Glucocorticoids In Adipose Tissue Research Articles

Inhibition of CXCR2 by Glucocorticoids in Adipose Tissue

Obesity-induced chronic adipose tissue inflammation is a significant risk factor for metabolic and cardiovascular disease (CVD), which affects 30.3 million adults in the United States. Interaction of adipocytes with hormonal, metabolic and immune systems play an integral role in the underlying pathophysiological mechanisms that leads to development of obesity-related complications. Despite this association, the mechanisms that coordinate the inflammatory mediators in causing adipose tissue inflammation are not well understood. Glucocorticoids (GC) are well known for their potent anti-inflammatory actions; however, the mechanism by which GC coordinate the inflammatory response of adipocytes are unknown. From our genome-wide microarray data derived from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice, we found that GR inactivation leads to a significant increase in pro-inflammatory gene in white adipose tissue (WAT). Additionally, WAT isolated from AdipoGRKO mice showed significant increase in immune cell infiltration, which correlates with our gene expression data. Among the top up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (Cxcr2), which is a powerful mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of Cxcr2 in adipocytes and suggested the contribution of Cxcr2 signaling in adipocyte development, its role in integrating adipose tissue inflammatory response is unknown. This led us to hypothesize that GR is critical to repress Cxcr2 gene expression and its pro inflammatory effects in adipocytes. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of Cxcr2 mRNA and protein levels. Furthermore, these effects are mediated by GR acting directly to repress Cxcr2 gene expression. Systemic administration of corticosterone significantly altered Cxcr2 expression in adipose tissue compared to untreated mice further supporting our results. Together our findings suggest that administration of glucocorticoids could inhibit adipose tissue inflammation and alleviate the comorbidities that arise from inflamed adipose tissue.

SUN-586 CXCR2 Repression by Glucocorticoids in Adipose Tissue

Obesity-induced type 2 diabetes (T2D) is a significant risk factor of cardiovascular disease (CVD), which affects 28.1 million adults in the United States. Adipose tissue chronic inflammation is one of the main factors that drive obesity-induced insulin resistance (IR) and T2D. Despite several studies that have shown a link between obesity, adipose tissue inflammation, and IR/T2D, the mechanisms underlying this association are not well understood. Synthetic glucocorticoids are widely used for their potent anti-inflammatory actions; however, their use is hampered due to off-target side effects. Glucocorticoids exert profound effects on adipose tissue, including the regulation of adipocyte metabolism and immune functions. However, whether their effects on adipose tissue are positive or negative it is still a controversial topic. Genome-wide microarray data obtained from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice showed that lack of GR leads to a significant increase in the expression of pro-inflammatory genes in white adipose tissue (WAT). Moreover, WAT isolated from adipoGRKO mice demonstrated significant increase in immune cell infiltration, which correlates with our gene expression data. Among the most up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (CXCR2), which is a critical mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of CXCR2 in adipocytes and suggested the contribution of CXCR2 signaling in adipocyte development, its role in obesity-driven adipose tissue inflammation is unknown. This led us to hypothesize that adipocyte specific administration of glucocorticoids can reduce obesity-induced adipocyte inflammation by inhibiting CXCR2 gene transcription and signaling. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of CXCR2 mRNA and protein levels. Correlating with these results, Dex treatment significantly inhibited macrophage migration to adipocytes in a mechanism dependent on GR activation and repression of CXCR2. Furthermore, these results were recapitulated in vivo. Together our findings suggest that local delivery of glucocorticoids to adipose tissue could ameliorate inflammation and reduce the risk of developing IR and T2D.

SAT-591 Lack of Adipose-Specific Hexose-6-Phosphate Dehydrogenase Improves Fat Metabolic Phenotype and Increases Insulin Sensitivity in Mice

Lack of adipose-specific hexose-6-phosphate dehydrogenase improves fat metabolic phenotype and increases insulin sensitivity in mice.ABSTRACTIncreased glucocorticoids (GCs) production in adipose tissue promotes the development of visceral obesity and the MS. The action of GCs in adipose tissue is tightly regulated by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH). However, the phenotypic consequences of reduction of fat-specific GC action caused by inactivation of H6PDH specifically in adipose tissue have not been explored. To better understand the physiological effects of adipose H6PDH, we generated a tissue-specific animal model of adipocyte-specific H6PDH deletion under the control of the murine adipocyte-specific adiponectin promoter (H6PDHAcKO mice). H6PDHAcKO mice exhibited complete absence of H6PDH expression and decreased GC production with reduction of 11β-HSD1 in adipose tissue. These mice had decreased abdominal fat mass with decreased adipose lipogenic gene expression associated with reduction of their transcription factor C/EBPs mRNA levels. Moreover, H6PDHAcKO mice also decreased adipose lipolysis and reduced plasma FFA levels. In addition, H6PDHAcKO mice decreased fasting glucose levels and increase tolerance to glucose and insulin. These data suggest that H6PDHAcKO mice may provide a good model for study the potential contribution of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo.

