MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

in European Journal of Endocrinology
Authors:
Michael SwarbrickBone Research Program, ANZAC Research Institute, Concord, University of Sydney, Sydney, New South Wales, Australia
Concord Clinical School, The University of Sydney, Sydney, New South Wales, Australia

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Hong ZhouBone Research Program, ANZAC Research Institute, Concord, University of Sydney, Sydney, New South Wales, Australia
Concord Clinical School, The University of Sydney, Sydney, New South Wales, Australia

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Markus SeibelBone Research Program, ANZAC Research Institute, Concord, University of Sydney, Sydney, New South Wales, Australia
Concord Clinical School, The University of Sydney, Sydney, New South Wales, Australia

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Correspondence should be addressed to M Swarbrick Email michael.swarbrick@sydney.edu.au
DOI:
https://doi.org/10.1530/EJE-21-0553
Volume/Issue:
Volume 185: Issue 5
Page Range:
R113–R129
Article Type:
Review Article
Online Publication Date:
08 Oct 2021
Copyright:
© European Society of Endocrinology 2021
Free access

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

Abstract

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

Invited Author’s profile

Michael Swarbrick, PhD, is a Senior Hospital Scientist at the ANZAC Research Institute in Sydney, Australia. His first paper was published in EJE in 2001, and in the 20 years since, he has conducted research into obesity and its relationship with metabolic syndrome, using both humans and animal models. His postdoctoral work at the University of California, San Francisco, investigated monogenic causes of severe human obesity. This was followed by studies investigating the metabolic effects of adipocyte hormones, in response to nutritional and surgical interventions, with Prof. Peter Havel at the University of California, Davis. Since returning to Australia in 2008, Michael has investigated the beneficial effects of adipose tissue transplantation in mice, and he performed some of the first in vitro studies of human brown/beige adipocytes (with Dr Paul Lee). Michael is currently investigating the metabolic effects of glucocorticoids with Prof. Siebel and Zhou at the ANZAC Institute.

Introduction: glucocorticoids and metabolic disease

Glucocorticoids are steroid hormones required for normal development, immunomodulation, electrolyte balance and entrainment of the circadian rhythm. They are critical effectors of the physiological adaptation to stress, which affects each of these processes (1). Endogenous glucocorticoids (mainly cortisol in humans, corticosterone in mice) are secreted from the adrenal cortex. Excessive production of endogenous glucocorticoids, usually arising from a pituitary adenoma secreting adrenocorticotropic hormone (ACTH), is the defining feature of Cushing’s disease, a rare condition afflicting one to two patients/million/year. In contrast, exogenous glucocorticoids, such as dexamethasone and prednisone, are used therapeutically to suppress inflammation in autoimmune diseases. In Western countries, >1–2% of the population is currently being treated with glucocorticoids, with one-quarter of them taking it for five years or more (2).

Chronic exposure to glucocorticoids at high concentrations, regardless of their origin, produces characteristic changes in body composition (central obesity, sarcopenia, osteoporosis and skin atrophy) and metabolism (insulin resistance, dyslipidaemia, hypercoagulability and hypertension). Understanding how glucocorticoids produce these negative side effects is, therefore, critical for managing patients undergoing long-term glucocorticoid treatment.

The first purpose of this review is to outline the acute metabolic effects of glucocorticoids so that we can understand how chronic exposure contributes to metabolic and ageing-related diseases. During acute stress, glucocorticoids ensure survival by increasing energy availability for the brain, which relies on glucose for energy. This mobilization of energy stores diverts energy away from anabolic processes, such as bone formation or the maintenance of skeletal muscle mass. While this shift is advantageous in the short term, chronic glucocorticoid exposure predictably leads to the adverse effects listed above.

Glucocorticoid actions in target tissues depend not only on circulating concentrations but also on their intracellular availability. Thus, the local ‘pre-receptor’ availability of active glucocorticoids is regulated by 11β-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively (3). Excessive HSD11B1 activity, increasing local cortisol/corticosterone availability, is implicated in the aetiology of obesity and insulin resistance, as well as in ageing-related declines in cognition and lean mass. These conditions represent an enormous and growing burden to societies worldwide; therefore, identifying the critical sites of glucocorticoid action is important for the future treatment and prevention of these diseases.

The second aim of this review is to highlight several recent findings in mice that have expanded our understanding of glucocorticoid actions in tissues that contribute to energy homeostasis. Specifically, disrupting glucocorticoid signalling in either adipose tissues (white and brown) or in bone has revealed that glucocorticoid actions in these tissues markedly influence body weight, adiposity and carbohydrate/lipid metabolism. In parallel, there is accumulating evidence that many dysmetabolic effects of glucocorticoids are sexually dimorphic, at least in mice. Together, these studies have considerably expanded our understanding of glucocorticoid physiology and have brought closer the possibility of tissue-specific glucocorticoid modulators for the treatment and prevention of metabolic disease.

The glucocorticoid system and its dysregulation in metabolic disease

There are many excellent reviews on glucocorticoid physiology in the literature (1, 4). Briefly, circulating glucocorticoids (cortisol/corticosterone) exhibit a diurnal rhythm, with peak levels at the time of arousal (morning in humans, evening in rodents) and higher levels during times of stress. In the circulation, glucocorticoids have short half-lives (~1 to 2 h for cortisol, 15–30 min for corticosterone (5)), and their bioavailability is limited by binding to corticosteroid-binding globulin (CBG/transcortin) (6).

Circulating glucocorticoids are regulated by the HPA (hypothalamic–pituitary–adrenal) axis (Fig. 1, left panel). Parvocellular neurons in the hypothalamic paraventricular nucleus (PVN) receive and integrate sensory inputs (related to nutrients, stressors, hormones and the time of day) from other CNS regions. These neurons activate the HPA axis by secreting appropriate amounts of corticotrophin-releasing factor (CRF) and arginine–vasopressin (AVP) into blood vessels leading to the anterior pituitary, which subsequently secretes ACTH into the circulation. ACTH then stimulates cortisol/corticosterone secretion from the adrenal cortex. When a fall in blood glucose concentrations is sensed, for example, this activates the HPA axis, triggering ACTH production and glucocorticoid release, which in turn stimulates hepatic gluconeogenesis. Further, HPA axis activation is prevented by the negative feedback actions of glucocorticoids upon CRF and ACTH secretion.

Figure 1
Figure 1

Glucocorticoids acutely increase energy availability via coordinated actions in multiple metabolic tissues. Endogenous glucocorticoid concentrations are regulated by the hypothalamus–pituitary–adrenal (HPA) axis (left panel). In addition to following a pronounced diurnal rhythm, glucocorticoid secretion increases in response to diverse stimuli such as acute stress or declining blood glucose concentrations. At high circulating/tissue levels, glucocorticoids activate pathways in numerous tissues critical for systemic energy homeostasis, including the liver, skeletal muscle, white adipose tissue (WAT), brown adipose tissue (BAT) and pancreas. These actions are primarily directed at increasing systemic glucose availability. Reduced glucose utilization by osteoblasts in bone may indirectly contribute to increased systemic glucose availability. Mobilization of energy stores in this way ensures a steady supply of glucose to the brain during times of increased demand.

Citation: European Journal of Endocrinology 185, 5; 10.1530/EJE-21-0553

Glucocorticoids are ligands for two related nuclear receptors, the glucocorticoid receptor (GR, NR3C1) and the mineralocorticoid receptor (MR, NR3C2). GRs have a low affinity for cortisol and are widely distributed throughout the body, where they mediate glucocorticoid responses over a wide range of concentrations, such as during stress. In contrast, MRs bind both cortisol and mineralocorticoids (e.g. aldosterone) with high affinity, and their distribution is restricted to the renal tubule, sweat glands, colon and specific brain regions. MRs only respond to cortisol at low physiological concentrations, as they become saturated at higher concentrations. Following ligand binding, GRs and MRs undergo conformational changes and translocate to the nucleus, where they regulate the transcription of target genes (recently reviewed in (7)). It has been estimated that up to 20% of all genes respond to glucocorticoids (8).

Glucocorticoids also produce rapid non-genomic actions, which occur within minutes of agonist treatment and do not involve transcriptional regulation by GRs/MRs. In animal models, these actions include effects on memory formation (9), negative feedback on the HPA axis (10) and inhibition of tracheal smooth muscle contraction (11). Interestingly, the rapid non-genomic responses to cortisol (and its inactive form, cortisone), as well as several synthetic glucocorticoids, involve the activation of the adhesion G-protein-coupled receptor G3/GPR97 (12), which is highly specific for human immune cells and is involved in antimicrobial responses (13).

As described above, intracellular activation/inactivation of glucocorticoids by HSD11Bs is also critical for their effects. HSD11B2 expression is restricted to the renal tubule, colon, sweat glands, placenta and developing brain, where it converts active cortisol (corticosterone in mice) to inactive cortisone (11-dihydrocortisone). In these tissues, HSD11B2 prevents inadvertent activation of the MR by cortisol, allowing aldosterone to bind instead (14, 15). In contrast, HSD11B1, which activates glucocorticoids, is much more widely expressed than HSD11B2, being particularly abundant in the liver, lungs, gonads, brain and adipose tissues. In these tissues, MR expression is much lower than that of GR (~250-fold lower in human adipocytes, for example (16)), and HSD11B’s function is to amplify local glucocorticoid activity, independently of circulating cortisol concentrations.

Amplification of local glucocorticoid actions by HSD11B1 may contribute to central obesity and its associated metabolic complications. In human obesity, cortisol levels are not normally elevated (17), but increased adipose tissue HSD11B1 expression and/or activity has been reported in obese, insulin-resistant subjects compared to lean controls (18, 19), particularly in visceral adipose tissue (VAT) (20, 21). These differences have led many to hypothesize that high intracellular glucocorticoid availability in VAT contributes to central obesity and its metabolic sequelae in humans.

This concept is well supported by studies of HSD11B1-deficient mice, which are phenotypically indistinguishable from WT mice, although they do not develop stress-induced hyperglycaemia (22). When fed a high-fat diet (HFD), however, Hsd11b1−/− mice gain less weight than WT mice and are protected against visceral obesity and glucose intolerance (23). Although HSD11B1 expression and activity are highest in the liver, studies in mice with a liver-specific knockout of HSD11B1 have revealed that HSD11B1 activity in extrahepatic tissues (i.e. adipose) makes a greater contribution to the deleterious metabolic effects of HFD feeding (24) or exogenous glucocorticoid excess (25).

Dysregulation of local glucocorticoids may also contribute to ageing-related declines in bone mass and cognition. Consistent with the deleterious effects of exogenous glucocorticoids on the bone (26), increased skeletal HSD11B1 expression and activity have been observed in both mice (27, 28) and humans (29) during ageing. In mice, chronic HFD feeding increases skeletal Hsd11b1 mRNA expression, and the disruption of glucocorticoid signalling in osteoblasts and osteocytes (by transgenic overexpression of HSD11B2) protects against HFD-induced bone loss (30). Similarly, declining cognitive function with ageing in mice is also characterized by dysregulation of glucocorticoids in the hippocampus (31). Excessive glucocorticoid activity within tissues, independently of circulating glucocorticoids, has been proposed as a common underlying cause of metabolic and ageing-related diseases and has led to the development of HSD11B1 inhibitors for these conditions (32).

Glucocorticoids acutely increase nutrient availability

The acute effects of glucocorticoids on energy homeostasis are complex but can be broadly summarized as the mobilization of energy stores (Fig. 1), to ensure a continuous supply of glucose to the brain. This shift also diverts energy away from anabolic processes such as bone formation or the maintenance of muscle mass, which are not immediately necessary for survival. Insulin is normally secreted in response to feeding, increasing glucose utilization by stimulating glucose uptake and glycolysis in tissues, while concomitantly suppressing gluconeogenesis. Acute glucocorticoid effects involve both synergy with and antagonism of insulin’s actions, depending on the tissue or fed/fasted state, as well as interactions with catecholamines, which are secreted immediately in response to stress (1). While the metabolic effects of glucocorticoids have been well-studied in humans, here, we will use results from studies in rodents and cell lines to illustrate the underlying mechanisms.

