Role Of 11β-HSD1 Research Articles

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11β-HSD1 and 11β-HSD2 in Aspect of Carcinogenesis Prevention.

Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11β-hydroxysteroid dehydrogenase (11β-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11β-HSD1 and 11β-HSD2 as autocrine factors of tumor cell proliferation and differentiation. Herein, we report the synthesis of novel 2-(isopropylamino)thiazol-4(5H)-one derivatives and their inhibitory activity for 11β-HSD1 and 11β-HSD2. The derivative containing the spiro system of thiazole and cyclohexane rings shows the highest degree of 11β-HSD1 inhibition (54.53% at 10 µM) and is the most selective inhibitor of this enzyme among the tested compounds. In turn, derivatives containing ethyl and n-propyl group at C-5 of thiazole ring inhibit the activity of 11β-HSD2 to a high degree (47.08 and 54.59% at 10 µM respectively) and are completely selective. Inhibition of the activity of these enzymes may have a significant impact on the process of formation and course of tumors. Therefore, these compounds can be considered as potential pharmaceuticals supporting anti-cancer therapy.

The ratio of 11β-hydroxysteroid dehydrogenase 1/11β-hydroxysteroid dehydrogenase 2 predicts glucocorticoid response in nasal polyps.

Glucocorticoids are the first-line medical treatment for chronic rhinosinusitis with nasal polyps (CRSwNP), whose local metabolism is catalyzed by 11β-HSD1 and 11β-HSD2. This study investigates the role of 11β-HSD1 and 11β-HSD2 on the glucocorticoid response of CRSwNP patients and the pathogenic mechanism of these polyps. Forty-three adult CRSwNP patients were enrolled in this study. We evaluated the endoscopic scores by a nasal polyp grading system before and after treatment. We estimated the response to glucocorticoids by the total endoscopic scores. The logistic regression models and inflammatory characteristic curves were conducted to explore the prediction of the response to glucocorticoid in CRSwNP. The expression of 11β-HSD1 and 11β-HSD2 on human sinonasal epithelial cells (HSECS) was measured under the stimulation of toll-like receptor agonists and dexamethasone. The endoscopic scores in the CRSwNP group declined, the expression of 11β-HSD1/11β-HSD2 increased (r = 0.5276, P = 0.0011), and the cutoff value of the ratio of 11β-HSD1/11β-HSD2 was 0.4654 (sensitivity 79.17%, specificity 88.89%). Dexamethasone induced a decrease in the ratio of 11β-HSD1/11β-HSD2 (P = 0.049) by the stimulation of PGN-BS. We found a strong correlation between the response to glucocorticoids and the ratio of 11β-HSD1/11β-HSD2, which could be used as a marker in predicting the level of tissue response to glucocorticoid therapy in CRSwNP. In addition, PGN-BS could also be a therapeutic target, as it is the negative factor that will decrease the sensitivity of glucocorticoids by reducing the ratio of 11β-HSD1/11β-HSD2.

Acute anti-obesity effects of intracerebroventricular 11β-HSD1 inhibitor administration in diet-induced obese mice.

The hypothalamus is the regulatory centre of both appetite and energy balance and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 β hydroxysteroid dehydrogenase type1 (11β-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, the link between the role of 11β-HSD1 in the hypothalamus and obesity has yet to be determined. In the present study, embryonal primary hypothalamic neurones and high-fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11β-HSD1 inhibitors both in vitro and in vivo. In hypothalamic neurones, carbenoxolone (a non selecitve 11β-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, i.c.v. administration of carbenoxolone or KR67500 (nonselective and selective 11β-HSD1 inhibitors, respectively) was associated with less weight gain compared to control mice for 24hours after treatment, presumably by reducing food intake. Furthermore, glucose regulated protein (Grp78), spliced X-box binding protein (Xbp-1s), c/EBP homologous protein (chop) and ER DnaJ homologue protein (Erdj4) expression was decreased in the hypothalami of mice administrated 11β-HSD1 inhibitors compared to controls. Conversely, the phosphorylation of protein kinase B (PKB/Akt), signal transducer and activator of transcription 3 (Stat3), mitogen-activated protein kinase (MAPK/ERK) and S6 kinase1 (S6K1) in the hypothalamus was induced more in mice treated using the same regimes. In conclusion, acute 11β-HSD1 inhibition in the hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1 (mTORC1) signalling.