JNK and IKKβ phosphorylation is reduced by glucocorticoids in adipose tissue from insulin-resistant rats

ObjectivesPeripheral insulin resistance (IR) is one of the main side effects caused by glucocorticoid (GC)-based therapies, and the molecular mechanisms of GC-induced IR are not yet fully elucidated. Thus, we aimed to investigate the effects of dexamethasone treatment on the main components of insulin and inflammatory signaling in the adipose tissue of rats. Materials/methodsMale Wistar rats received daily injections of dexamethasone (1mg/kg body weight (b.w.), intraperitoneally (i.p.)) for 5 days (DEX), whereas control rats received saline (CTL). The metabolic status was investigated, and the epididymal fat fragments were collected for lipolysis and western blot analyses. ResultsThe DEX rats became hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, compared with the CTL rats (P<0.05). The basal glycerol release in the fat fragments was 1.5-fold higher in the DEX rats (P<0.05). The phosphorylation of protein kinase B (PKB) at ser473 decreased by 44%, whereas, the phosphorylation of insulin receptor substrate (IRS)-1 at ser307 increased by 93% in the adipose tissue of the DEX rats after an oral bolus of glucose (P<0.05). The basal phosphorylation of c-jun-N-terminal kinase (JNK) and inhibitor of nuclear factor kappa-B (IKKβ) proteins was reduced by 46% and 58%, respectively, in the adipose tissue of the DEX rats (P<0.05). This was paralleled with a significant reduction (47%) in the glucocorticoid receptor (GR) protein content in the adipose tissue of the DEX rats (P<0.05). ConclusionThe insulin-resistant status of rats induced by dexamethasone administration have PKB and IRS-1 activity attenuated in epididymal fat without increases in the phosphorylation of the proinflammatory signals JNK and IKKβ.

Adipose Tissue and Adrenal Glands: Novel Pathophysiological Mechanisms and Clinical Applications

Hormones produced by the adrenal glands and adipose tissues have important roles in normal physiology and are altered in many disease states. Obesity is associated with changes in adrenal function, including increase in adrenal medullary catecholamine output, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, elevations in circulating aldosterone together with changes in adipose tissue glucocorticoid metabolism, and enhanced adipocyte mineralocorticoid receptor activity. It is unknown whether these changes in adrenal endocrine function are in part responsible for the pathogenesis of obesity and related comorbidities or represent an adaptive response. In turn, adipose tissue hormones or “adipokines” have direct effects on the adrenal glands and interact with adrenal hormones at several levels. Here we review the emerging evidence supporting the existence of “cross talk” between the adrenal gland and adipose tissue, focusing on the relevance and roles of their respective hormones in health and disease states including obesity, metabolic syndrome, and primary disorders of the adrenals.

Vitamin A decreases pre-receptor amplification of glucocorticoids in obesity: study on the effect of vitamin A on 11beta-hydroxysteroid dehydrogenase type 1 activity in liver and visceral fat of WNIN/Ob obese rats