In humans, acute glucocorticoid-induced increases in glucose availability are achieved by suppression of glucose-stimulated insulin secretion (GSIS) (33), insulin secretory tone (34) and by inhibition of hepatic insulin action (35). Studies in rat insulinoma cell lines suggest that glucocorticoids may further impair insulin secretion by inducing apoptosis in pancreatic β-cells (36, 37). In the liver, glucocorticoids suppress insulin action both directly (they stimulate transcription of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK (38)) and glucose-6-phosphatase (G6PC) (39) in rat hepatoma cells) and also indirectly via sympathetic projections from the hypothalamic arcuate nucleus (ARC) to the liver, as shown in rats (40). Rodent studies indicate that glucocorticoids also stimulate hepatic glycogen production (41).

Increased glucose availability in glucocorticoid-treated humans is also facilitated by reduced whole-body glucose clearance (42). In stressed human patients suffering from trauma or from severe burns, for example, the maximal glucose uptake rate in peripheral tissues was reduced by ~35% compared to controls (43). Mechanistic studies in rats have shown that glucocorticoids acutely inhibit glucose uptake into skeletal muscle by preventing insulin-stimulated translocation of SLC2A4 (GLUT4) to the plasma membrane (44) and also increase muscle breakdown (proteolysis) by inducing the ubiquitin ligases TRIM63 (MuRF1) and FBXO32 (MAFbx) (45).

In the fed state, glucocorticoids synergize with insulin to stimulate lipogenesis (5), as demonstrated in cultured human adipocytes (46). Glucocorticoids stimulate lipogenic genes, such as fatty acid synthase (FASN) and acetyl-CoA-carboxylase (ACACB) (46) and also increase hepatic expression of the fatty acid scavenger receptor CD36 (47). In the absence of insulin (fasting), however, glucocorticoids inhibit lipogenesis in cultured human adipocytes (46), and systemic lipid availability is increased via angiopoietin-like 4 (ANGPTL4) secretion from adipose tissue and liver (48). ANGPTL4 increases fatty acid availability in two ways: (i) by promoting lipolysis (hydrolysis of stored triglycerides into non-esterified free fatty acids (NEFA) and glycerol) in adipose tissue; and (ii) also by inhibiting lipoprotein lipase (LPL) (48), the enzyme primarily responsible for the hydrolysis of chylomicrons and VLDL-triglycerides (and fatty acid uptake) in adipose tissue and skeletal muscle. In this manner, glucocorticoids increase energy availability in the fasting state (Fig. 1).

In adipose tissue, glucocorticoids antagonize insulin’s anti-lipolytic actions, although these effects are less than seen in other tissues, such as skeletal muscle (49, 50). Dexamethasone increases lipolysis in 3T3-L1 adipocytes, by inhibiting the expression of Plin1 (perilipin 1, which protects lipid droplets from hydrolysis), and concomitantly by increasing the expression of Pnpla2 (known in humans as adipose triglyceride lipase, ATGL) (51). Together with the increased amounts of specific amino acids obtained from muscle breakdown, the increased glycerol and NEFA from lipolysis provide the necessary precursors and energy to drive hepatic gluconeogenesis. Interestingly, glucocorticoid-induced increases in gluconeogenesis, proteolysis and lipolysis can occur in the absence of insulin, as they are preserved in animal models of streptozotocin-induced (insulin-deficient) diabetes (52).

Glucocorticoids also increase systemic energy availability by inhibiting anabolic processes in bone. Exposing human osteoblasts (responsible for bone formation) to dexamethasone induces genes related to apoptosis and oxidative stress (53); and in humans, i.v. glucocorticoids treatment leads to a rapid (within 24 h) fall in the bone formation markers, osteocalcin (54) and P1NP (55). Acutely, sympathetic nervous system activity inhibits bone formation as osteoblasts and osteocytes express β2 adrenergic receptors (56) and mice lacking catecholamines have increased bone formation (57).

The acute energy-sparing effects of glucocorticoids do not apply to brown adipose tissue (BAT), however. BAT is a specialized thermogenic organ that is activated by the sympathetic nervous system, and it uses circulating glucose and NEFAs to generate heat in response to feeding or cold exposure (diet- and cold-induced thermogenesis, respectively). While BAT is abundant in rodents and young mammals, small quantities have been recently rediscovered in human adults, prompting its re-evaluation as a therapeutic target for obesity and type 2 diabetes (58). In humans, glucocorticoids acutely increase BAT activity (59) by stimulating cold-induced glucose uptake into BAT and by directly increasing cellular respiration in isolated human brown adipocytes (60). It is possible that acute glucocorticoid-mediated BAT activation is directed at counteracting the increased availability of glucose and NEFAs. In the long-term, however, chronic glucocorticoid treatment suppresses BAT activity (see below).

Chronic metabolic effects of glucocorticoids

While the mobilization of energy stores by glucocorticoids is undoubtedly beneficial during stress, maintaining this response over the long term produces undesirable effects on health. In cases of chronic glucocorticoid exposure (whether due to Cushing’s disease or exogenous glucocorticoid treatment), continually increased substrate availability and inhibition of anabolic processes promote hyperglycaemia, dyslipidaemia, fatty liver, hepatic and peripheral insulin resistance, muscle atrophy, immunodeficiency, growth retardation, osteoporosis, topical skin thinning, glaucoma, infertility, depression and anxiety (Fig. 2). These metabolic effects are serious, as untreated Cushing’s disease has a 5-year mortality rate of ~50% (61).

Figure 2
Figure 2

Chronic glucocorticoid excess promotes obesity, insulin resistance and dyslipidaemia via their effects on multiple metabolic tissues. Many of the dysmetabolic side effects of glucocorticoid exposure result directly from their acute effects to mobilize energy stores (see text). Chronically, however, the stimulatory effects of glucocorticoids on hepatic gluconeogenesis and lipogenesis lead to insulin resistance and steatosis, respectively. This is likely exacerbated by impaired hepatic insulin clearance. The increased secretion of TG-rich VLDL particles from the liver leads to dyslipidaemia and results in lipid accumulation in skeletal muscle and adipose tissues. Chronic glucocorticoid exposure also promotes insulin resistance in adipose tissue and skeletal muscle, further reducing glucose uptake by these tissues. Glucocorticoid-mediated suppression of anabolic processes in skeletal muscle and bone leads to muscle atrophy and osteoporosis, respectively. Visceral adipose tissue (VAT) is a particularly important site of action for glucocorticoids, due to the amplification of glucocorticoid actions by 11β-HSD1 in this depot and its close relationship with dyslipidaemia and hepatic insulin resistance (see text).

Citation: European Journal of Endocrinology 185, 5; 10.1530/EJE-21-0553

Chronic glucocorticoids and obesity

Weight gain, due to increased appetite (62) rather than suppression of resting energy expenditure (60, 63), is one of the most significant side effects of chronic glucocorticoid treatment. In humans treated with exogenous glucocorticoids, weight gain is common but highly variable: ~10% of subjects gain >10% of their body weight, although many (45%) experience no weight change at all (64). Interestingly, glucocorticoids may also affect macronutrient preference, as healthy women who increased their cortisol levels upon stress exposure also increased their intake of sweets and high-fat foods (65). The stimulatory effects of oral glucocorticoids on appetite and weight gain have led to reduced patient compliance, particularly among young women (66).

The influence of glucocorticoids on weight gain was first established in studies of mice with severe hyperphagic obesity (due to defective leptin signalling); these mice also exhibited adrenal hyperplasia and high corticosterone levels, and weight gain was prevented by adrenalectomy (67). Similarly, in mice with diet-induced obesity, treatment with either the GR antagonist CORT 108297 or mifepristone (a GR and progesterone receptor antagonist) prevented weight gain (68).

GRs are widely expressed in the CNS, particularly in the hippocampus and in hypothalamic nuclei involved in feeding, including the ARC, parvocellular neurons of the PVN and the ventromedial hypothalamus (69). In cultures of ARC-derived hypothalamic neurons, dexamethasone increased mRNA expression of genes encoding the orexigenic peptides neuropeptide Y (Npy) and agouti-related protein (Agrp) (70).

Glucocorticoid-induced hyperinsulinaemia may further exacerbate weight gain. Although glucocorticoids acutely suppress GSIS in humans (see above), insulin resistance resulting from chronic glucocorticoid exposure provokes compensatory increases in insulinaemia and GSIS (71) (Fig. 2). Fasting hyperinsulinaemia is a strong predictor of future weight gain in human adolescents (72). Although there are no data from humans at present, rodent studies suggest that this situation is further exacerbated by impaired insulin clearance: 5 days of dexamethasone treatment impaired the activity of the hepatic insulin-degrading enzyme (IDE) in rats and mice (73). Chronic hyperinsulinaemia can itself promote obesity, as mice lacking one of their two insulin genes and fed a HFD have lower insulin levels and are protected against weight gain, compared to WT mice (74).

Effects of glucocorticoids on adipocytes and adipose tissue

Glucocorticoid excess also has direct effects on adipocytes and adipose tissue, including increased adipocyte size (hypertrophy), increased adipocyte number (hyperplasia) and altered secretion of adipose-derived hormones (adipokines). Microarray studies of human adipose tissue indicate that glucocorticoids promote lipid turnover, which involves increases in both lipid synthesis and breakdown (75). The metabolic response to glucocorticoids in adipose tissues is heterogeneous, however, as chronic glucocorticoid exposure leads to preferential expansion of central depots (VAT), at the expense of s.c. adipose tissue (SAT).

Adipose tissue distribution is a critical determinant of susceptibility to metabolic syndrome, a phenotypic cluster in insulin-resistant humans consisting of central obesity, glucose intolerance, hypertension and dyslipidaemia (76). The metabolic syndrome markedly increases the risk of both cardiovascular disease and type 2 diabetes (77). Accumulation of VAT (strictly defined as fat residing inside the abdominal cavity and drained by the portal circulation, for example, omental, mesenteric, retroperitoneal) is metabolically unfavourable due to its relationship with insulin resistance and cardiovascular disease (78). VAT generally has a higher rate of lipid turnover than SAT, as it has higher levels of LPL activity (79) (giving it a greater capacity for binding and internalizing circulating triglycerides) and a higher sensitivity to lipolytic stimuli (in men, although the opposite relationship is observed in premenopausal women) (80).

Adipocyte hypertrophy in VAT contributes to insulin resistance in three main ways: (i) promoting hepatic NEFA flux and ectopic lipid deposition (81); (ii) increased macrophage infiltration and inflammation in VAT (82); and (iii) an altered pattern of adipokine secretion (83). In contrast, SAT, particularly in the gluteofemoral depot, has a lower lipolytic rate and protects against metabolic syndrome (84).

VAT is an important site of glucocorticoid action. First, VAT possesses more receptors for glucocorticoids than SAT (85). Microarray studies support heightened responsiveness of carbohydrate and lipid metabolic pathways to glucocorticoids (75), and greater glucocorticoid-induced insulin resistance (86) in human omental vs s.c. fat. The greater induction of insulin resistance by glucocorticoids in VAT, compared to SAT, is supported by results from human studies in vivo as well as primary adipocyte cultures from these depots (49). Secondly, enhanced glucocorticoid responsiveness in VAT also reflects the increased expression and/or activity of HSD11B1 in this depot (18-21). Preferential energy storage in VAT, where it is more easily mobilized, suggests that glucocorticoids may recruit this depot in anticipation of future stressors, described as a 'preparative' effect (1).