11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI.

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1−/−) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in ‘host’ myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1−/− mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1−/− mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5. These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

11β-Hydroxysteroid Dehydrogenase Type 1(11β-HSD1) mediates insulin resistance through JNK activation in adipocytes.

Glucocorticoids are used to treat a number of human diseases but often lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. Despite the known role of 11β-HSD1 and active glucocorticoid in causing insulin resistance, the molecular mechanisms by which insulin resistance is induced remain elusive. The aim of this study is to identify these mechanisms in high fat diet (HFD) experimental models. Mice on a HFD were treated with 11β-HSD1 inhibitor as well as a JNK inhibitor. We then treated 3T3-L1-derived adipocytes with prednisone, a synthetic glucocorticoid, and cells with 11β-HSD1 overexpression to study insulin resistance. Our results show that 11β-HSD1 and JNK inhibition mitigated insulin resistance in HFD mice. Prednisone stimulation or overexpression of 11β-HSD1 also caused JNK activation in cultured adipocytes. Inhibition of 11β-HSD1 blocked the activation of JNK in adipose tissue of HFD mice as well as in cultured adipocytes. Furthermore, prednisone significantly impaired the insulin signaling pathway, and these effects were reversed by 11β-HSD1 and JNK inhibition. Our study demonstrates that glucocorticoid-induced insulin resistance was dependent on 11β-HSD1, resulting in the critical activation of JNK signaling in adipocytes.

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesity-associated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissue-specific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis

11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) plays an important role in inflammation. However, the role of 11β-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11β-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT-2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-κB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-κB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways. 11β-HSD1 inhibition may represent a potential therapeutic target for RA patients.

Identification of microRNAs as a potential novel regulatory mechanism in HSD11B1 expression

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1, gene HSD11B1) converts glucocorticoid receptor-inert cortisone to receptor-active cortisol. Multiple evidence supports a causal role for 11β-HSD1 in the current obesity epidemic. In obese, HSD11B1 expression is increased in adipose tissue but typically decreased in liver, and the underlying tissue-specific mechanisms are largely unknown. In this context, we investigated a potential role of microRNAs (miRNAs). We used several miRNA target prediction tools to identify possible candidates and a publicly available miRNA expression atlas to further select candidates expressed in hepatocytes. Using a dual luciferase reporter assay, we identified three potential miRNAs, hsa-miR-340, -561 and -579, as potential negative regulators of HSD11B1 expression. Disruption of the corresponding microRNA response elements abolished repression of luciferase activity for hsa-miR-561 and -579, but not for hsa-miR-340. Furthermore, levels of firefly luciferase mRNA were not changed by miR-561 and -579, indicating a mechanism based on translational repression rather than mRNA degradation. Finally, we were able to detect both, miR-561 and -579, in human total liver RNA by reverse-transcription-polymerase chain reaction (RT-PCR). According to the presented results, miR-561 and -579 are likely to be involved in the tissue-specific regulation of HSD11B1 expression. Moreover, literature findings and a pathway enrichment analysis support a potential role of these two miRNAs in glucocorticoid metabolism and signalling and associated diseases.

Osobennosti zhirovogo obmena pri bolezniItsenko-Kushinga

The reported clinical case represents an example of characteristic traits in lipid metabolism and fat tissue deposition in hypercorticosolism. Probable causes for fat mass expansion in glucocorticosteroid excess, its distinctive cushingoid distribution, role of 11β-HSD1 and glucocorticoid receptors and reversibility of specific abnormalities after correction of hypercortisolism are discussed in the context of physiological and pathological aspects of glucocorticosteroid action.

11β-Hydroxysteroid Dehydrogenase Type 1 and Its Role in the Hypothalamus-Pituitary-Adrenal Axis, Metabolic Syndrome, and Inflammation