Background11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and its inhibition ameliorates obesity and metabolic syndrome. So far, no studies have reported the effect of dietary vitamin A on 11β-HSD1 activity in visceral fat and liver under normal and obese conditions. Here, we studied the effect of chronic feeding of vitamin A-enriched diet (129 mg/kg diet) on 11β-HSD1 activity in liver and visceral fat of WNIN/Ob lean and obese rats.MethodsMale, 5-month-old, lean and obese rats of WNIN/Ob strain (n = 16 for each phenotype) were divided into two subgroups consisting of 8 rats of each phenotype. Control groups received stock diet containing 2.6 mg vitamin A/kg diet, where as experimental groups received diet containing 129 mg vitamin A/Kg diet for 20 weeks. Food and water were provided ad libitum. At the end of the experiment, tissues were collected and 11β-HSD1 activity was assayed in liver and visceral fat.ResultsVitamin A supplementation significantly decreased body weight, visceral fat mass and 11β-HSD1 activity in visceral fat of WNIN/Ob obese rats. Hepatic 11β-HSD1 activity and gene expression were significantly reduced by vitamin A supplementation in both the phenotypes. CCAAT/enhancer binding protein α (C/EBPα), the main transcription factor essential for the expression of 11β-HSD1, decreased in liver of vitamin A fed-obese rats, but not in lean rats. Liver × receptor α (LXRα), a nuclear transcription factor which is known to downregulate 11β-HSD1 gene expression was significantly increased by vitamin A supplementation in both the phenotypes.ConclusionsThis study suggests that chronic consumption of vitamin A-enriched diet decreases 11β-HSD1 activity in liver and visceral fat of WNIN/Ob obese rats. Decreased 11β-HSD1 activity by vitamin A may result in decreased levels of active glucocorticoids in adipose tissue and possibly contribute to visceral fat loss in these obese rats. Studying the role of various nutrients on the regulation of 11β-HSD1 activity and expression will help in the evolving of dietary approaches to treat obesity and insulin resistance.

Dietary fatty acid composition alters 11β-hydroxysteroid dehydrogenase type 1 gene expression in rat retroperitoneal white adipose tissue

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid action by converting inactive glucocorticoids to their active forms in vivo. Adipose-specific overexpression of 11β-HSD1 induces metabolic syndrome in mice, whereas 11β-HSD1 null mice are resistant to it. Dietary trans and saturated fatty acids (TFAs and SFAs) are involved in the development of metabolic syndrome, whereas polyunsaturated fatty acids (PUFA) offer protection against this. Here, we report the effects of chronic feeding of different diets containing vanaspati (TFA rich), palm oil (SFA rich) and sunflower oil (PUFA rich) at 10%level on 11β-HSD1 gene expression in rat retroperitoneal adipose tissue. 11β-HSD1 gene expression was significantly higher in TFA rich diet-fed rats compared to SFA rich diet-fed rats, which in turn was significantly higher than PUFA rich diet-fed rats. Similar trend was observed in the expression of CCAAT-enhancer binding protein-α (C/EBP-α), the main transcription factor required for the expression of 11β-HSD1. We propose that TFAs and SFAs increase local amplification of glucocorticoid action in adipose tissue by upregulating 11β-HSD1 by altering C/EBP-α-gene expression. The increased levels of glucocorticoids in adipose tissue may lead to development of obesity and insulin resistance, thereby increasing the risk of developing metabolic syndrome.

Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue

Adipose tissue glucocorticoid action relies on local enzymatic interconversion and glucocorticoid receptor (GR) availability. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), 2 (11β-HSD2) and hexose-6-phosphate dehydrogenase (H6PDH) are likely involved in glucocorticoid activation/inactivation within adipose tissue. We examined adipose tissue mRNA expression of genes related to glucocorticoid action and their association with total and visceral adiposity. Messenger RNA was measured in paired subcutaneous and omental fat samples obtained from 56 women (age: 47.3 ± 4.8 years, BMI: 27.1 ± 5.2 kg/m 2) undergoing gynaecological surgery. Expression levels of 11β-HSD2, H6PDH and GRα were higher in omental adipose tissue while 11β-HSD1 expression was similar between fat compartments. Subcutaneous and omental 11β-HSD1 mRNA abundances were positively associated with total and visceral adiposity whereas omental H6PDH mRNA abundance was negatively associated with these measures. Only omental 11β-HSD1 mRNA expression remained significantly associated with visceral adipose tissue area following statistical adjustment for fat mass, age and menopausal status. Omental 11β-HSD1 mRNA expression explained 19.1% of the variance in visceral adipose tissue area. Omental fat tissue 11β-HSD-1 protein and cortisol levels were higher in visceral obese women, supporting findings obtained with 11β-HSD-1 mRNA. These results suggest that among the transcripts examined only omental 11β-HSD1 is independently associated with visceral obesity in women.

