Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
 ...
PMID:11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. 1546 42

Dehydroepiandrosterone (DHEA) exerts beneficial effects on blood glucose levels and insulin sensitivity in obese rodents and humans, resembling the effects of peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and opposing those of glucocorticoids; however, the underlying mechanisms remain unclear. Glucocorticoids are reactivated locally by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which is currently considered as a promising target for the treatment of obesity and diabetes. Using differentiated 3T3-L1 adipocytes, we show that DHEA causes downregulation of 11beta-HSD1 and dose-dependent reduction of its oxoreductase activity. The effects of DHEA were comparable with those of the PPARgamma agonist rosiglitazone but not additive. Furthermore, DHEA reduced the expression of hexose-6-phosphate dehydrogenase, which stimulates the oxoreductase activity of 11beta-HSD1. These findings were confirmed in white adipose tissue and in liver from DHEA-treated C57BL/6J mice. Analysis of the transcription factors involved in the DHEA-dependent regulation of 11beta-HSD1 expression revealed a switch in CCAAT/enhancer-binding protein (C/EBP) expression. C/EBPalpha, a potent activator of 11beta-HSD1 gene transcription, was downregulated in 3T3-L1 adipocytes and in liver and adipose tissue of DHEA-treated mice, whereas C/EBPbeta and C/EBPdelta, attenuating the effect of C/EBPalpha, were unchanged or elevated. Our results further suggest a protective effect of DHEA on adipose tissue by upregulating PPARalpha and downregulating leptin, thereby contributing to the reduced expression of 11beta-HSD1. In summary, we provide evidence that some of the anti-diabetic effects of DHEA may be caused through inhibition of the local amplification of glucocorticoids by 11beta-HSD1 in adipose tissue.
 ...
PMID:Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue. 1561 80

Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert active cortisol and inactive cortisone. 11 beta-HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11 beta-HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11 beta-HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11 beta-HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 beta-HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11 beta-HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11 beta-HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 beta-HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 beta-HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 beta-HSD1 oxo-reductase activity whilst simultaneously increasing 11 beta-HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11 beta-HSD1 oxo-reductase activity, independent of 11 beta-HSD1 mRNA levels. H6PDH expression increased 5.3-fold across adipocyte differentiation (P < 0.05) and was associated with a switch from 11 beta-HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11 beta-HSD1 oxo-reductase activity in intact cells. Through its interaction with 11 beta-HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.
 ...
PMID:Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1. 1595 39

11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver, and other tissues. It is located in the intraluminal compartment of the endoplasmic reticulum. Inasmuch as an oxo-reductase requires NADPH, we reasoned that 11 beta-HSD1 would be metabolically interconnected with the cytosolic pentose pathway because this pathway is the primary producer of reduced cellular pyridine nucleotides. To test this theory, 11 beta-HSD1 activity and pentose pathway were simultaneously measured in isolated intact rodent adipocytes. Established inhibitors of NAPDH production via the pentose pathway (dehydroandrostenedione or norepinephrine) inhibited 11 beta-HSD1 oxo-reductase while decreasing cellular NADPH content. Conversely these compounds slightly augmented the reverse, or dehydrogenase, reaction of 11 beta-HSD1. Importantly, using isolated intact microsomes, the inhibitors did not directly alter the tandem microsomal 11 beta-HSD1 and hexose-6-phosphate dehydrogenase enzyme unit. Metabolites of 11 beta-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity. Using isolated intact liver or fat microsomes, glucose-6 phosphate stimulated 11 beta-HSD1 oxo-reductase, and this effect was blocked by selective inhibitors of glucose-6-phosphate transport. In summary, we have demonstrated a metabolic interconnection between pentose pathway and 11 beta-HSD1 oxo-reductase activities that is dependent on cytosolic NADPH production. These observations link cytosolic carbohydrate flux with paracrine glucocorticoid formation. The clinical relevance of these findings may be germane to the regulation of paracrine glucocorticoid formation in disturbed nutritional states such as obesity.
 ...
PMID:Evidence that the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is regulated by pentose pathway flux. Studies in rat adipocytes and microsomes. 1623 47

11Beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) plays a key role in the regulation of intracellular glucocorticoid concentrations. Increased message and/or activity of adipose 11beta-HSD-1 are characteristics of human and animal models of obesity. Hexose-6-phosphate dehydrogenase (H6PDH) is colocalized with 11beta-HSD-1 and may be a critical factor in determining the oxo-reductase activity of 11beta-HSD-1. This study examined the effects of sucrose solution access on body weight, body composition, and message of 11beta-HSD-1 and H6PDH in mesenteric adipose and liver. Rats were assigned to 3 groups: 1) control (ad libitum intake of nonpurified diet and water only); 2) ad libitum intake of 16% sucrose solution (S16); or 3) ad libitum intake of 32% sucrose solution (S32) in addition to ad libitum intake of diet and water. The S32 group consumed more energy daily than the S16 and control groups, yet body weight did not differ among groups. Percentages of body fat did not differ between the S16 and S32 groups but were higher than in controls. Hepatic 11beta-HSD-1 message was suppressed by 46% in the S16 group and by 47% in the S32 group, whereas the H6PDH message nearly doubled in the S16 group compared to the control group. In mesenteric fat, 11beta-HSD-1 message increased 23-fold in the S16 group and 32-fold in the S32 group and the H6PDH message increased 3.5-fold in the S16 group compared to the control group. These data demonstrate that sucrose can promote increased 11beta-HSD-1 and H6PDH message in mesenteric fat while concomitantly decreasing 11beta-HSD-1 message and increasing H6PDH message in liver. These observations support the hypothesis that sucrose access causes obesity via its ability to increase adipose 11beta-HSD-1.
 ...
PMID:Sucrose access differentially modifies 11beta-hydroxysteroid dehydrogenase-1 and hexose-6-phosphate dehydrogenase message in liver and adipose tissue in rats. 1802 73

