Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene

In animal models, prenatal and postnatal stress is associated with elevated hypothalamic–pituitary axis (HPA) reactivity mediated via altered glucocorticoid receptor (GR) gene expression. Postnatal tactile stimulation is associated with reduced HPA reactivity mediated via increased GR gene expression. In this first study in humans to examine the joint effects of prenatal and postnatal environmental exposures, we report that GR gene (NR3C1) 1-F promoter methylation in infants is elevated in the presence of increased maternal postnatal depression following low prenatal depression, and that this effect is reversed by self-reported stroking of the infants by their mothers over the first weeks of life.

Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in offspring

Neonatal mortality is greater in commercial porcine genotypes, compared with the ancient Meishan breed that rapidly lay down adipose tissue; this may be related to hormones, such as triiodothyronine (T3) or leptin. Leptin is present in maternal milk; however, the extent to which this supply provides the neonate with leptin is unknown, but may play a role in growth and development. We investigated whether thyroid hormones and leptin concentrations in maternal milk differed between genotypes; and whether this influenced piglet concentrations or expression of genes involved in adipose tissue regulation. Eight Meishan and six commercial sows were entered into the study and milk samples from the day of parturition to day 4 postpartum was taken daily. The median birth weight piglet in each litter had a daily venous blood sample taken and was euthanised on day 4. Gene expressions of IGF-I, IGF-binding protein 3 (IGFBP-3), peroxisome proliferators activated receptor (PPAR) and glucocorticoid receptor (GR) were measured in adipose tissue using real-time PCR. T3 was increased in Meishan milk, but not in piglet plasma. Milk thyroxine was similar between breeds but commercial piglet levels were significantly higher. Leptin was higher in commercial sow milk throughout the study. Milk leptin was strongly correlated to plasma leptin during the first postnatal days and also to organ and body weight in Meishan piglets that also had significantly higher expression of GR, but not IGF-I, IGFBP-3 or PPAR. In conclusion, we have found a significant disparity in the provision of thyroid hormones in Meishan and commercial sow’s milk. These changes are not always translated to plasma concentrations of hormone in the piglet. Leptin appears to have a stronger role in growth and development in the Meishan genotype compared with commercial; along with the increased GR expression, this may also represent a potential mechanism behind the rapid accumulation of adipose tissue in Meishan piglets.

Non-genomic signalling of the retinoic X receptor through inhibition of Gq signalling in human platelets

Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) gamma, PPARbeta, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXRalpha and RXRbeta. RXR ligands inhibit platelet aggregation and TXA(2) release to ADP and the TXA(2) receptors, but only weakly to collagen. ADP and TXA(2) both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families.

Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets

Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) gamma, PPAR beta, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXR alpha, and RXR beta. RXR ligands inhibit platelet aggregation and TXA(2) release to ADP and the TXA(2) receptors, but only weakly to collagen. ADP and TXA(2) both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families. (C) 2007 by The American Society of Hematology.

21-Deoxycortisone (17 alpha-hydroxy4-pregnene-3,11,20-trione)

The title compound, C21H28O4, a synthetic glucocorticoid, crystallizes with a single molecule in the asymmetric unit. Ring A is almost in a half-chair conformation, rings B and C are almost in chair conformations, and ring D is between a twist and a 13 beta-envelope conformation. The A/B ring junction is quasi-trans, whereas the B/C and C/D ring junctions both approach trans characteristics. The molecule as a whole is slightly convex towards the beta side, with an angle of 9.60 (2)degrees between the C10-C19 and C13-C18 vectors. Molecular-packing and hydrogen-bonding (both intra- and inter-molecular) interactions play a major role in the structural association of the compound.

ACTH reduces the rise in ApoB-48 levels after fat intake

It has been repeatedly demonstrated that ACTH administration lowers plasma lipid concentrations in man. The present study was designed to test the hypothesis, based on observations of decreased apolipoprotein B (ApoB) synthesis and secretion in vitro, that ACTH administration inhibits the postprandial output of ApoB in man. Therefore, we studied the response to a fat-rich meal supplemented with Vitamin A in eight healthy volunteers, who underwent this test without premedication, after 4 days administration of ACTH, and after 4 days administration of a glucocorticoid (betamethasone). As expected, fasting plasma levels of low-density lipoproteins (LDL)-cholesterot (-25%) and ApoB (-17%) decreased after ACTH, but not after betamethasone administration. Also, the elevation of plasma ApoB-48 in response to fat intake (to twice the basal levels) was markedly reduced after ACTH administration. However, the postprandial rise in plasma triglycerides and retinyl palmitate was unimpaired, suggesting that ACTH administration induced the secretion of fewer but larger chylomicrons. The effect of betamethasone on the postprandial response was similar but less pronounced. This study confirms earlier reports on the lipid-lowering effects of ACTH and supports our theory, based on in vitro studies, that the lipid-lowering effects of ACTH administration in man involves an inhibition of ApoB production. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

The ACTH response to dexamethasone in PTSD

Objective: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSID). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSID. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSID relative to healthy comparison subjects. Method: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSID and 19 subjects (14 men and five women) without psychiatric disorder. Results: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. Conclusions: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.

Exposure to postnatal depression predicts elevated cortisol in adolescent offspring

Background. Animal research shows that early adverse experience results in altered glucocorticoid levels in adulthood, either raised basal levels or accentuated responses to stress. If a similar phenomenon operates in humans, this suggests a biological mechanism whereby early adversity might transmit risk for major depression, glucocorticoid elevations being associated with the development of this disorder. Methods. We measured salivary cortisol at 8:00 Am and 8:00 Pm over 10 days in 13-year-old adolescents who had (n = 48) or bad not (n = 39) been exposed to postnatal maternal depression. Results: Maternal postnatal depression was associated with higher, more variable morning cortisol in offspring, a pattern previously found to predict major depression. Conclusions. Early adverse experiences might alter later steroid levels in humans. Because maternal depression confers added risk for depression to children, these alterations might provide a link between early events and later psychopathology.

Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation

Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production.

Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes

Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking.

Membrane-initiated non-genomic signaling by estrogens in the hypothalamus: cross-talk with glucocorticoids with implications for behavior

The estrogen receptor and glucocorticoid receptor are members of the nuclear receptor superfamily that can signal using both non-genomic and genomic transcriptional modes. Though genomic modes of signaling have been well characterized and several behaviors attributed to this signaling mechanism, the physiological significance of non-genomic modes of signaling has not been well understood. This has partly been due to the controversy regarding the identity of the membrane ER (mER) or membrane GR (mGR) that may mediate rapid, non-genomic signaling and the downstream signaling cascades that may result as a consequence of steroid ligands binding the mER or the mGR. Both estrogens and glucocorticoids exert a number of actions on the hypothalamus, including feedback. This review focuses on the various candidates for the mER or mGR in the hypothalamus and the contribution of non-genomic signaling to classical hypothalamically driven behaviors and changes in neuronal morphology. It also attempts to categorize some of the possible functions of non-genomic signaling at both the cellular level and at the organismal level that are relevant for behavior, including some behaviors that are regulated by both estrogens and glucocorticoids in a potentially synergistic manner. Lastly, it attempts to show that steroid signaling via non-genomic modes may provide the organism with rapid behavioral responses to stimuli.