Endurance exercise training increases adipose tissue glucocorticoid exposure: adaptations that facilitate lipolysis

Glucocorticoids (GCs) have long been thought to be lipolytic in nature. Recently, however, increased exposure to GCs in insulin-sensitive tissues has been associated with lipid accumulation and metabolic complications, regardless of plasma concentrations. Intracellular GC action is determined by both 11- β hydroxysteroid dehydrogenase type 1 (11 βHSD1) and the GC receptor (GR). We hypothesized that exercise training would increase 11 βHSD1 and GR protein in adipose tissue, resulting in increased lipolysis. To test the effects of exercise on adipose tissue GR and 11 βHSD1 protein, 2 sets of hamsters were trained for 6 weeks: young, diet-induced obese animals and older, overweight animals. Young (6 week old) hamsters, fructose-fed to induce an obese phenotype, and older (6 month old) hamsters were randomly divided into exercising and sedentary groups. Exercise training decreased adipose tissue mass in both fructose-fed and older hamsters. In addition, exercise training increased 11 βHSD1 (31.5% ± 15% and 20.0% ± 7%, fructose-fed and older, respectively) and GR (45.6% ± 14% and 61.1% ± 27%, fructose-fed and older, respectively) protein expression in the perirenal adipose depot and increased 11 βHSD1 (16.7% ± 7%, P = .09) and GR (47.4% ± 19%, P < .05) in the subcutaneous adipose depot of the older hamsters. To determine the metabolic effect of increased GC exposure in adipocytes, 3T3-L1 adipocytes were treated with corticosterone for 24 hours; and measures of lipolytic rates were conducted. Low concentrations of GCs (0.01-0.1 μmol/L) increased GR (44.1% ± 18%, P < .05) and 11 βHSD1 (95.3% ± 24%) protein expression, as well as lipolytic rates (34.6% ± 6%) as measured by glycerol release. The increased lipolysis was blocked by RU486, a GR antagonist, suggesting that the elevated lipolysis was a direct result of GC action. These results suggest that exercise training amplifies the activity of GCs in adipose tissue of overweight animals through alterations in 11 βHSD1 and GR despite differences in age and amounts of adiposity. In vitro, GCs are capable of increasing lipolysis, but depend upon the presence of GR. We propose that GCs play a significant role in changing the phenotype of adipose tissue during exercise training, resulting in decreased fat mass.

The Skinny on Fat: How Oxysterols May Regulate Functional Glucocorticoids in Adipose Tissue

The Skinny on Fat: How Oxysterols May Regulate Functional Glucocorticoids in Adipose Tissue

7-Oxysterols Modulate Glucocorticoid Activity in Adipocytes through Competition for 11β-Hydroxysteroid Dehydrogenase Type

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11beta-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7beta-HC). Here, we report that 11beta-HSD1 catalyzes the reduction of 7KC to 7beta-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7beta-HC. Approximately 73% of added 7KC was reduced to 7beta-HC within 24 h; this conversion was prevented by selective inhibition of 11beta-HSD1. Oxysterol and glucocorticoid conversion by 11beta-HSD1 was competitive and occurred with a physiologically relevant IC(50) range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11beta-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7beta-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7beta-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11beta-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11beta-HSD1. Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.

Postnatal Programming of Glucocorticoid Metabolism in Rats Modulates High-Fat Diet–Induced Regulation of Visceral Adipose Tissue Glucocorticoid Exposure and Sensitivity and Adiponectin and Proinflammatory Adipokines Gene Expression in Adulthood

Alterations of the perinatal environment, which lead to increased prevalence of the metabolic syndrome in adulthood, program an upregulation of systemic and/or adipose tissue glucocorticoid metabolism (11 beta-hydroxysteroid dehydrogenase type 1 [11 beta-HSD-1]-induced corticosterone reactivation). We hypothesized that postnatal programming could modulate high-fat diet-induced adipose tissue dysregulation in adulthood. We compared the effects of chronic (since weaning) high- or low-fat diet in postnatally normofed (control) or overfed (programmed) rats. Postnatal programming accentuated high-fat diet-induced overweight, insulin resistance, glucose intolerance, and decrease in circulating and epididymal adipose tissue adiponectin. Neither manipulation altered liver function. Postnatal programming or high-fat diet increased systemic corticosterone production, which was not further modified when both manipulations were associated. Postnatal programming suppressed high-fat diet-induced decrease in mesenteric adipose tissue (MAT) glucocorticoid sensitivity and triggered high-fat diet-induced increase in MAT glucocorticoid exposure, subsequent to enhanced MAT 11 beta-HSD-1 gene expression. MAT tumor necrosis factor (TNF)-alpha, TNF-receptor 1, interleukin (IL)-6, resistin, and plasminogen activator inhibitor-1 mRNAs were not changed by high-fat feeding in control rats and showed a large increase in programmed animals, with this effect further enhanced by high-fat diet for TNF-alpha and IL-6. Our data show for the first time that postnatal manipulation programs high-fat diet-induced upregulation of MAT glucocorticoid exposure, sensitivity, and inflammatory status and therefore reveal the pivotal role of the environment during the perinatal period on the development of diet-induced adipose tissue dysregulation in adulthood. They also urge the need for clinical trials with specific 11 beta-HSD-1 inhibitors.