Adipose tissue HSD11B1 activity has been linked with metabolic syndrome in rodent studies. Transgenic mice overexpressing HSD11B1 in adipose tissue, under the control of the aP2 promoter, developed greater central obesity and insulin resistance on a HFD than equivalent WT mice (87). Conversely, overexpression of HSD11B2 (which inactivates glucocorticoids) in the same tissues conferred a degree of protection against HFD-induced obesity, glucose intolerance and insulin resistance in follow-up studies (88). One important caveat of these studies is that the aP2 promoter is not adipocyte-specific; being also expressed in the brain, endothelial cells, macrophages, adipocyte precursors, cardiomyocytes and embryonic tissues (89). Regardless, a study of rats fed with high-sucrose/high-fat diet and treated with an HSD11B1 inhibitor also suggested that certain VAT depots may be critical sites of HSD11B1 activity. HSD11B1 inhibitor treatment not only reduced liver fat and circulating triglycerides but also reduced adipocyte size and lipogenic gene expression, while increasing those involved in lipid oxidation, specifically in mesenteric fat (90). These effects were not observed in epididymal or retroperitoneal fat.

Historically, studies using preadipocyte cultures suggested that the adipogenic effects of glucocorticoids may promote obesity via adipocyte hyperplasia (91). Elegant studies, more than 25 years ago, identified a transcription factor ‘cascade’ regulating adipogenesis, involving the transcription factors CEBPA (C/EBPα), CEBPB (C/EBPβ) and CEBPD (C/EPBδ), and PPARG, irreversibly driving the development of fat cells by inducing each other’s expression (91, 92). CEBPB and CEBPD are expressed very early in adipocyte differentiation, while CEBPA is induced by both CEBPB and CEBPD, whereupon it controls the acquisition of the mature adipocyte phenotype (91). Glucocorticoids (and the activated GR) contribute to this adipogenic programme by rapidly inducing CEBPD expression (91, 93) and by associating with CEBPB to activate PPARG, the master regulator of adipogenesis (94). Glucocorticoids also induce the adipogenic transcription factor KLF15, which also activates PPARG (95).

In recent years, however, the requirement for glucocorticoids in adipogenesis has been challenged. In 3T3-L1 cells, adipogenesis is impaired by knockdown of GR, due to impaired PPARγ activation (94). Similarly, adipocyte precursors lacking GR have an impaired ability to undergo adipogenesis (96, 97), although they do catch up to WT cells later (96). Interestingly, implanting GR-deficient preadipocytes into male mice yielded small fat pads that were fully formed, even in adrenalectomized mice, suggesting that glucocorticoids and the GR enhance adipogenesis but are not essential for adipose tissue development (97).

Glucocorticoid actions in fat have also been investigated using adipose-specific GR knockout (AGRKO) mice, using adiponectin-Cre, which is specific for mature adipocytes (89). Compared to WT mice, AGRKO mice are indistinguishable from their WT littermates with respect to body weight, body composition and adipose tissue morphology (51, 98). Metabolic studies in AGRKO mice indicate that although glucocorticoids are dispensable for adipocyte development, they are critical for the regulation of lipolysis. Deleting GR from adipose tissues reduces lipid efflux to the liver during fasting, and AGRKO mice are protected against weight gain and hepatic steatosis in old age (98).

Lastly, glucocorticoids also influence the synthesis and secretion of adipokines, which often have systemic effects on energy homeostasis and insulin sensitivity. Dexamethasone directly stimulates transcription of the leptin (ob) gene in adipose tissue (99). Leptin levels in Cushing’s patients are higher than in subjects matched for adiposity, and they decline following surgical treatment, before weight loss (100). Glucocorticoids also inhibit the synthesis and secretion of adiponectin, the insulin-sensitising adipokine (101), although adiponectin concentrations are not dysregulated in Cushing’s patients (102). Regardless, it is more likely that the effects of glucocorticoids on central obesity and insulin resistance result from dysregulation of appetite and lipid flux than changes in adipocyte-derived hormones per se.

Glucocorticoids and BAT thermogenesis

As described earlier, glucocorticoids exert biphasic effects on BAT function: acutely, they stimulate cold-induced BAT thermogenesis (60), while BAT activity is suppressed by chronic glucocorticoid treatment. BAT thermogenesis is regulated by uncoupling protein-1 (UCP1), a mitochondrial membrane protein that generates heat by uncoupling substrate oxidation from ATP production (103). Studies in obese Zucker rats (lacking functional leptin receptors) suggested that defects in BAT thermogenesis and UCP1 activity were glucocorticoid-dependent, as they were resolved by adrenalectomy (104). In healthy rats, corticosterone treatment dose-dependently inhibits UCP1 activity and thermogenesis (105); and in cultured human brown adipocytes, similarly, dexamethasone inhibits adrenergically-stimulated respiration (106). Interestingly, the suppressive effects of glucocorticoids on BAT are enhanced by induction of HSD11B1 expression and activity in this tissue (107). As for adipogenesis, glucocorticoids (and the GR) are not essential for brown adipocyte development (96), thermogenic gene expression, or the response to cold exposure (108), although they do exert some influence on these processes, likely aimed at conserving energy during chronic stress.

Intracellular lipid accumulation (‘whitening’) is a striking feature of glucocorticoid-treated BAT in rodents (105), that is also resolved by adrenalectomy (109). In mice treated with corticosterone for 4 weeks, we observed marked lipid accumulation in BAT, together with an ~8% decrease in UCP1 protein expression (110). Elsewhere, treating mice with the GR antagonist CORT125281 increased both fatty acid uptake and combustion in BAT (111). The factors contributing to BAT whitening are not well understood: we could not attribute it to changes in adipogenic (Pparg) or lipogenic (Acaca, Fasn) gene expression (110).

Intriguingly, two recent studies in mice implanted with corticosterone pellets have independently concluded that glucocorticoids stimulate BAT whitening by disrupting circadian rhythms related to lipid uptake (112, 113). The uptake of triglyceride-derived fatty acids into BAT displays a circadian rhythm in mice: it is highest in the evening (when endogenous glucocorticoids are elevated), and this pattern was disrupted within a few days of pellet implantation (112, 113). Lipid uptake was not perturbed by daily injections of corticosterone in the evening, however, suggesting that continuous elevation of corticosterone levels is required for BAT whitening. Interestingly, human BAT also displays a diurnal uptake of glucose (114) and lipids (115) from the circulation, although peak uptake occurs in the morning instead.

Transcriptomic analysis of BAT from corticosterone-treated mice revealed increases in genes involved in lipid synthesis and degradation, including Lpin1 (encoding lipin-1, which regulates adipose tissue triglyceride metabolism) and Acsm5 (Acyl-CoA synthetase medium chain family member 5). Corticosterone-mediated flattening of circadian rhythm also induced expression of the lipid uptake receptor CD36, and corticosterone-induced obesity and lipid accumulation in BAT and VAT were partially abrogated in CD36-null mice (113). These studies have illuminated potential relationships for further study in humans, linking chronic stress and/or disruption of a circadian rhythm with blunted BAT activity and dysregulated lipid metabolism.

Chronic glucocorticoids and bone

Consistent with its suppression of anabolic processes, chronic glucocorticoid treatment, even small doses, can dose-dependently cause bone loss and increase fracture risk in human adults (26). Studies in mice have shown that glucocorticoids promote apoptosis in osteoblasts (116) while favouring the development of adipocytes over osteoblasts in common bone marrow precursors (117). At the same time, glucocorticoids increase the survival of bone-resorbing osteoclasts (118), resulting in excessive bone resorption relative to formation. Glucocorticoid-induced bone loss occurs rapidly, within a few days of exposure, as shown in a sheep model of burn injury (119).

We and others have found that disrupting skeletal glucocorticoid signalling, by transgenically overexpressing 11β-HSD2 in osteoblastic cells (osteoblasts and osteocytes), protects against bone loss induced by chronic stress (120), HFD (30) and ageing (27). Interestingly, disrupting glucocorticoid signalling in these cells also produced beneficial metabolic effects. Unlike WT mice, transgenic HSD2OB/OCY-tg mice were protected against ageing-related declines in leptin sensitivity: as they aged, HSD2OB/OCY-tg mice maintained their leptin-mediated suppression of food intake and stimulation of adipose tissue sympathetic outflow, in contrast to their WT littermates (121). While the mechanisms linking osteoblastic glucocorticoid signalling with the CNS are not well understood, they do not appear to involve changes in the osteoblast-derived hormones osteocalcin or lipocalin-2 (121). Similarly, deleting the GR from osteoprogenitor cells also reduces body weight in mice by ~10% (122).

Notably, when HSD2OB/OCY-tg mice were fed HFD, they not only increased their rates of bone formation and skeletal glucose uptake compared to WT mice but they were also protected against HFD-induced central obesity, insulin resistance, glucose intolerance and dyslipidaemia (30). It is, therefore, conceivable that during stress, glucocorticoids limit energy (glucose) uptake into osteoblasts and osteocytes, which is used by these cells for anabolic processes (bone formation and remodelling, respectively). Other studies in mice have shown that increasing the uptake and utilization of glucose by these cells produces marked beneficial effects on whole-body glucose homeostasis (123). Further studies will be required to confirm whether glucocorticoid signalling in osteoblasts and osteocytes makes a similar contribution to whole-body metabolism in humans.

Sexual dimorphism in glucocorticoid action

Glucocorticoid-regulated metabolic pathways display a marked sexual dimorphism in humans. For example, women have a greater predisposition to inflammatory diseases (124); and during fasting, women (but not men) synthesize lipids from amino acids (125). In addition, men commonly possess an android pattern of fat distribution, with more VAT and less gluteofemoral SAT than women, and women are generally protected from the cardiometabolic consequences of obesity, at least until after menopause (126). Similarly, male rodents are preferred for metabolic studies as they are more sensitive to HFD (127).

Pioneering studies on the sexually dimorphic effects of glucocorticoids were performed by Cidlowski’s group, who showed differential induction of hepatic gene expression by glucocorticoids between male and female rats, with a greater anti-inflammatory response in males (128). Further studies in mice confirmed that nearly one-quarter of inflammatory genes in the livers were sexually dimorphic. Differentially regulated pathways were related to bacterial/viral recognition, rheumatoid arthritis, the complement system, and TREM1 and NFKB signalling (129). Functionally, female mice displayed an exaggerated IL1B response to lipopolysaccharide injection compared to males.

Many other metabolic effects of glucocorticoids have been found to be sexually dimorphic. Male mice are more sensitive to the dysmetabolic effects of chronic glucocorticoid excess (central obesity, hyperinsulinaemia, hyperglycaemia, dyslipidaemia and BAT whitening) than females (110, 130), independently of the dose, duration or route of administration (drinking water vs pellet). Interestingly, corticosterone-induced loss of lean mass was equivalent between males and females, suggesting that this response is not sex-dependent (110). The lack of sexual dimorphism in skeletal muscle glucocorticoid responses has been described in microarray studies (131).

The increased sensitivity of males to glucocorticoids likely reflects differences in both HPA axis regulation and in tissue-specific glucocorticoid actions. Differences in the HPA response to restraint stress have been reported between male and female mice (132). In addition, CBG/transcortin levels are usually higher in female mice; therefore, there may be more active glucocorticoids circulating in males (133). In rat livers, HSD11B1 activity and expression are also generally higher in males than in females, and it is suppressed by oestradiol (134).

Indeed, oestrogens antagonize many metabolic effects of glucocorticoids (Fig. 3). Oestrogen suppresses the number of corticosteroid-binding sites in the pituitary (135), and central oestradiol infusion increases leptin’s anorexic effects in rats (136). In breast cancer cells, oestrogen inhibits GR function by reducing its ligand-mediated phosphorylation and activation of target genes (137). During pregnancy, increases in circulating oestrogen (from the placenta) also stimulate hepatic production of CBG/transcortin, which, in turn, reduces both the levels of free cortisol and its negative feedback on the HPA axis (138). Accordingly, treating male mice with oestradiol prevented diet-induced obesity, hyperinsulinaemia and glucose intolerance (139), and some dysmetabolic effects of corticosterone treatment (obesity and hypercholesterolemia) only became evident in female mice after ovariectomy (110). Ovarian hormones prevent activation of hepatic glucocorticoid signalling, which manifests as steatosis and insulin resistance in ovariectomized mice (140).

