the 1987 breeding season at the Atterbury Fish and Wildlife Area. Nutrient supplements, consi of either deionized water (controls) or 150 meq aqueous NaCl, were delivered via dripper bottles to replicates of each treatment throughout the spring and summer of 1986-87. Additionally, NaCl was del via impregnated pegs through winter 1986 and spring 1987. Hypotheses tests relative to the 1985 harv served to evaluate adrenal morphology with respect to treatments prior to experimental manipulation. the 1985 pretreatment period there was no evidence (P [less than or equal to]0.99, n = 828) of extan morphology by treatment type. Following introduction of supplements, adrenal mass (mg/g body mass) declined uniformly across age (adult, juvenile) and sex classes among rabbits with access to ancilla (1986: P [less than or equal to]0.05, n = 422; 1987: P [less than or equal to]0.10, n = 456). Relati (P [less than or equal to]0.05) in response to Na provision. Although mass and cortical area decline cortical area of the zona glomerulosa, in which the hormone aldosterone is produced, did not additio decline, but did differ by sex. The marked response of the adrenal gland to Na provision suggests th Na poor environments, Na nutrition may be a valid management concern.

Byline: F. G. Sitdikov (1), M. V. Shaikhelislamova (1), I. R. Valeev (1), L. Yu. Kuz'mina (1) Author Affiliation: (1) Kazan State Pedagogical University, Kazan, Tatarstan, 420021, Russia Article History: Registration Date: 06/10/2004

ACTH inhibits the capsaicin-evoked release of CGRP from rat adrenal afferent nerves. Am J Physiol Regulatory Integrative Comp Physiol 280: R137-R142, 2001.--The adrenal cortex is innervated by afferent fibers that have been implicated in affecting cortical steroidogenesis. Modulation of neurotransmitter release from afferents may represent a regulatory system for the control of adrenal cortical function. The present studies validate an in vitro superfusion technique for adrenal capsules employing the drug capsaicin, which activates a subset of afferent fibers and induces the release of calcitonin gene-related peptide (CGRP). Capsaicin-evoked CGRP release from adrenal afferents was blocked by capsazepine, a competitive antagonist for the capsaicin receptor, or by removal of extracellular calcium. Exogenous ACTH prevented capsaicin-evoked CGRP release, elevated basal aldosterone release, and prevented capsaicin-induced reduction in aldosterone release. Immunolabeling for the recently cloned capsaicin vanilloid receptor 1 demonstrated its presence in adrenal nerves. These results show that in vitro superfusion of adrenal capsules can be used to characterize factors that modulate neurotransmitter release from adrenal afferents. Furthermore, the results suggest that activation of adrenal afferents in vivo may attenuate aldosterone steroidogenesis and that high levels of ACTH may prevent this phenomenon. adrenal cortex; aldosterone; vanilloid receptor 1, zona glomerulosa

Raff, Hershel, Eric D. Bruder, Barbara M. Jankowski, and Theodore L. Goodfriend. Neonatal hypoxic hyperlipidemia in the rat: effects on aldosterone and corticosterone synthesis in vitro. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278: R663-R668, 2000.--Neonatal hypoxia increases aldosterone production and plasma lipids. Because fatty acids can inhibit aldosterone synthesis, we hypothesized that increases in plasma lipids restrain aldosteronogenesis in the hypoxic neonate. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Plasma was analyzed for lipid content, and steroidogenesis was studied in dispersed whale adrenal glands untreated and treated to wash away lipids. Hypoxia increased plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rat only. Washing away lipids increased aldosterone production in cells from 7-day-old rats exposed to hypoxia, but not in cells from normoxic 7-day-old rats or from normoxic or hypoxic 35-day-old rats. Addition of oleic or linolenic acid to washed cells inhibited both aldosterone and corticosterone production, although cells from hypoxic 7-day-old rats were less sensitive. We conclude that hypoxia induces hyperlipidemia in the suckling neonate and that elevated nonesterified fatty acids inhibit aldosteronogenesis. adrenal cortex; steroidogenesis; fatty acids; cholesterol; triglycerides

Solano, Joel M., and Lauren Jacobson. Glucocorticoids reverse leptin effects on food intake and body fat in mice without increasing NPY mRNA. Am. J. Physiol. 277 (Endocrinol. Metab. 40): E708-E716, 1999.--Glucocorticoid stimulation of appetite and leptin expression conflicts with leptin inhibition of food intake and suggests that glucocorticoids reduce sensitivity to leptin. To determine if glucocorticoids impair feeding and metabolic responses to leptin, we measured leptin-induced changes in food intake, body weight, hormones, carcass fat, and hypothalamic neuropeptide Y (NPY) mRNA in adrenalectomized mice with and without corticosterone replacement. Leptin infusion (0.5 [micro]g/h) significantly decreased food intake and body weight in adrenalectomized mice. Corticosterone replacement approximating normal 24-h mean levels restored food intake but did not permit weight gain equivalent to PBS-infused controls. Corticosterone levels comparable to stress-induced production completely reversed leptin-induced reductions in weight gain and body fat, despite significant attenuation by leptin of corticosterone-induced increases in plasma insulin levels. Glucocorticoid replacement increased food intake without reversing leptin inhibition of hypothalamic NPY mRNA levels. We conclude that glucocorticoid levels within the physiological range can interfere with leptin action and that glucocorticoid effects are at least partly independent of NPY. adrenal cortex; feeding behavior; obesity; body composition; metabolism

Although the sympathoadrenal axis has long been known to play a role in adaptation to the environment, the complexity of molecular mechanisms underlying these responses has been appreciated only recently. [...]