ABSTRACT Context 11β-Hydroxysteroid dehydrogenase (11β-HSD) enzymes are now appreciated to be important regulators of hormone action at a tissue level. 11β-HSD1 is widely expressed and increases glucocorticoid action through its unique ability to convert inactive glucocorticoids (cortisone in man, 11-dehydrocorticosterone in rodents) to their active forms (cortisol and corticosterone, respectively). The enzyme has roles in the normal hypothalamus-pituitary-adrenal (HPA) axis, has been implicated in metabolic syndrome, and may modulate various aspects of the immune response. Evidence Acquisition A review of published, peer-reviewed medical literature (1990 to June 2009) on the physiology and pathophysiology of 11β-HSD1 was performed with an emphasis on HPA axis consequences, the metabolic syndrome, and the inflammatory response. Evidence Synthesis Studies of patients with genetic defects in 11β-HSD1 action show abnormal HPA axis responses with hyperandrogenism being a major consequence. The mechanisms underlying these abnormalities have been explored in mouse models with targeted deletion of components of the 11β-HSD1 system. A range of experimental studies emphasize the role of 11β-HSD1 in the metabolic syndrome and the potential for treatment with chemical inhibitors. An emerging area is the role of 11β-HSD1 in the inflammatory response. Conclusions 11β-HSD1 activity is an important component of the HPA axis and contributes to the metabolic syndrome and the normal immune response. Ongoing clinical observations and the development of selective inhibitors will further clarify the role of 11β-HSD1 in these areas.

Suppression of 11β-hydroxysteroid dehydrogenase type 1 with RNA interference substantially attenuates 3T3-L1 adipogenesis

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regulates the local level of glucocorticoids, has been suggested to be involved in the development of obesity. A definitive functional role for 11beta-HSD1 in adipogenesis, however, remains to be established. We developed 3T3-L1 cell lines stably transfected with a small hairpin RNA (shRNA) targeting 11beta-HSD1. A shRNA containing two nucleotide substitutions was used as a control. Silencing of 11beta-HSD1 substantially attenuated the accumulation of lipid droplets and the expression of adipogenesis marker genes, which was induced by a mixture containing either corticosterone or dexamethasone. Silencing of 11beta-HSD1 increased the concentration of 11-dehydrocorticosterone in the culture supernatant but did not significantly affect the levels of corticosterone or dexamethasone. Translocation of glucocorticoid receptors to the nucleus in response to glucocorticoids was significantly attenuated by silencing 11beta-HSD1. The number of cells entering the S phase of the cell cycle following the induction of adipogenesis was significantly reduced by silencing 11beta-HSD1. 11beta-HSD1 shRNA delivered by lentiviral vectors after the induction of differentiation, however, did not affect the progression of adipogenesis. These results indicate that 11beta-HSD1 plays a significant functional role in the initiation of 3T3-L1 adipogenesis and provide new mechanistic insights into the role of 11beta-HSD1 in the development of obesity and related diseases.

Distinct features of dehydrocorticosterone reduction into corticosterone in the liver and duodenum of the domestic fowl ( Gallus gallus domesticus)

The mammalian 11-β hydroxysteroid dehydrogenase type 1 (11βHSD1) reduces glucocorticoids (GC) at C11 from the 11-keto-GC nonactive form to the 11-hydroxy-GC active form, an action essential for survival. Whereas GC metabolism at C11 and the role of 11βHSD1 are studied extensively in mammals, information about these in birds is scattered. Herein, we report the GC bidirectional metabolism in chickens. In hens’ liver and duodenal mucosa, 11βHSD1-like mRNA expression was detected; and 11βHSD1-like immunoreactivity was found linked to membranes of hepatocytes and duodenal enterocytes. With either NADH or NADPH, the membranal fraction of liver and duodenal mucosa converted dehydrocorticosterone (A) into corticosterone (B) with K m (1.1–8.7 μM) and V max (10–40 pmol/mg protein/min) values similar to those reported for mammalian 11βHSD1. In the presence of NADP + or NAD +, these membranal fractions oxidized B into A. With either NADPH or NADH, the cytosol of chicken liver and duodenal mucosa reduced A into B ( K m of 1.1 – 2.3 μM and V max of 260–960 pmol/mg protein/min). These cytosolic fractions did not convert any amount of B into A when incubated with either NADP + or NAD +. This may suggest that chicken liver and duodenal mucosa express 11βHSD1 that is a membrane-bound oxoreductase which uses both NADPH/NADP + and NADH/NAD + as cosubstrates. The substantial reduction of A into B (but no conversion of B into A) found in the cytosol is most likely executed by a unidirectional soluble reductase, different than 11βHSD1.