Adrenal steroids and the metabolic syndrome

The many similarities between the metabolic syndrome and Cushing's syndrome led to the hypothesis that excess glucocorticoids (GC) are part of the pathogenesis linking their features. We review recent work that confirms the initial similarities (obesity, glucose intolerance, hypertension, and hyperlipidemia) and extends them to associated features of both syndromes (osteopenia, hypogonadism, leukocytosis, depression, and muscle weakness). Recent studies report that these features also occur in subclinical Cushing's syndrome, hypercortisolemic depression, and the transgenic overexpression of 11beta-hydoxysteroid dehydrogenase type 1 (11beta-HSD1) in mouse models of excess GC in adipose tissue. Reducing excess GC--in the clinical syndromes and in the mouse model-reverses many of these features. Because local tissue excess GC may have a central role in the pathogenesis of the metabolic syndrome, selective 11beta-HSD1 inhibitors are under active development by several pharmaceutical companies.

Prenatal nutritional programming of central obesity and the metabolic syndrome: role of adipose tissue glucocorticoid metabolism

central obesity, with respect to its continuously growing frequency and the severity of its complications, is now becoming a major public health concern. Central obesity is part of the metabolic syndrome, which associates insulin resistance, high blood pressure, and dyslipidemia, leading to

Effect of High-fat Diet on KKAyandob/obMouse Liver and Adipose Tissue Corticosterone and 11-dehydrocorticosterone Concentrations

The present study was performed to compare glucocorticoid levels in obese KKA (y) and ob/ob mice with those in normal C57BL/6J mice, and the effect of high-fat diet on glucocorticoids in KKA (y) and ob/ob mice. Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured. The KKA (y) and ob/ob mice displayed elevated serum corticosterone levels compared to normal mice, 2.0 to 2.8-fold in KKA (y), and 11 to 16-fold in ob/ob mice. Liver corticosterone levels were 3.0 to 5.1 and 6.2 to 8.1-fold, and 11-dehydrocorticosterone levels were 3.4 to 3.6 and 6.7 to 8.2-fold higher in KKA (y) and ob/ob mice compared to normal mice. Mesenteric adipose tissue corticosterone levels were 2.7 to 4.2-fold higher, and 11-dehydrocorticosterone levels were 2 to 4-fold higher in ob/ob than in KKA (y) mice. Epididymal adipose tissue corticosterone levels were 3.0 to 6.2-fold higher, and 11-dehydrocorticosterone levels were 1.8 to 2.0-fold higher in ob/ob than in KKA (y) mice. Circulating, hepatic, and mesenteric and epididymal adipose tissue glucocorticoid concentrations were low in the normal C57BL/6J mouse, high in the ob/ob mouse, and intermediate in the KKA (y) mouse. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA levels were doubled in ob/ ob compared to KKA (y) mice in all three tissues. Glucocorticoid concentrations correlated with 11beta-HSD1 mRNA levels. High-fat diet had no effect on the tissue glucocorticoid concentrations.

Postnatal Diet-Induced Obesity in Rats Upregulates Systemic and Adipose Tissue Glucocorticoid Metabolism During Development and in Adulthood

In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11beta-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes.

Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue.

The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action. 11beta-HSD1 is elevated in adipose tissue in obese humans and rodents, suggesting that adipose tissue glucocorticoid excess may explain the conundrum. Indeed, transgenic mice overexpressing 11beta-HSD1 in adipose tissue faithfully replicate the metabolic syndrome. Conversely, 11beta-HSD1(-/-) mice resist the metabolic consequences of stress and high-fat feeding via insulin sensitisation and other advantageous effects in the liver and adipose tissue. Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome.

Aromatization of steroids in peripheral tissues

The action of glucocorticoids on aromatase activity in human adipose tissue has been investigated. Oestrogen production was increased in tissue maintained in the presence of dexamethasone and Cortisol. Dexamethasone was effective at concentrations as low as 1 nmol/l. In contrast, over the 40 h incubation period, cortisol was only effective at concentrations in excess of 500 nmol/l, although after conditions of prolonged incubation, induction of aromatase activity was measurable using cortisol concentrations as low as 28 nmol/l. There were apparent variations in both basal levels of aromatase activity and in response to glucocorticoids in adipose tissue taken from various sites within the body.