Figure 3
Figure 3

Androgens and oestrogens exert both synergistic and antagonistic effects on glucocorticoid actions, and these effects are tissue-specific. Glucocorticoid-regulated metabolic pathways display a marked sexual dimorphism in mice. Compared to females, male mice have a more exaggerated hepatic inflammatory response to infection and are more susceptible to glucocorticoid-induced obesity, insulin resistance and dyslipidaemia. Recent studies have indicated that androgens exacerbate many of the dysmetabolic effects of chronic glucocorticoid exposure. Ectopic lipid accumulation in highly metabolically active tissues, such as skeletal muscle and BAT, interferes with insulin action and results from increased hepatic VLDL-TG export. In parallel, studies in mice have shown that oestrogens antagonize many of the dysmetabolic effects of glucocorticoid treatment, and may, in part, explain the protection from cardiovascular disease in premenopausal women. In mice, oestradiol protects against diet-induced obesity and insulin resistance, while the metabolic effects of chronic glucocorticoid exposure become more apparent following ovariectomy.

Citation: European Journal of Endocrinology 185, 5; 10.1530/EJE-21-0553

In parallel, androgens have been found to potentiate glucocorticoid-induced dysmetabolism in mice. Spaanderman et al. reported that co-administration of an androgen receptor (AR) agonist in male mice potentiated the effects of corticosterone on GR target genes in WAT (and to some extent, BAT) (141). These effects were abolished by treatment with the AR antagonist enzalutamide. While the underlying mechanisms are incompletely understood, in this model, enzalutamide inhibited corticosterone-mediated induction of HSD11B1 activity in WAT. Similarly, treating female rats with 5α-dihydrotestosterone increased hepatic HSD11B1 expression and GR activity (142). We have also found that many of the dysmetabolic effects of chronic corticosterone exposure (hyperinsulinaemia, insulin resistance, dyslipidaemia and BAT whitening) in mice were androgen-dependent (110). Notably, in other tissues, such as skeletal muscle, androgens can antagonize glucocorticoid actions (143).

The underlying mechanisms are complex but may include reciprocal regulation of target genes by AR and GR, as has been shown in some castration-resistant prostate cancers (144). Reciprocity between AR and GR may explain, at least in part, why adipogenesis is impaired in preadipocytes lacking GR in vitro, but their implantation into male mice yields fully formed fat pads (97). AR and GR share many genomic binding sites, but AR/GR specificity depends on many other factors, including the DNA sequence of the response element, nearby enhancers, chromatin accessibility (145) and potentially by the expression of co-factors such as Bag1 and Ppid (146).

This situation is further complicated by glucocorticoid-induced GR resistance: for example, leukocytes from Cushing’s patients exhibit subtle changes in the distribution of GR splice variants that reduce dexamethasone binding (147). Regardless of the exact mechanism, there is substantial emerging evidence that many of the dysmetabolic effects of glucocorticoids are androgen-dependent. This idea raises many exciting possibilities for the future treatment of metabolic diseases in humans, particularly for women with polycystic ovary syndrome (which is characterized by androgen excess) and clinical features of the metabolic syndrome (148).

Conclusions

By regulating systemic nutrient availability, glucocorticoids are critical for many essential physiological functions, most notably the response to stress (1). Chronic exposure to (endogenous/exogenous) glucocorticoids not only suppresses inflammation and mobilizes energy but also promotes muscle loss, osteoporosis, and a cluster of dysmetabolic effects that closely mirror the metabolic syndrome in humans. Understanding how glucocorticoids influence metabolism, and how they synergize with/oppose other regulatory hormones, has become important for minimizing the side effects of chronic glucocorticoid exposure. Glucocorticoids are widely used in Western countries, where ageing- and inflammatory-related conditions are common.

Here, we describe in animal models how glucocorticoid signalling in adipose tissues (white and brown) and in bone contributes to energy homeostasis, nutrient partitioning and insulin sensitivity. Clearly, glucocorticoids have deleterious effects on adipose tissue, especially VAT, that involve insulin resistance and increased hepatic lipid flux. Accumulation of VAT leads to a marked increase in the risk of type 2 diabetes and cardiovascular disease (77, 78). In bone, glucocorticoids may inhibit bone formation, promoting bone loss, via suppression of glucose metabolism. Lastly, recent studies have reported marked effects of sex hormones on the metabolic effects of chronic glucocorticoid exposure, particularly in adipose tissues and the liver. It is possible that glucocorticoid-induced mobilization of energy stores may provide a large source of energy for skeletal muscle activity (and therefore, survival) in males. In the future, elucidating the mechanisms underlying glucocorticoid actions in metabolic tissues will allow us to minimize potential side effects and develop effective new therapeutic agents for metabolic diseases.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work has been supported by Project Grants (APP5017436, APP 5030790) and an Ideas Grant (APP1185915) from the National Health and Medical Research Council (NHMRC) of Australia. M J S is also supported by an NHMRC Investigator Grant (APP 1196062).

Author contribution statement

This manuscript was written by M M S, with input from H Z and M J S.

References

  • 1↑

    Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Reviews 2000 21 55–89. (https://doi.org/10.1210/edrv.21.1.0389)

    • Search Google Scholar
    • Export Citation
  • 2↑

    Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care and Research 2013 65 294–298. (https://doi.org/10.1002/acr.21796)

    • Search Google Scholar
    • Export Citation
  • 3↑

    Chapman K, Holmes M, Seckl J. 11beta-Hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiological Reviews 2013 93 1139–1206. (https://doi.org/10.1152/physrev.00020.2012)

    • Search Google Scholar
    • Export Citation
  • 4↑

    Buckingham JC Glucocorticoids: exemplars of multi-tasking. British Journal of Pharmacology 2006 147 (Supplement 1) S258–S268. (https://doi.org/10.1038/sj.bjp.0706456)

    • Search Google Scholar
    • Export Citation
  • 5↑

    Berdanier CD Role of glucocorticoids in the regulation of lipogenesis. FASEB Journal 1989 3 2179–2183. (https://doi.org/10.1096/fasebj.3.10.2666232)

    • Search Google Scholar
    • Export Citation
  • 6↑

    Perogamvros I, Ray DW, Trainer PJ. Regulation of cortisol bioavailability – effects on hormone measurement and action. Nature Reviews: Endocrinology 2012 8 717–727. (https://doi.org/10.1038/nrendo.2012.134)

    • Search Google Scholar
    • Export Citation
  • 7↑

    Timmermans S, Souffriau J, Libert C. A general introduction to glucocorticoid biology. Frontiers in Immunology 2019 10 1545. (https://doi.org/10.3389/fimmu.2019.01545)

    • Search Google Scholar
    • Export Citation
  • 8↑

    Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O’Shea JJ, Chrousos GP, Bornstein SR. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB Journal 2002 16 61–71. (https://doi.org/10.1096/fj.01-0245com)

    • Search Google Scholar
    • Export Citation
  • 9↑

    Wiegert O, Joels M, Krugers H. Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus. Learning and Memory 2006 13 110–113. (https://doi.org/10.1101/lm.87706)

    • Search Google Scholar
    • Export Citation
  • 10↑

    Di S, Malcher-Lopes R, Halmos KC, Tasker JG. Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. Journal of Neuroscience 2003 23 4850–4857. (https://doi.org/10.1523/JNEUROSCI.23-12-04850.2003)

    • Search Google Scholar
    • Export Citation
  • 11↑

    Sun HW, Miao CY, Liu L, Zhou J, Su DF, Wang YX, Jiang CL. Rapid inhibitory effect of glucocorticoids on airway smooth muscle contractions in guinea pigs. Steroids 2006 71 154–159. (https://doi.org/10.1016/j.steroids.2005.09.019)

    • Search Google Scholar
    • Export Citation
  • 12↑

    Ping YQ, Mao C, Xiao P, Zhao RJ, Jiang Y, Yang Z, An WT, Shen DD, Yang F & Zhang H et al.Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex. Nature 2021 589 620–626. (https://doi.org/10.1038/s41586-020-03083-w)

    • Search Google Scholar
    • Export Citation
  • 13↑

    Hsiao CC, Chu TY, Wu CJ, van den Biggelaar M, Pabst C, Hebert J, Kuijpers TW, Scicluna BP, KY KY & Chen TC et al.The adhesion G protein-coupled receptor GPR97/ADGRG3 is expressed in human granulocytes and triggers antimicrobial effector functions. Frontiers in Immunology 2018 9 2830. (https://doi.org/10.3389/fimmu.2018.02830)

    • Search Google Scholar
    • Export Citation
  • 14↑

    Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet ER, Monder C. Localisation of 11 beta-hydroxysteroid dehydrogenase – tissue specific protector of the mineralocorticoid receptor. Lancet 1988 2 986–989. (https://doi.org/10.1016/s0140-6736(8890742-8)

    • Search Google Scholar
    • Export Citation
  • 15↑

    Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988 242 583–585. (https://doi.org/10.1126/science.2845584)

    • Search Google Scholar
    • Export Citation
  • 16↑

    Lee MJ, Fried SK. The glucocorticoid receptor, not the mineralocorticoid receptor, plays the dominant role in adipogenesis and adipokine production in human adipocytes. International Journal of Obesity 2014 38 1228–1233. (https://doi.org/10.1038/ijo.2014.6)

    • Search Google Scholar
    • Export Citation
  • 17↑

    Bjorntorp P, Rosmond R. The metabolic syndrome – a neuroendocrine disorder? British Journal of Nutrition 2000 83 (Supplement 1) S49–S57. (https://doi.org/10.1017/s0007114500000957)

    • Search Google Scholar
    • Export Citation
  • 18↑

    Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, Johnson O, Andrew R, Olsson T. Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. Journal of Clinical Endocrinology and Metabolism 2002 87 3330–3336. (https://doi.org/10.1210/jcem.87.7.8661)

    • Search Google Scholar
    • Export Citation
  • 19↑

    Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE, Permana PA, Tataranni PA, Walker BR. Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. Journal of Clinical Endocrinology and Metabolism 2003 88 2738–2744. (https://doi.org/10.1210/jc.2002-030017)

    • Search Google Scholar
    • Export Citation
  • 20↑

    Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect ‘Cushing’s disease of the omentum’? Lancet 1997 349 1210–1213. (https://doi.org/10.1016/S0140-6736(9611222-8)

    • Search Google Scholar
    • Export Citation
  • 21↑

    Mariniello B, Ronconi V, Rilli S, Bernante P, Boscaro M, Mantero F, Giacchetti G. Adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing’s syndrome. European Journal of Endocrinology 2006 155 435–441. (https://doi.org/10.1530/eje.1.02228)

    • Search Google Scholar
    • Export Citation
  • 22↑

    Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR & Seckl JR et al.11Beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. PNAS 1997 94 14924–14929. (https://doi.org/10.1073/pnas.94.26.14924)

    • Search Google Scholar
    • Export Citation
  • 23↑

    Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 2004 53 931–938. (https://doi.org/10.2337/diabetes.53.4.931)

    • Search Google Scholar
    • Export Citation
  • 24↑

    Lavery GG, Zielinska AE, Gathercole LL, Hughes B, Semjonous N, Guest P, Saqib K, Sherlock M, Reynolds G & Morgan SA et al.Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11beta-hydroxysteroid dehydrogenase type 1. Endocrinology 2012 153 3236–3248. (https://doi.org/10.1210/en.2012-1019)

    • Search Google Scholar
    • Export Citation
  • 25↑

    Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP, Bujalska IJ, Stewart PM, Tomlinson JW, Lavery GG. 11beta-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. PNAS 2014 111 E2482–E2491. (https://doi.org/10.1073/pnas.1323681111)

    • Search Google Scholar
    • Export Citation
  • 26↑

    van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis International 2002 13 777–787. (https://doi.org/10.1007/s001980200108)

