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Glucocorticoid excess causes visceral obesity and its accompanying insulin resistance, dyslipidemia and hypertension. Glucocorticoids enhance preadipocyte (PA) differentiation and increase their aromatase activity (oestrogen production) and there is regional variability in these PA processes. Therefore, we studied human PAs for the presence of, and any regional or gender differences in, glucocorticoid receptors (GRs). Confluent subcultured human subcutaneous (Sc) and visceral (Vis) PAs from both genders contained GRs as assessed by GR gene expression and specific glucocorticoid (dexamethasone) binding. The dissociation constant was similar to that of other human cells and there was no difference between Sc and Vis sites or between males and females. There was significantly less GR mRNA in Vis PAs compared with Sc PAs in females (P=0.008) but not in males. There was less glucocorticoid binding in Vis compared with Sc PAs in females, measured by maximal binding capacity (P=0.035) or single saturating dose glucocorticoid binding (Bssd) (P=0.019). There was no regional difference in specific glucocorticoid binding in males. There was a gender difference with fewer GRs in Vis PAs in females compared with males measured by Bssd (P=0.006). In summary, GRs are present in human PAs. There is a lower GR density in Vis compared with Sc PAs in females, and females have fewer GRs in Vis PAs compared with males. These differences are likely to affect regional aromatase activity and to contribute to the smaller visceral fat mass in females compared with males.
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Muséum National d'Histoire Naturelle, Marine Station of Concarneau, DMPA USM 0401, UMR 7208 CNRS BOREA ‘Biologie des Organismes et Ecosystèmes Aquatiques’, 7 rue Cuvier, CP 32, 75231 Paris Cedex 05, France
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. Glucocorticoid-induced osteoporosis (GIO), in pathological conditions of endogenous hypercortisolism such as Cushing's syndrome ( Mancini et al . 2004 ) or after cortico-therapy, has been well demonstrated in human bone ( Mazziotti et al . 2006 , Canalis et
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Introduction
It is generally considered that adrenocorticotrophin (ACTH) is the only important factor controlling glucocorticoid secretion from the adrenal (suprarenal) cortex. However, there is actually a considerable body of evidence to suggest that adrenal nerves also have a role in modulating the hypothalamo-pituitary-adrenal (HPA) axis.
Morphological evidence
Most undergraduate textbooks state that the adrenal cortex, in contrast to the medulla, has no nerve supply (see references cited by Robinson, Perry, Hardy et al. 1977; Migally, 1979). Recent work, however, has demonstrated that the cortex shares with the medulla both efferent post-ganglionic adrenergic and sensory (afferent) nerve endings, some of which run in the splanchnic nerves while others travel to the gland with blood vessels (Holzwarth, Cunningham & Kleitman, 1987; Kesse, Parker & Coupland, 1988; Mohamed, Parker & Coupland, 1988). This confirms a series of anatomical observations stretching back many years (Alpert, 1931; Willard, 1938) describing an
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effects on offspring. In the non-pregnant animal, immune challenge with either LPS or interleukin-1β (IL-1β) elicits a prominent acute release of glucocorticoids (GCs), accompanied by an increase in circulating levels of the pro-inflammatory cytokines
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Pharmacological doses of glucocorticoids inhibit thyroid function in man and laboratory animals due to suppression of thyrotrophin (TSH) secretion (Wilber & Utiger, 1969). Administration of prednisolone or dexamethasone for 1–2 days results in a suppression of basal serum TSH levels in normal subjects and in patients with primary hypothyroidism, whilst the pituitary TSH reserve capacity, as assessed by the response to synthetic thyrotrophin releasing hormone (TRH), remains unaltered (Wilber & Utiger, 1969; Besser, Ratcliffe, Kilborn, Ormston & Hall, 1971; Haigler, Pittman & Hershman, 1971). However, impairment of serum TSH response to administered TRH does occur in patients treated with glucocorticoids for 1 or more months (Otsuki, Dakoda & Baba, 1973). These studies suggest that glucocorticoids may inhibit TSH secretion at both hypothalamic and pituitary levels but the main effect of the short-term treatment is suppression of TRH production.
Nicoloff, Fisher & Appleman (1970) found that the circadian rhythm of thyroidal
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We have studied the effects of glucocorticoids on the activity and viability of neonatal rat osteoclasts in vitro. In the bone slice assay, glucocorticoids caused a dose-dependent decrease in the amount of bone resorbed, which was accompanied by a parallel decrease in osteoclast number. Loss of osteoclasts was due to their death, which occurred by the process of apoptosis. Evidence for the latter was obtained by a range of techniques, including time-lapse video microscopy, acridine orange staining, DNA fragment detection and transmission electron microscopy. Immunocytochemistry revealed the presence of glucocorticoid receptors in osteoclasts, and glucocorticoid-induced cell death could be prevented by the glucocorticoid receptor antagonist, RU486. These observations suggest that glucocorticoids promote receptor-mediated apoptosis of rat osteoclasts in vitro. This finding may help to explain recent data indicating that, in sharp contrast with their effects on the human skeleton, glucocorticoids inhibit bone resorption and increase bone mass in rats in vivo.
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ABSTRACT
Blood samples were obtained from two male and two female platypuses at various times after capture and anaesthesia for other experimental purposes. In samples obtained during ketamine–xylazine or pregnanediol anaesthesia 15–24 h after capture, the concentration of total glucocorticoids, measured as 'cortisol equivalent' in a radioligand assay, was 207– 620 nmol/l. In samples taken 14–35 h after injection of dexamethasone (0·2 mg/kg) total glucocorticoid concentration was 79–88 nmol/l.