Dehydroepiandrosterone 7α-hydroxylation in human tissues: Possible interference with type 1 11β-hydroxysteroid dehydrogenase-mediated processes

Dehydroepiandrosterone (DHEA) is 7α-hydroxylated by the cytochome P450 7B1 (CYP7B1) in the human brain and liver. This produces 7α-hydroxy-DHEA that is a substrate for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which exists in the same tissues and carries out the inter-conversion of 7α- and 7β-hydroxy-DHEA through a 7-oxo-intermediary. Since the role of 11β-HSD1 is to transform the inactive cortisone into active cortisol, its competitive inhibition by 7α-hydroxy-DHEA may support the paradigm of native anti-glucocorticoid arising from DHEA. Therefore, our objective was to use human tissues to assess the presences of both CYP7B1 and 11β-HSD1. Human skin was selected then and used to test its ability to produce 7α-hydroxy-DHEA, and to test the interference of 7α- and 7β-hydroxy-DHEA and 7-oxo-DHEA with the 11β-HSD1-mediated oxidoreduction of cortisol and cortisone. Immuno-histochemical studies showed the presence of both CYP7B1 and 11β-HSD1 in the liver, skin and tonsils. DHEA was readily 7α-hydroxylated when incubated using skin slices. A S9 fraction of dermal homogenates containing the 11β-HSD1 carried out the oxidoreduction of cortisol and cortisone. Inhibition of the cortisol oxidation by 7α-hydroxy-DHEA and 7β-hydroxy-DHEA was competitive with a K i at 1.85 ± 0.495 and 0.255 ± 0.005 μM, respectively. Inhibition of cortisone reduction by 7-oxo-DHEA was of a mixed type with a K i at 1.13 ± 0.15 μM. These findings may support the previously proposed native anti-glucocorticoid paradigm and suggest that the 7α-hydroxy-DHEA production is a key for the fine tuning of glucocorticoid levels in tissues.

Augmentation of 11β-hydroxysteroid dehydrogenase type 1 in LPS-activated J774.1 macrophages – Role of 11β-HSD1 in pro-inflammatory properties in macrophages

Macrophage infiltration in obese adipose tissue provokes local inflammation and insulin resistance. Evidence has accumulated that activation of 11β-HSD1 in adipocytes is critically involved in dysfunction of adipose tissue. However, the potential role of 11β-HSD1 in macrophages still remains unclear. We here demonstrate that a murine macrophage cell line, J774.1 cells expressed 11β-HSD1 mRNA and reductase activity, both of which were augmented by lipopolysaccharide (LPS)-induced cell activation. Three kinds of pharmacological inhibition of 11β-HSD1 in LPS-treated macrophages significantly suppressed the expression and secretion of interleukin 1β, tumor necrosis factor α or monocyte chemoattractant protein 1, thereby highlighting a novel role of 11β-HSD1 in pro-inflammatory properties of activated macrophages.

Inhibition of 11β-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role?

The metabolic syndrome (syndrome X) is a cluster of risk factors and a common cause of cardiovascular disease in humans. Although the underlying mechanism for metabolic syndrome is still poorly understood, recent clinical data and studies with transgenic animals implicate elevated intracellular glucocorticoid tone in the etiology of metabolic syndrome. Development of selective inhibitors of 11β-hydroxysteroid dehydrogenase (11β-HSD)-1 and their use in rodent animal disease models encompassing several aspects of metabolic syndrome indicate the possibility of therapeutic intervention. This review will focus on recent advances in our understanding of the role of 11β-HSD1 in metabolic disorders and other disease processes.