    • Search Google Scholar
    • Export Citation
  • 27↑

    Weinstein RS, Wan C, Liu Q, Wang Y, Almeida M, O’Brien CA, Thostenson J, Roberson PK, Boskey AL & Clemens TL et al.Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 2010 9 147–161. (https://doi.org/10.1111/j.1474-9726.2009.00545.x)

    • Search Google Scholar
    • Export Citation
  • 28↑

    Tu J, Zhang P, Ji Z, Henneicke H, Li J, Kim S, Swarbrick MM, Wu Y, Little CB & Seibel MJ et al.Disruption of glucocorticoid signalling in osteoblasts attenuates age-related surgically induced osteoarthritis. Osteoarthritis and Cartilage 2019 27 1518–1525. (https://doi.org/10.1016/j.joca.2019.04.019)

    • Search Google Scholar
    • Export Citation
  • 29↑

    Cooper MS, Rabbitt EH, Goddard PE, Bartlett WA, Hewison M, Stewart PM. Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. Journal of Bone and Mineral Research 2002 17 979–986. (https://doi.org/10.1359/jbmr.2002.17.6.979)

    • Search Google Scholar
    • Export Citation
  • 30↑

    Kim S, Henneicke H, Cavanagh LL, Macfarlane E, Thai LJ, Foong D, Gasparini SJ, Fong-Yee C, Swarbrick MM & Seibel MJ et al.Osteoblastic glucocorticoid signalling exacerbates high-fat diet-induced bone loss and obesity. Bone Research 2021 9 40. (https://doi.org/10.1038/s41413-021-00159-9)

    • Search Google Scholar
    • Export Citation
  • 31↑

    Holmes MC, Carter RN, Noble J, Chitnis S, Dutia A, Paterson JM, Mullins JJ, Seckl JR, Yau JL. 11Beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments. Journal of Neuroscience 2010 30 6916–6920. (https://doi.org/10.1523/JNEUROSCI.0731-10.2010)

    • Search Google Scholar
    • Export Citation
  • 32↑

    Gregory S, Hill D, Grey B, Ketelbey W, Miller T, Muniz-Terrera G, Ritchie CW. 11Beta-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis. Metabolism: Clinical and Experimental 2020 108 154246. (https://doi.org/10.1016/j.metabol.2020.154246)

    • Search Google Scholar
    • Export Citation
  • 33↑

    Kalhan SC, Adam PA. Inhibitory effect of prednisone on insulin secretion in man: model for duplication of blood glucose concentration. Journal of Clinical Endocrinology and Metabolism 1975 41 600–610. (https://doi.org/10.1210/jcem-41-3-600)

    • Search Google Scholar
    • Export Citation
  • 34↑

    van Raalte DH, Nofrate V, Bunck MC, van Iersel T, Elassaiss Schaap J, Nassander UK, Heine RJ, Mari A, Dokter WH, Diamant M. Acute and 2-week exposure to prednisolone impair different aspects of beta-cell function in healthy men. European Journal of Endocrinology 2010 162 729–735. (https://doi.org/10.1530/EJE-09-1034)

    • Search Google Scholar
    • Export Citation
  • 35↑

    Petersons CJ, Mangelsdorf BL, Jenkins AB, Poljak A, Smith MD, Greenfield JR, Thompson CH, Burt MG. Effects of low-dose prednisolone on hepatic and peripheral insulin sensitivity, insulin secretion, and abdominal adiposity in patients with inflammatory rheumatologic disease. Diabetes Care 2013 36 2822–2829. (https://doi.org/10.2337/dc12-2617)

    • Search Google Scholar
    • Export Citation
  • 36↑

    Ranta F, Avram D, Berchtold S, Dufer M, Drews G, Lang F, Ullrich S. Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 2006 55 1380–1390. (https://doi.org/10.2337/db05-1220)

    • Search Google Scholar
    • Export Citation
  • 37↑

    Guo B, Zhang W, Xu S, Lou J, Wang S, Men X. GSK-3beta mediates dexamethasone-induced pancreatic beta cell apoptosis. Life Sciences 2016 144 1–7. (https://doi.org/10.1016/j.lfs.2015.11.017)

    • Search Google Scholar
    • Export Citation
  • 38↑

    Sasaki K, Cripe TP, Koch SR, Andreone TL, Petersen DD, Beale EG, Granner DK. Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin. Journal of Biological Chemistry 1984 259 15242–15251. (https://doi.org/10.1016/S0021-9258(1742541-5)

    • Search Google Scholar
    • Export Citation
  • 39↑

    Lin B, Morris DW, Chou JY. Hepatocyte nuclear factor 1alpha is an accessory factor required for activation of glucose-6-phosphatase gene transcription by glucocorticoids. DNA and Cell Biology 1998 17 967–974. (https://doi.org/10.1089/dna.1998.17.967)

    • Search Google Scholar
    • Export Citation
  • 40↑

    Yi CX, Foppen E, Abplanalp W, Gao Y, Alkemade A, la Fleur SE, Serlie MJ, Fliers E, Buijs RM & Tschop MH et al.Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity. Diabetes 2012 61 339–345. (https://doi.org/10.2337/db11-1239)

    • Search Google Scholar
    • Export Citation
  • 41↑

    Mersmann HJ, Segal HL. Glucocorticoid control of the liver glycogen synthetase-activating system. Journal of Biological Chemistry 1969 244 1701–1704. (https://doi.org/10.1016/S0021-9258(1891740-0)

    • Search Google Scholar
    • Export Citation
  • 42↑

    Schneiter P, Tappy L. Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans. American Journal of Physiology 1998 275 E806–E813. (https://doi.org/10.1152/ajpendo.1998.275.5.E806)

    • Search Google Scholar
    • Export Citation
  • 43↑

    Black PR, Brooks DC, Bessey PQ, Wolfe RR, Wilmore DW. Mechanisms of insulin resistance following injury. Annals of Surgery 1982 196 420–435. (https://doi.org/10.1097/00000658-198210000-00005)

    • Search Google Scholar
    • Export Citation
  • 44↑

    Dimitriadis G, Leighton B, Parry-Billings M, Sasson S, Young M, Krause U, Bevan S, Piva T, Wegener G, Newsholme EA. Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle. Biochemical Journal 1997 321 707–712. (https://doi.org/10.1042/bj3210707)

    • Search Google Scholar
    • Export Citation
  • 45↑

    Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E & Dharmarajan K et al.Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001 294 1704–1708. (https://doi.org/10.1126/science.1065874)

    • Search Google Scholar
    • Export Citation
  • 46↑

    Gathercole LL, Morgan SA, Bujalska IJ, Hauton D, Stewart PM, Tomlinson JW. Regulation of lipogenesis by glucocorticoids and insulin in human adipose tissue. PLoS ONE 2011 6 e26223. (https://doi.org/10.1371/journal.pone.0026223)

    • Search Google Scholar
    • Export Citation
  • 47↑

    D’Souza AM, Beaudry JL, Szigiato AA, Trumble SJ, Snook LA, Bonen A, Giacca A, Riddell MC. Consumption of a high-fat diet rapidly exacerbates the development of fatty liver disease that occurs with chronically elevated glucocorticoids. American Journal of Physiology: Gastrointestinal and Liver Physiology 2012 302 G850–G863. (https://doi.org/10.1152/ajpgi.00378.2011)

    • Search Google Scholar
    • Export Citation
  • 48↑

    Koliwad SK, Kuo T, Shipp LE, Gray NE, Backhed F, So AY, Farese Jr RV, Wang JC. Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism. Journal of Biological Chemistry 2009 284 25593–25601. (https://doi.org/10.1074/jbc.M109.025452)

    • Search Google Scholar
    • Export Citation
  • 49↑

    Hazlehurst JM, Gathercole LL, Nasiri M, Armstrong MJ, Borrows S, Yu J, Wagenmakers AJ, Stewart PM, Tomlinson JW. Glucocorticoids fail to cause insulin resistance in human subcutaneous adipose tissue in vivo. Journal of Clinical Endocrinology and Metabolism 2013 98 1631–1640. (https://doi.org/10.1210/jc.2012-3523)

    • Search Google Scholar
    • Export Citation
  • 50↑

    Radhakutty A, Mangelsdorf BL, Drake SM, Samocha-Bonet D, Heilbronn LK, Smith MD, Thompson CH, Burt MG. Effects of prednisolone on energy and fat metabolism in patients with rheumatoid arthritis: tissue-specific insulin resistance with commonly used prednisolone doses. Clinical Endocrinology 2016 85 741–747. (https://doi.org/10.1111/cen.13138)

    • Search Google Scholar
    • Export Citation
  • 51↑

    Shen Y, Roh HC, Kumari M, Rosen ED. Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding. Molecular Metabolism 2017 6 1150–1160. (https://doi.org/10.1016/j.molmet.2017.06.013)

    • Search Google Scholar
    • Export Citation
  • 52↑

    Dallman MF, Strack AM, Akana SF, Bradbury MJ, Hanson ES, Scribner KA, Smith M. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Frontiers in Neuroendocrinology 1993 14 303–347. (https://doi.org/10.1006/frne.1993.1010)

    • Search Google Scholar
    • Export Citation
  • 53↑

    Hurson CJ, Butler JS, Keating DT, Murray DW, Sadlier DM, O’Byrne JM, Doran PP. Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis. BMC Musculoskeletal Disorders 2007 8 12. (https://doi.org/10.1186/1471-2474-8-12)

    • Search Google Scholar
    • Export Citation
  • 54↑

    Ekenstam E, Stalenheim G, Hallgren R. The acute effect of high dose corticosteroid treatment on serum osteocalcin. Metabolism: Clinical and Experimental 1988 37 141–144. (https://doi.org/10.1016/s0026-0495(9890008-7)

    • Search Google Scholar
    • Export Citation
  • 55↑

    Dovio A, Perazzolo L, Osella G, Ventura M, Termine A, Milano E, Bertolotto A, Angeli A. Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. Journal of Clinical Endocrinology and Metabolism 2004 89 4923–4928. (https://doi.org/10.1210/jc.2004-0164)

    • Search Google Scholar
    • Export Citation
  • 56↑

    Togari A, Arai M, Mizutani S, Mizutani S, Koshihara Y, Nagatsu T. Expression of mRNAs for neuropeptide receptors and beta-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells. Neuroscience Letters 1997 233 125–128. (https://doi.org/10.1016/s0304-3940(9700649-6)

    • Search Google Scholar
    • Export Citation
  • 57↑

    Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002 111 305–317. (https://doi.org/10.1016/s0092-8674(0201049-8)

    • Search Google Scholar
    • Export Citation
  • 58↑

    Nedergaard J, Cannon B. The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metabolism 2010 11 268–272. (https://doi.org/10.1016/j.cmet.2010.03.007)

    • Search Google Scholar
    • Export Citation
  • 59↑

    Scotney H, Symonds ME, Law J, Budge H, Sharkey D, Manolopoulos KN. Glucocorticoids modulate human brown adipose tissue thermogenesis in vivo. Metabolism: Clinical and Experimental 2017 70 125–132. (https://doi.org/10.1016/j.metabol.2017.01.024)

    • Search Google Scholar
    • Export Citation
  • 60↑

    Ramage LE, Akyol M, Fletcher AM, Forsythe J, Nixon M, Carter RN, van Beek EJ, Morton NM, Walker BR, Stimson RH. Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metabolism 2016 24 130–141. (https://doi.org/10.1016/j.cmet.2016.06.011)

    • Search Google Scholar
    • Export Citation
  • 61↑

    Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing’s syndrome. American Journal of Medicine 1952 13 597–614. (https://doi.org/10.1016/0002-9343(5290027-2)

    • Search Google Scholar
    • Export Citation
  • 62↑

    Tataranni PA, Larson DE, Snitker S, Young JB, Flatt JP, Ravussin E. Effects of glucocorticoids on energy metabolism and food intake in humans. American Journal of Physiology 1996 271 E317–E325. (https://doi.org/10.1152/ajpendo.1996.271.2.E317)