Individual glucocorticoids were isolated on columns of Sephadex LH-20 and measured separately against appropriate standards. In all except two haemolysed samples obtained from a male that died 25 h after capture, the major glucocorticoid behaved as cortisol, contributing 77–94% of the total. The remainder was made up of varying proportions of substances behaving as corticosterone, 11-deoxycortisol and cortisone. In the haemolysed samples from the moribund animal the major reactive substance, contributing 52–54% of the total, behaved as cortisone. The total adrenal gland weight of this animal was 747 mg, compared with 200–286 mg in two others, suggesting preceding exposure to stress.
Equilibrium dialysis and polyacrylamide gel electrophoresis (PAGE) revealed no evidence for a transcortin-like glucocorticoid- and progesterone-binding protein in platypus plasma. However, as in the echidna, there was a heat-labile, high-capacity binding system migrating with albumin on PAGE.
Glucose was undetectable in the plasma of the moribund animal and only 1·7–2·8 mmol/l in the initial plasma samples from the others. In two animals, injection of glucose i.p and dexamethasone i.m. was followed by an increase in the plasma concentration of glucose to the range 3·8–9·9 mmol/l and commencement of normal swimming and feeding activity for the next 36–48 h.
J. Endocr. (1988) 118, 407–415
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Abstract
The effect of glucocorticoids on the expression of intestinal cholecystokinin (CCK) was investigated both in vivo and in cell culture systems. In vivo, 2-day administration of methylprednisolone to adult male rats induced a decrease in CCK-like immunoreactivity (CCK-LI) and CCK mRNA levels in mucosal extracts. In two CCK-producing cell lines, RIN 1056E and STC-1 of pancreatic and intestinal origin respectively, dexamethasone induced dose-dependent decreases in both CCK-LI and steady-state CCK mRNA levels. The decrease in CCK mRNA was totally prevented by incubation of cells with an excess of RU 38486, a competitive inhibitor for the binding of glucocorticoids to their receptor. Actinomycin D, used to prevent RNA synthesis, did not modify CCK mRNA stability in dexamethasone-pretreated cells as compared with cells not exposed to dexamethasone. When cells were first incubated with actinomycin D, subsequent addition of dexamethasone left the steady-state CCK mRNA levels unaltered in both cell lines. Nuclear run-on assays performed in RIN 1056E cells showed that glucocorticoids decreased the rate of transcription of the CCK gene. In addition, cycloheximide, used to prevent protein synthesis, abolished the inhibitory effects of dexamethasone on steady-state CCK mRNA levels. These results demonstrate that glucocorticoids down-regulate CCK gene expression in the rat intestinal mucosa and in two CCK-producing cell lines. The effect is blocked by a glucocorticoid receptor antagonist. Inhibition of CCK gene expression may result from a decrease in the transcription rate, and probably involves one or several steps that depend on protein synthesis.
Journal of Endocrinology (1996) 151, 137–145
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Cytokines and steroid hormones use different sets of signal transduction pathways, which seem to be unrelated. Interleukin-6 (IL-6) uses JAK tyrosine kinase and STAT (signal transducer and activator of transcription) transcription factor. Glucocorticoid binds glucocorticoid receptor (GR), which is a member of the steroid receptor superfamily. We have studied the crosstalk between the IL-6-JAK-STAT and glucocorticoid-nuclear receptor pathways. IL-6 and glucocorticoid synergistically activated the IL-6 response element on the rat alpha2-macroglobulin promoter (APRE)-driven luciferase gene. The exogenous expression of GR enhanced the synergism. The exogenous expression of dominant negative STAT3 completely abolished the IL-6 plus glucocorticoid-induced activation of the APRE-luciferase gene. Tyrosine phosphorylation of STAT3 stimulated by IL-6 alone was not different from that by IL-6 plus glucocorticoid. The protein level of STAT3 was also not increased by glucocorticoid stimulation. The time course of STAT3 tyrosine phosphorylation by IL-6 plus glucocorticoid was not different from that by IL-6 alone. The synergism was studied on the two other IL-6 response elements, the junB promoter (JRE-IL-6) and the interferon regulatory factor-1 (IRF-1) promoter (IRF-GAS) which could be activated by STAT3. The synergistic activation by glucocorticoid on the IL-6-activated JRE-IL-6 and the IRF-GAS-driven luciferase gene was not detected. Glucocorticoid did not change the mobility of IL-6-induced APRE-binding proteins in a gel shift assay. These results suggest that the synergism was through the GR and STAT3, and the coactivation pathway which was specific for APRE was the target of glucocorticoid.
Department of Microbiology, University of Virginia Health Sciences, PO Box 800734, Charlottesville, Virginia 22908, USA
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Department of Microbiology, University of Virginia Health Sciences, PO Box 800734, Charlottesville, Virginia 22908, USA
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Department of Microbiology, University of Virginia Health Sciences, PO Box 800734, Charlottesville, Virginia 22908, USA
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Introduction Glucocorticoids trigger mucosal maturation during weaning and can accelerate the process if given exogenously in the week immediately prior to weaning ( Henning & Sims 1979 , Oesterreicher et al. 1998 , Solomon et