Healing hearts and fighting fat

Arresting intracellular hormone production helps keep arteries clear, according to a study on page 517. Hermanowski-Vosatka and colleagues describe a novel chemical inhibitor that blocks the intracellular build up of the hormone cortisol, thereby preventing the development of atherosclerotic plaques in mice. This compound also alleviated multiple symptoms of a common disorder known as metabolic syndrome.As the epidemics of obesity and type 2 diabetes grow, so does the incidence of metabolic syndrome—a disorder characterized by hypertension, insulin resistance, and visceral obesity. These symptoms add up to an elevated risk of atherosclerosis and coronary heart disease. Figure Inhibition of the cortisol-producing enzyme 11β-HSD1 prevents the development of atherosclerosis and improves the symptoms of metabolic syndrome. Although the etiology of metabolic syndrome remains obscure, increased intracellular levels of the glucocorticoid cortisol may be partly to blame. Cortisol is an adrenal hormone that regulates nutrient metabolism and inflammation. Recent studies in mice showed that overexpression of 11β-HSD1—the intracellular enzyme that converts inactive cortisone into active cortisol—leads to a disorder resembling metabolic syndrome, suggesting that an excess of intracellular cortisol may contribute to disease. Although cardiovascular disease is the leading cause of mortality among patients with metabolic syndrome, a role for 11β-HSD1 in the development of cardiovascular symptoms had never been explored. Hermanowski-Vosatka et al. now describe a novel inhibitor of 11β-HSD1 that reduced the accumulation of plaque-forming cholesterol by nearly 90% in the aortas of mice. This inhibitor also protected mice from diet-induced obesity and type 2 diabetes, suggesting that deregulation of intracellular cortisol may be a unifying cause of the symptoms of metabolic syndrome. The dramatic protection against plaque formation was associated with only modest reductions in serum lipids and glucose (known contributors to atherosclerotic plaque formation), suggesting that the inhibitor also affects other pathways. The authors suspect that the drug may suppress inflammation in vessels, which could help protect against atherosclerosis, as inflammation is associated with exacerbated cardiovascular disease in both mice and humans.

A transgenic model of visceral obesity and the metabolic syndrome

Obesity is often associated with the metabolic syndrome, which includes insulin resistance, glucose intolerance and dyslipidemia. The best predictor of these morbidities is not the total body adipose mass, but the specific quantity of visceral fat, with ‘apple-shaped’ people who carry excess weight around their waists being more susceptible to these illnesses than people who are equally overweight but with the weight around their hips. The role of glucocorticoids in this process remained elusive for many years, because in most obese patients plasma glucocorticoid levels are normal. However, the activity of 11β hydroxysteroid dehydrogenase type 1 enzyme (11β HSD-1), which regenerates active cortisol from inactive cortisone, was recently shown to be greater in abdominal fat than in subcutaneous abdominal tissue, suggesting a role for increased local cortisol activity in human obesity.To test the role of 11β HSD-1 and local glucocorticoid production in the development of visceral obesity and the metabolic syndrome, Masuzaki et al. [1xA transgenic model of visceral obesity and the metabolic syndrome. Masuzaki, H. et al. Science. 2001; 294: 2166–2170Crossref | PubMed | Scopus (1268)See all References][1] created transgenic mice selectively overexpressing 11β HSD-1 in the adipose tissue. The overexpression caused a 2.4-fold increase in 11β HSD-1 activity in the adipose tissue of these mice, a magnitude similar to that found in obese humans. Corticosterone levels in the adipose tissue were significantly elevated (by 15–30%), but the serum levels of the hormone were normal, as were several other parameters, including thymic weight, bone mineral density, lean body mass weight and linear growth, which reflect the consequences of circulating glucocorticoids.By 15 weeks of age, the transgenic mice showed increased sensitivity to weight gain compared with normal mice, and the fat accumulation had a prominent abdominal component: even on a low-fat diet, the transgenic mice carried 37.9% of their adipose weight in the abdominal region compared with 27.5% in non-transgenic mice. Food intake was increased by at least 10%, which paralleled the increase in body weight. These data demonstrate that overexpression of 11β HSD-1 in adipose tissue produces disproportionate fat accumulation and hyperphagia.The transgenic mice also seemed to exhibit most symptoms of the metabolic syndrome, including pronounced insulin-resistant diabetes, hyperlipidemia and hyperphagia, in spite of showing hyperleptinemia. The expression of several genes that could influence systemic metabolic pathways was also studied in these mice: mRNA encoding resistin and Acrp30-AdipoQ decreased, whereas angiotensinogen expression in the mesenteric fat increased; mitochondrial uncoupling protein-1 mRNA was significantly decreased in brown adipose tissue.This provides evidence that a modest increase in the activity of 11β HSD-1 in the adipose tissue of mice, similar to that found in obese humans, can cause hyperphagia, visceral obesity and most symptoms of the metabolic syndrome. The authors suggest that this enzyme could be a potential pharmaceutical target for the treatment of this prevalent problem. In fact, it has been shown that thiazolidinedione antidiabetic agents markedly reduce 11β HSD-1 mRNA and activity in adipose tissue. Based on the data of Masuzaki et al., this could be a mechanism for their visceral fat-reducing action in humans, and might play a role in their antidiabetic effects.