    • Search Google Scholar
    • Export Citation
  • 63↑

    Thuzar M, Law WP, Ratnasingam J, Jang C, Dimeski G, Ho KKY. Glucocorticoids suppress brown adipose tissue function in humans: a double-blind placebo-controlled study. Diabetes, Obesity and Metabolism 2018 20 840–848. (https://doi.org/10.1111/dom.13157)

    • Search Google Scholar
    • Export Citation
  • 64↑

    Fardet L, Nazareth I, Petersen I. Long-term systemic glucocorticoid therapy and weight gain: a population-based cohort study. Rheumatology 2021 60 1502–1511. (https://doi.org/10.1093/rheumatology/keaa289)

    • Search Google Scholar
    • Export Citation
  • 65↑

    Epel E, Lapidus R, McEwen B, Brownell K. Stress may add bite to appetite in women: a laboratory study of stress-induced cortisol and eating behavior. Psychoneuroendocrinology 2001 26 37–49. (https://doi.org/10.1016/s0306-4530(0000035-4)

    • Search Google Scholar
    • Export Citation
  • 66↑

    Morrison E, Crosbie D, Capell HA. Attitude of rheumatoid arthritis patients to treatment with oral corticosteroids. Rheumatology 2003 42 1247–1250. (https://doi.org/10.1093/rheumatology/keg355)

    • Search Google Scholar
    • Export Citation
  • 67↑

    Bray GA, York DA. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiological Reviews 1979 59 719–809. (https://doi.org/10.1152/physrev.1979.59.3.719)

    • Search Google Scholar
    • Export Citation
  • 68↑

    Asagami T, Belanoff JK, Azuma J, Blasey CM, Clark RD, Tsao PS. Selective glucocorticoid receptor (GR-II) antagonist reduces body weight gain in mice. Journal of Nutrition and Metabolism 2011 2011 235389. (https://doi.org/10.1155/2011/235389)

    • Search Google Scholar
    • Export Citation
  • 69↑

    Aronsson M, Fuxe K, Dong Y, Agnati LF, Okret S, Gustafsson JA. Localization of glucocorticoid receptor mRNA in the male rat brain by in situ hybridization. PNAS 1988 85 9331–9335. (https://doi.org/10.1073/pnas.85.23.9331)

    • Search Google Scholar
    • Export Citation
  • 70↑

    Shimizu H, Arima H, Watanabe M, Goto M, Banno R, Sato I, Ozaki N, Nagasaki H, Oiso Y. Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via adenosine monophosphate-activated protein kinase signaling in the arcuate nucleus of rats. Endocrinology 2008 149 4544–4553. (https://doi.org/10.1210/en.2008-0229)

    • Search Google Scholar
    • Export Citation
  • 71↑

    Beard JC, Halter JB, Best JD, Pfeifer MA, Porte Jr D. Dexamethasone-induced insulin resistance enhances B cell responsiveness to glucose level in normal men. American Journal of Physiology 1984 247 E592–E596. (https://doi.org/10.1152/ajpendo.1984.247.5.E592)

    • Search Google Scholar
    • Export Citation
  • 72↑

    Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 1997 46 1341–1345. (https://doi.org/10.2337/diab.46.8.1341)

    • Search Google Scholar
    • Export Citation
  • 73↑

    Protzek AO, Rezende LF, Costa-Junior JM, Ferreira SM, Cappelli AP, de Paula FM, de Souza JC, Kurauti MA, Carneiro EM & Rafacho A et al.Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme. Journal of Steroid Biochemistry and Molecular Biology 2016 155 1–8. (https://doi.org/10.1016/j.jsbmb.2015.09.020)

    • Search Google Scholar
    • Export Citation
  • 74↑

    Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG & Kieffer TJ et al.Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metabolism 2012 16 723–737. (https://doi.org/10.1016/j.cmet.2012.10.019)

    • Search Google Scholar
    • Export Citation
  • 75↑

    Lee MJ, Gong DW, Burkey BF, Fried SK. Pathways regulated by glucocorticoids in omental and subcutaneous human adipose tissues: a microarray study. American Journal of Physiology: Endocrinology and Metabolism 2011 300 E571–E580. (https://doi.org/10.1152/ajpendo.00231.2010)

    • Search Google Scholar
    • Export Citation
  • 76↑

    Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH. The metabolic syndrome. Endocrine Reviews 2008 29 777–822. (https://doi.org/10.1210/er.2008-0024)

    • Search Google Scholar
    • Export Citation
  • 77↑

    Shah RV, Murthy VL, Abbasi SA, Blankstein R, Kwong RY, Goldfine AB, Jerosch-Herold M, Lima JA, Ding J, Allison MA. Visceral adiposity and the risk of metabolic syndrome across body mass index: the MESA Study. JACC: Cardiovascular Imaging 2014 7 1221–1235. (https://doi.org/10.1016/j.jcmg.2014.07.017)

    • Search Google Scholar
    • Export Citation
  • 78↑

    Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiological Reviews 1994 74 761–811. (https://doi.org/10.1152/physrev.1994.74.4.761)

    • Search Google Scholar
    • Export Citation
  • 79↑

    Ruge T, Sukonina V, Myrnas T, Lundgren M, Eriksson JW, Olivecrona G. Lipoprotein lipase activity/mass ratio is higher in omental than in subcutaneous adipose tissue. European Journal of Clinical Investigation 2006 36 16–21. (https://doi.org/10.1111/j.1365-2362.2006.01584.x)

    • Search Google Scholar
    • Export Citation
  • 80↑

    Rebuffe-Scrive M, Andersson B, Olbe L, Bjorntorp P. Metabolism of adipose tissue in intraabdominal depots of nonobese men and women. Metabolism: Clinical and Experimental 1989 38 453–458. (https://doi.org/10.1016/0026-0495(8990198-4)

    • Search Google Scholar
    • Export Citation
  • 81↑

    Veilleux A, Caron-Jobin M, Noel S, Laberge PY, Tchernof A. Visceral adipocyte hypertrophy is associated with dyslipidemia independent of body composition and fat distribution in women. Diabetes 2011 60 1504–1511. (https://doi.org/10.2337/db10-1039)

    • Search Google Scholar
    • Export Citation
  • 82↑

    Verboven K, Wouters K, Gaens K, Hansen D, Bijnen M, Wetzels S, Stehouwer CD, Goossens GH, Schalkwijk CG & Blaak EE et al.Abdominal subcutaneous and visceral adipocyte size, lipolysis and inflammation relate to insulin resistance in male obese humans. Scientific Reports 2018 8 4677. (https://doi.org/10.1038/s41598-018-22962-x)

    • Search Google Scholar
    • Export Citation
  • 83↑

    Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nature Reviews: Immunology 2011 11 85–97. (https://doi.org/10.1038/nri2921)

    • Search Google Scholar
    • Export Citation
  • 84↑

    Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. International Journal of Obesity 2010 34 949–959. (https://doi.org/10.1038/ijo.2009.286)

    • Search Google Scholar
    • Export Citation
  • 85↑

    Rebuffe-Scrive M, Bronnegard M, Nilsson A, Eldh J, Gustafsson JA, Bjorntorp P. Steroid hormone receptors in human adipose tissues. Journal of Clinical Endocrinology and Metabolism 1990 71 1215–1219. (https://doi.org/10.1210/jcem-71-5-1215)

    • Search Google Scholar
    • Export Citation
  • 86↑

    Lundgren M, Buren J, Ruge T, Myrnas T, Eriksson JW. Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes. Journal of Clinical Endocrinology and Metabolism 2004 89 2989–2997. (https://doi.org/10.1210/jc.2003-031157)

    • Search Google Scholar
    • Export Citation
  • 87↑

    Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001 294 2166–2170. (https://doi.org/10.1126/science.1066285)

    • Search Google Scholar
    • Export Citation
  • 88↑

    Kershaw EE, Morton NM, Dhillon H, Ramage L, Seckl JR, Flier JS. Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity. Diabetes 2005 54 1023–1031. (https://doi.org/10.2337/diabetes.54.4.1023)

    • Search Google Scholar
    • Export Citation
  • 89↑

    Jeffery E, Berry R, Church CD, Yu S, Shook BA, Horsley V, Rosen ED, Rodeheffer MS. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 2014 3 206–211. (https://doi.org/10.4161/adip.29674)

    • Search Google Scholar
    • Export Citation
  • 90↑

    Berthiaume M, Laplante M, Festuccia W, Gelinas Y, Poulin S, Lalonde J, Joanisse DR, Thieringer R, Deshaies Y. Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. Endocrinology 2007 148 2391–2397. (https://doi.org/10.1210/en.2006-1199)

    • Search Google Scholar
    • Export Citation
  • 91↑

    Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes and Development 1995 9 168–181. (https://doi.org/10.1101/gad.9.2.168)

    • Search Google Scholar
    • Export Citation
  • 92↑

    Farmer SR Transcriptional control of adipocyte formation. Cell Metabolism 2006 4 263–273. (https://doi.org/10.1016/j.cmet.2006.07.001)

  • 93↑

    Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes and Development 1991 5 1538–1552. (https://doi.org/10.1101/gad.5.9.1538)

    • Search Google Scholar
    • Export Citation
  • 94↑

    Steger DJ, Grant GR, Schupp M, Tomaru T, Lefterova MI, Schug J, Manduchi E, Stoeckert Jr CJ, Lazar MA. Propagation of adipogenic signals through an epigenomic transition state. Genes and Development 2010 24 1035–1044. (https://doi.org/10.1101/gad.1907110)

    • Search Google Scholar
    • Export Citation
  • 95↑

    Asada M, Rauch A, Shimizu H, Maruyama H, Miyaki S, Shibamori M, Kawasome H, Ishiyama H, Tuckermann J, Asahara H. DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Kruppel-like factor 15 gene expression. Laboratory Investigation 2011 91 203–215. (https://doi.org/10.1038/labinvest.2010.170)

    • Search Google Scholar
    • Export Citation
  • 96↑

    Park YK, Ge K. Glucocorticoid receptor accelerates, but is dispensable for, adipogenesis. Molecular and Cellular Biology 2017 37. (https://doi.org/10.1128/MCB.00260-16)

    • Search Google Scholar
    • Export Citation
  • 97↑

    Bauerle KT, Hutson I, Scheller EL, Harris CA. Glucocorticoid receptor signaling is not required for in vivo adipogenesis. Endocrinology 2018 159 2050–2061. (https://doi.org/10.1210/en.2018-00118)

    • Search Google Scholar
    • Export Citation
  • 98↑

    Mueller KM, Hartmann K, Kaltenecker D, Vettorazzi S, Bauer M, Mauser L, Amann S, Jall S, Fischer K & Esterbauer H et al.Adipocyte glucocorticoid receptor deficiency attenuates aging- and HFD-induced obesity and impairs the feeding-fasting transition. Diabetes 2017 66 272–286. (https://doi.org/10.2337/db16-0381)

    • Search Google Scholar
    • Export Citation
  • 99↑

    De Vos P, Lefebvre AM, Shrivo I, Fruchart JC, Auwerx J. Glucocorticoids induce the expression of the leptin gene through a non-classical mechanism of transcriptional activation. European Journal of Biochemistry 1998 253 619–626. (https://doi.org/10.1046/j.1432-1327.1998.2530619.x)

    • Search Google Scholar
    • Export Citation
  • 100↑

    Masuzaki H, Ogawa Y, Hosoda K, Miyawaki T, Hanaoka I, Hiraoka J, Yasuno A, Nishimura H, Yoshimasa Y & Nishi S et al.Glucocorticoid regulation of leptin synthesis and secretion in humans: elevated plasma leptin levels in Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism 1997 82 2542–2547. (https://doi.org/10.1210/jcem.82.8.4128)

    • Search Google Scholar
    • Export Citation
  • 101↑

    Degawa-Yamauchi M, Moss KA, Bovenkerk JE, Shankar SS, Morrison CL, Lelliott CJ, Vidal-Puig A, Jones R, Considine RV. Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor alpha. Obesity Research 2005 13 662–669. (https://doi.org/10.1038/oby.2005.74)

    • Search Google Scholar
    • Export Citation
  • 102↑

    Fallo F, Scarda A, Sonino N, Paoletta A, Boscaro M, Pagano C, Federspil G, Vettor R. Effect of glucocorticoids on adiponectin: a study in healthy subjects and in Cushing’s syndrome. European Journal of Endocrinology 2004 150 339–344. (https://doi.org/10.1530/eje.0.1500339)

    • Search Google Scholar
    • Export Citation
  • 103↑

    Heaton GM, Wagenvoord RJ, Kemp Jr A, Nicholls DG. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. European Journal of Biochemistry 1978 82 515–521. (https://doi.org/10.1111/j.1432-1033.1978.tb12045.x)

    • Search Google Scholar
    • Export Citation
  • 104↑

    Holt S, York DA. The effect of adrenalectomy on GDP binding to brown-adipose-tissue mitochondria of obese rat. Biochemical Journal 1982 208 819–822. (https://doi.org/10.1042/bj2080819)

    • Search Google Scholar
    • Export Citation
  • 105↑

    Strack AM, Bradbury MJ, Dallman MF. Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue. American Journal of Physiology 1995 268 R183–R191. (https://doi.org/10.1152/ajpregu.1995.268.1.R183)

    • Search Google Scholar
    • Export Citation
  • 106↑

    Barclay JL, Agada H, Jang C, Ward M, Wetzig N, Ho KK. Effects of glucocorticoids on human brown adipocytes. Journal of Endocrinology 2015 224 139–147. (https://doi.org/10.1530/JOE-14-0538)

    • Search Google Scholar
    • Export Citation
  • 107↑

    Doig CL, Fletcher RS, Morgan SA, McCabe EL, Larner DP, Tomlinson JW, Stewart PM, Philp A, Lavery GG. 11beta-HSD1 modulates the set point of brown adipose tissue response to glucocorticoids in male mice. Endocrinology 2017 158 1964–1976. (https://doi.org/10.1210/en.2016-1722)

    • Search Google Scholar
    • Export Citation
  • 108↑

    Glantschnig C, Mattijssen F, Vogl ES, Ali Khan A, Rios Garcia M, Fischer K, Muller T, Uhlenhaut H, Nawroth P & Scheideler M et al.The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis. EMBO Reports 2019 20 e48552.

    • Search Google Scholar
    • Export Citation
  • 109↑

    Fawcett DW, Jones IC. The effects of hypophysectomy, adrenalectomy and of thiouracil feeding on the cytology of brown adipose tissue. Endocrinology 1949 45 609–62 1, illust. (https://doi.org/10.1210/endo-45-6-609)

    • Search Google Scholar
    • Export Citation
  • 110↑

    Gasparini SJ, Swarbrick MM, Kim S, Thai LJ, Henneicke H, Cavanagh LL, Tu J, Weber MC, Zhou H, Seibel MJ. Androgens sensitise mice to glucocorticoid-induced insulin resistance and fat accumulation. Diabetologia 2019 62 1463–1477. (https://doi.org/10.1007/s00125-019-4887-0)

    • Search Google Scholar
    • Export Citation
  • 111↑

    Kroon J, Koorneef LL, van den Heuvel JK, Verzijl CRC, van de Velde NM, Mol IM, Sips HCM, Hunt H, Rensen PCN, Meijer OC. Selective glucocorticoid receptor antagonist CORT125281 activates brown adipose tissue and alters lipid distribution in male mice. Endocrinology 2018 159 535–546. (https://doi.org/10.1210/en.2017-00512)

    • Search Google Scholar
    • Export Citation
  • 112↑

    Kroon J, Schilperoort M, In Het Panhuis W, van den Berg R, van Doeselaar L, Verzijl CRC, van Trigt N, Mol IM, Sips HHCM & van den Heuvel JK et al.A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function. Molecular Metabolism 2021 47 101179. (https://doi.org/10.1016/j.molmet.2021.101179)

    • Search Google Scholar
    • Export Citation
  • 113↑

    Tholen S, Kovary K, Rabiee A, Bielczyk-Maczynska YW, Teruel M. Flattened circadian glucocorticoid oscillations cause obesity due to increased lipid turnover and lipid uptake. bioRxiv 2020. (https://doi.org/10.1101/2020.01.02.893081)

    • Search Google Scholar
    • Export Citation
  • 114↑

    Lee P, Bova R, Schofield L, Bryant W, Dieckmann W, Slattery A, Govendir MA, Emmett L, Greenfield JR. Brown adipose tissue exhibits a glucose-responsive thermogenic biorhythm in humans. Cell Metabolism 2016 23 602–609. (https://doi.org/10.1016/j.cmet.2016.02.007)

    • Search Google Scholar
    • Export Citation
  • 115↑

    van den Berg R, Kooijman S, Noordam R, Ramkisoensing A, Abreu-Vieira G, Tambyrajah LL, Dijk W, Ruppert P, Mol IM & Kramar B et al.A diurnal rhythm in brown adipose tissue causes rapid clearance and combustion of plasma lipids at wakening. Cell Reports 2018 22 3521–3533. (https://doi.org/10.1016/j.celrep.2018.03.004)

    • Search Google Scholar
    • Export Citation
  • 116↑

    Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. Journal of Clinical Investigation 1998 102 274–282. (https://doi.org/10.1172/JCI2799)

    • Search Google Scholar
    • Export Citation
  • 117↑

    Yao W, Cheng Z, Busse C, Pham A, Nakamura MC, Lane NE. Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis and Rheumatism 2008 58 1674–1686. (https://doi.org/10.1002/art.23454)

    • Search Google Scholar
    • Export Citation
  • 118↑

    Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, Jilka RL, Parfitt AM, Manolagas SC. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. Journal of Clinical Investigation 2002 109 1041–1048. (https://doi.org/10.1172/JCI14538)

    • Search Google Scholar
    • Export Citation
  • 119↑

    Klein GL, Xie Y, Qin YX, Lin L, Hu M, Enkhbaatar P, Bonewald LF. Preliminary evidence of early bone resorption in a sheep model of acute burn injury: an observational study. Journal of Bone and Mineral Metabolism 2014 32 136–141. (https://doi.org/10.1007/s00774-013-0483-4)

    • Search Google Scholar
    • Export Citation
  • 120↑

    Henneicke H, Li J, Kim S, Gasparini SJ, Seibel MJ, Zhou H. Chronic mild stress causes bone loss via an osteoblast-specific glucocorticoid-dependent mechanism. Endocrinology 2017 158 1939–1950. (https://doi.org/10.1210/en.2016-1658)

    • Search Google Scholar
    • Export Citation
  • 121↑

    Henneicke H, Kim S, Swarbrick MM, Li J, Gasparini SJ, Thai J, Foong D, Cavanagh LL, Fong-Yee C & Karsten E et al.Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice. Molecular Metabolism 2020 42 101098. (https://doi.org/10.1016/j.molmet.2020.101098)

    • Search Google Scholar
    • Export Citation
  • 122↑

    Pierce JL, Ding KH, Xu J, Sharma AK, Yu K, Del Mazo Arbona N, Rodriguez-Santos Z, Bernard P, Bollag WB & Johnson MH et al.The glucocorticoid receptor in osteoprogenitors regulates bone mass and marrow fat. Journal of Endocrinology 2019 243 27– 42. (https://doi.org/10.1530/JOE-19-0230)

    • Search Google Scholar
    • Export Citation
  • 123↑

    Dirckx N, Tower RJ, Mercken EM, Vangoitsenhoven R, Moreau-Triby C, Breugelmans T, Nefyodova E, Cardoen R, Mathieu C & Van der Schueren B et al.Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. Journal of Clinical Investigation 2018 128 1087–1105. (https://doi.org/10.1172/JCI97794)

    • Search Google Scholar
    • Export Citation
  • 124↑

    Da Silva JA Sex hormones and glucocorticoids: interactions with the immune system. Annals of the New York Academy of Sciences 1999 876 102–117; discussion 117–108. (https://doi.org/10.1111/j.1749-6632.1999.tb07628.x)

    • Search Google Scholar
    • Export Citation
  • 125↑

    Della Torre S, Mitro N, Meda C, Lolli F, Pedretti S, Barcella M, Ottobrini L, Metzger D, Caruso D, Maggi A. Short-term fasting reveals amino acid metabolism as a major sex-discriminating factor in the liver. Cell Metabolism 2018 28 256–267.e5. (https://doi.org/10.1016/j.cmet.2018.05.021)

    • Search Google Scholar
    • Export Citation
  • 126↑

    Kautzky-Willer A, Handisurya A. Metabolic diseases and associated complications: sex and gender matter! European Journal of Clinical Investigation 2009 39 631–648. (https://doi.org/10.1111/j.1365-2362.2009.02161.x)

    • Search Google Scholar
    • Export Citation
  • 127↑

    Nishikawa S, Yasoshima A, Doi K, Nakayama H, Uetsuka K. Involvement of sex, strain and age factors in high fat diet-induced obesity in C57BL/6J and BALB/cA mice. Experimental Animals 2007 56 263–272. (https://doi.org/10.1538/expanim.56.263)

    • Search Google Scholar
    • Export Citation
  • 128↑

    Duma D, Collins JB, Chou JW, Cidlowski JA. Sexually dimorphic actions of glucocorticoids provide a link to inflammatory diseases with gender differences in prevalence. Science Signaling 2010 3 ra74. (https://doi.org/10.1126/scisignal.2001077)

    • Search Google Scholar
    • Export Citation
  • 129↑

    Quinn MA, Cidlowski JA. Endogenous hepatic glucocorticoid receptor signaling coordinates sex-biased inflammatory gene expression. FASEB Journal 2016 30 971–982. (https://doi.org/10.1096/fj.15-278309)

    • Search Google Scholar
    • Export Citation
  • 130↑

    Kaikaew K, Steenbergen J, van Dijk TH, Grefhorst A, Visser JA. Sex difference in corticosterone-induced insulin resistance in mice. Endocrinology 2019 160 2367–2387. (https://doi.org/10.1210/en.2019-00194)

    • Search Google Scholar
    • Export Citation
  • 131↑

    Yoshikawa N, Oda A, Yamazaki H, Yamamoto M, Kuribara-Souta A, Uehara M, Tanaka H. The influence of glucocorticoid receptor on sex differences of gene expression profile in skeletal muscle. Endocrine Research 2021 46 99–113. (https://doi.org/10.1080/07435800.2021.1884874)

    • Search Google Scholar
    • Export Citation
  • 132↑

    Solomon MB, Loftspring M, de Kloet AD, Ghosal S, Jankord R, Flak JN, Wulsin AC, Krause EG, Zhang R & Rice T et al.Neuroendocrine function After hypothalamic depletion of glucocorticoid receptors in male and female mice. Endocrinology 2015 156 2843–2853. (https://doi.org/10.1210/en.2015-1276)

    • Search Google Scholar
    • Export Citation
  • 133↑

    Faict D, De Moor P, Bouillon R, Heyns W, Heiniger HJ, Corrow D, Lesaffre E. Transcortin and vitamin D-binding protein levels in mouse serum. Journal of Endocrinology 1986 109 141–147. (https://doi.org/10.1677/joe.0.1090141)

    • Search Google Scholar
    • Export Citation
  • 134↑

    Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CR, Seckl JR. Regulation of 11 beta-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. Journal of Endocrinology 1993 139 27–35. (https://doi.org/10.1677/joe.0.1390027)

    • Search Google Scholar
    • Export Citation
  • 135↑

    Turner BB Sex difference in glucocorticoid binding in rat pituitary is estrogen dependent. Life Sciences 1990 46 1399–1406. (https://doi.org/10.1016/0024-3205(9090340-w)

    • Search Google Scholar
    • Export Citation
  • 136↑

    Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 2006 55 978–987. (https://doi.org/10.2337/diabetes.55.04.06.db05-1339)

    • Search Google Scholar
    • Export Citation
  • 137↑

    Zhang Y, Leung DY, Nordeen SK, Goleva E. Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation. Journal of Biological Chemistry 2009 284 24542–24552. (https://doi.org/10.1074/jbc.M109.021469)

    • Search Google Scholar
    • Export Citation
  • 138↑

    Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrine Reviews 2005 26 775–799. (https://doi.org/10.1210/er.2004-0025)

    • Search Google Scholar
    • Export Citation
  • 139↑

    Dakin RS, Walker BR, Seckl JR, Hadoke PW, Drake AJ. Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism. International Journal of Obesity 2015 39 1539–1547. (https://doi.org/10.1038/ijo.2015.102)

    • Search Google Scholar
    • Export Citation
  • 140↑

    Quinn MA, Xu X, Ronfani M, Cidlowski JA. Estrogen deficiency promotes hepatic steatosis via a glucocorticoid receptor-dependent mechanism in mice. Cell Reports 2018 22 2690–2701. (https://doi.org/10.1016/j.celrep.2018.02.041)

    • Search Google Scholar
    • Export Citation
  • 141↑

    Spaanderman DCE, Nixon M, Buurstede JC, Sips HC, Schilperoort M, Kuipers EN, Backer EA, Kooijman S, Rensen PCN & Homer NZM et al.Androgens modulate glucocorticoid receptor activity in adipose tissue and liver. Journal of Endocrinology 2018 240 51– 63. (https://doi.org/10.1530/JOE-18-0503)

    • Search Google Scholar
    • Export Citation
  • 142↑

    Vojnovic Milutinovic D, Teofilovic A, Velickovic N, Brkljacic J, Jelaca S, Djordjevic A, Macut D. Glucocorticoid signaling and lipid metabolism disturbances in the liver of rats treated with 5alpha-dihydrotestosterone in an animal model of polycystic ovary syndrome. Endocrine 2021 72 562–572. (https://doi.org/10.1007/s12020-020-02600-1)

    • Search Google Scholar
    • Export Citation
  • 143↑

    Zhao W, Pan J, Zhao Z, Wu Y, Bauman WA, Cardozo CP. Testosterone protects against dexamethasone-induced muscle atrophy, protein degradation and MAFbx upregulation. Journal of Steroid Biochemistry and Molecular Biology 2008 110 125–129. (https://doi.org/10.1016/j.jsbmb.2008.03.024)

    • Search Google Scholar
    • Export Citation
  • 144↑

    Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E & Logothetis C et al.Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 2013 155 1309–1322. (https://doi.org/10.1016/j.cell.2013.11.012)

    • Search Google Scholar
    • Export Citation
  • 145↑

    Kulik M, Bothe M, Kibar G, Fuchs A, Schone S, Prekovic S, Mayayo-Peralta I, Chung HR, Zwart W & Helsen C et al.Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites. Nucleic Acids Research 2021 49 3856–3875. (https://doi.org/10.1093/nar/gkab185)

    • Search Google Scholar
    • Export Citation
  • 146↑

    Bourke CH, Raees MQ, Malviya S, Bradburn CA, Binder EB, Neigh GN. Glucocorticoid sensitizers Bag1 and Ppid are regulated by adolescent stress in a sex-dependent manner. Psychoneuroendocrinology 2013 38 84–93. (https://doi.org/10.1016/j.psyneuen.2012.05.001)

    • Search Google Scholar
    • Export Citation
  • 147↑

    Hagendorf A, Koper JW, de Jong FH, Brinkmann AO, Lamberts SW, Feelders RA. Expression of the human glucocorticoid receptor splice variants alpha, beta, and P in peripheral blood mononuclear leukocytes in healthy controls and in patients with hyper- and hypocortisolism. Journal of Clinical Endocrinology and Metabolism 2005 90 6237–6243. (https://doi.org/10.1210/jc.2005-1042)

    • Search Google Scholar
    • Export Citation
  • 148↑

    Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2005 90 1929–1935. (https://doi.org/10.1210/jc.2004-1045)

    • Search Google Scholar
    • Export Citation

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     European Society of Endocrinology

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© European Society of Endocrinology 2021
Article Type:
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Received Date:
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01 Nov 2021
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  • Figure 1
    View in gallery
    Figure 1

    Glucocorticoids acutely increase energy availability via coordinated actions in multiple metabolic tissues. Endogenous glucocorticoid concentrations are regulated by the hypothalamus–pituitary–adrenal (HPA) axis (left panel). In addition to following a pronounced diurnal rhythm, glucocorticoid secretion increases in response to diverse stimuli such as acute stress or declining blood glucose concentrations. At high circulating/tissue levels, glucocorticoids activate pathways in numerous tissues critical for systemic energy homeostasis, including the liver, skeletal muscle, white adipose tissue (WAT), brown adipose tissue (BAT) and pancreas. These actions are primarily directed at increasing systemic glucose availability. Reduced glucose utilization by osteoblasts in bone may indirectly contribute to increased systemic glucose availability. Mobilization of energy stores in this way ensures a steady supply of glucose to the brain during times of increased demand.

  • Figure 2
    View in gallery
    Figure 2

    Chronic glucocorticoid excess promotes obesity, insulin resistance and dyslipidaemia via their effects on multiple metabolic tissues. Many of the dysmetabolic side effects of glucocorticoid exposure result directly from their acute effects to mobilize energy stores (see text). Chronically, however, the stimulatory effects of glucocorticoids on hepatic gluconeogenesis and lipogenesis lead to insulin resistance and steatosis, respectively. This is likely exacerbated by impaired hepatic insulin clearance. The increased secretion of TG-rich VLDL particles from the liver leads to dyslipidaemia and results in lipid accumulation in skeletal muscle and adipose tissues. Chronic glucocorticoid exposure also promotes insulin resistance in adipose tissue and skeletal muscle, further reducing glucose uptake by these tissues. Glucocorticoid-mediated suppression of anabolic processes in skeletal muscle and bone leads to muscle atrophy and osteoporosis, respectively. Visceral adipose tissue (VAT) is a particularly important site of action for glucocorticoids, due to the amplification of glucocorticoid actions by 11β-HSD1 in this depot and its close relationship with dyslipidaemia and hepatic insulin resistance (see text).

  • Figure 3
    View in gallery
    Figure 3

    Androgens and oestrogens exert both synergistic and antagonistic effects on glucocorticoid actions, and these effects are tissue-specific. Glucocorticoid-regulated metabolic pathways display a marked sexual dimorphism in mice. Compared to females, male mice have a more exaggerated hepatic inflammatory response to infection and are more susceptible to glucocorticoid-induced obesity, insulin resistance and dyslipidaemia. Recent studies have indicated that androgens exacerbate many of the dysmetabolic effects of chronic glucocorticoid exposure. Ectopic lipid accumulation in highly metabolically active tissues, such as skeletal muscle and BAT, interferes with insulin action and results from increased hepatic VLDL-TG export. In parallel, studies in mice have shown that oestrogens antagonize many of the dysmetabolic effects of glucocorticoid treatment, and may, in part, explain the protection from cardiovascular disease in premenopausal women. In mice, oestradiol protects against diet-induced obesity and insulin resistance, while the metabolic effects of chronic glucocorticoid exposure become more apparent following ovariectomy.

Figure 1

Glucocorticoids acutely increase energy availability via coordinated actions in multiple metabolic tissues. Endogenous glucocorticoid concentrations are regulated by the hypothalamus–pituitary–adrenal (HPA) axis (left panel). In addition to following a pronounced diurnal rhythm, glucocorticoid secretion increases in response to diverse stimuli such as acute stress or declining blood glucose concentrations. At high circulating/tissue levels, glucocorticoids activate pathways in numerous tissues critical for systemic energy homeostasis, including the liver, skeletal muscle, white adipose tissue (WAT), brown adipose tissue (BAT) and pancreas. These actions are primarily directed at increasing systemic glucose availability. Reduced glucose utilization by osteoblasts in bone may indirectly contribute to increased systemic glucose availability. Mobilization of energy stores in this way ensures a steady supply of glucose to the brain during times of increased demand.
Figure 2

Chronic glucocorticoid excess promotes obesity, insulin resistance and dyslipidaemia via their effects on multiple metabolic tissues. Many of the dysmetabolic side effects of glucocorticoid exposure result directly from their acute effects to mobilize energy stores (see text). Chronically, however, the stimulatory effects of glucocorticoids on hepatic gluconeogenesis and lipogenesis lead to insulin resistance and steatosis, respectively. This is likely exacerbated by impaired hepatic insulin clearance. The increased secretion of TG-rich VLDL particles from the liver leads to dyslipidaemia and results in lipid accumulation in skeletal muscle and adipose tissues. Chronic glucocorticoid exposure also promotes insulin resistance in adipose tissue and skeletal muscle, further reducing glucose uptake by these tissues. Glucocorticoid-mediated suppression of anabolic processes in skeletal muscle and bone leads to muscle atrophy and osteoporosis, respectively. Visceral adipose tissue (VAT) is a particularly important site of action for glucocorticoids, due to the amplification of glucocorticoid actions by 11β-HSD1 in this depot and its close relationship with dyslipidaemia and hepatic insulin resistance (see text).
Figure 3

Androgens and oestrogens exert both synergistic and antagonistic effects on glucocorticoid actions, and these effects are tissue-specific. Glucocorticoid-regulated metabolic pathways display a marked sexual dimorphism in mice. Compared to females, male mice have a more exaggerated hepatic inflammatory response to infection and are more susceptible to glucocorticoid-induced obesity, insulin resistance and dyslipidaemia. Recent studies have indicated that androgens exacerbate many of the dysmetabolic effects of chronic glucocorticoid exposure. Ectopic lipid accumulation in highly metabolically active tissues, such as skeletal muscle and BAT, interferes with insulin action and results from increased hepatic VLDL-TG export. In parallel, studies in mice have shown that oestrogens antagonize many of the dysmetabolic effects of glucocorticoid treatment, and may, in part, explain the protection from cardiovascular disease in premenopausal women. In mice, oestradiol protects against diet-induced obesity and insulin resistance, while the metabolic effects of chronic glucocorticoid exposure become more apparent following ovariectomy.
  • 1

    Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Reviews 2000 21 55–89. (https://doi.org/10.1210/edrv.21.1.0389)

    • Search Google Scholar
    • Export Citation
  • 2

    Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care and Research 2013 65 294–298. (https://doi.org/10.1002/acr.21796)

    • Search Google Scholar
    • Export Citation
  • 3

    Chapman K, Holmes M, Seckl J. 11beta-Hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiological Reviews 2013 93 1139–1206. (https://doi.org/10.1152/physrev.00020.2012)

    • Search Google Scholar
    • Export Citation
  • 4

    Buckingham JC Glucocorticoids: exemplars of multi-tasking. British Journal of Pharmacology 2006 147 (Supplement 1) S258–S268. (https://doi.org/10.1038/sj.bjp.0706456)

    • Search Google Scholar
    • Export Citation
  • 5

    Berdanier CD Role of glucocorticoids in the regulation of lipogenesis. FASEB Journal 1989 3 2179–2183. (https://doi.org/10.1096/fasebj.3.10.2666232)

    • Search Google Scholar
    • Export Citation
  • 6

    Perogamvros I, Ray DW, Trainer PJ. Regulation of cortisol bioavailability – effects on hormone measurement and action. Nature Reviews: Endocrinology 2012 8 717–727. (https://doi.org/10.1038/nrendo.2012.134)

    • Search Google Scholar
    • Export Citation
  • 7

    Timmermans S, Souffriau J, Libert C. A general introduction to glucocorticoid biology. Frontiers in Immunology 2019 10 1545. (https://doi.org/10.3389/fimmu.2019.01545)

    • Search Google Scholar
    • Export Citation
  • 8

    Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O’Shea JJ, Chrousos GP, Bornstein