Glucocorticoid excess promotes visceral obesity and cardiovascular disease. Similar features are found in the highly prevalent metabolic syndrome in the absence of high levels of systemic cortisol. Although elevated activity of the glucocorticoid-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within adipocytes might explain this paradox, the potential role of 11beta-HSD1 in preadipocytes is less clear; human omental adipose stromal vascular (ASV) cells exhibit 11beta-dehydrogenase activity (inactivation of glucocorticoids) probably due to the absence of cofactor provision by hexose-6-phosphate dehydrogenase. To clarify the depot-specific impact of 11beta-HSD1, we assessed whether preadipocytes in ASV from mesenteric (as a representative of visceral adipose tissue) and sc tissue displayed 11beta-HSD1 activity in mice. 11beta-HSD1 was highly expressed in freshly isolated ASV cells, predominantly in preadipocytes. 11beta-HSD1 mRNA and protein levels were comparable between ASV and adipocyte fractions in both depots. 11beta-HSD1 was an 11beta-reductase, thus reactivating glucocorticoids in ASV cells, consistent with hexose-6-phosphate dehydrogenase mRNA expression. Unexpectedly, glucocorticoid reactivation was higher in intact mesenteric ASV cells despite a lower expression of 11beta-HSD1 mRNA and protein (homogenate activity) levels than sc ASV cells. This suggests a novel depot-specific control over 11beta-HSD1 enzyme activity. In vivo, high-fat diet-induced obesity was accompanied by increased visceral fat preadipocyte differentiation in wild-type but not 11beta-HSD1(-/-) mice. The results suggest that 11beta-HSD1 reductase activity is augmented in mouse mesenteric preadipocytes where it promotes preadipocyte differentiation and contributes to visceral fat accumulation in obesity.
 ...
PMID:Preadipocyte 11beta-hydroxysteroid dehydrogenase type 1 is a keto-reductase and contributes to diet-induced visceral obesity in vivo. 1817 84

Intracellular glucocorticoid (GC) receptor (GR) function determines tissue sensitivity to GCs and strongly affects the development of type 2 diabetes and obesity. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mediates intracellular steroid exposure to mouse liver GR by prereceptor reactivation of GCs and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH)-generating NADPH system. Pharmacological inhibition of 11beta-HSD1 improves insulin intolerance and obesity. Here, we evaluated the potential beneficial effects of 11beta-HSD1 inhibitor carbenoxolone (CBX) in diet-induced obese (DIO) and insulin-resistant mice by examining the possible influence of CBX on the expression of GR, 11beta-HSD1, and H6PDH in vivo and in vitro in hepatocytes. Treatment of DIO mice with CBX markedly reduced hepatic GR mRNA levels and reduced weight gain, hyperglycemia, and insulin resistance. The reduction of hepatic GR gene expression was accompanied by CBX-induced inhibition of both 11beta-HSD1 and H6PDH activity and mRNA in the liver. Moreover, CBX treatment also suppressed the expression of both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase enzyme (G6Pase) mRNA and improved hepatic [1, 2-(3)H] deoxy-d-glucose uptake in DIO mice. In addition, the treatment of primary cultures of hepatocytes with increasing concentrations of CBX led to a dose-dependent downregulation of GR mRNA levels, which correlated with the suppression of both 11beta-HSD1 and H6PDH activity and their gene expression. Addition of CBX to primary hepatocytes also resulted in suppression of both PEPCK and G6Pase mRNA levels. These findings suggest that CBX exerts some of its beneficial effects, at least in part, by inhibiting hepatic GR and H6PDH expression.
 ...
PMID:Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice. 1852 70

Hexose-6-phosphate dehydrogenase (H6PD) got into the focus of interest due to its role in the prereceptorial activation of glucocorticoids, which has been implicated in the pathomechanism of metabolic syndrome. Genetic observations, results gained in H6PD knockout mice, and studies on differentiating adipocytes demonstrated the importance of the enzyme in metabolic regulation. A nutrient-sensing function can be postulated for the enzyme, which links metabolism to endocrinology in the endoplasmic reticulum. This review provides an overview of the recent developments concerning the enzyme and its impact on various branches of the intermediary metabolism, which make it an important subject for the research on obesity, diabetes, and metabolic syndrome.
 ...
PMID:Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum. 1906 Jan 78

Tissue specific amplification of glucocorticoid action through NADPH-dependent reduction of inactive glucocorticoid precursors by 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) contributes to the development of visceral obesity, insulin resistance and Type 2 Diabetes. Hexose-6-phosphate dehydrogenase (H6PDH) is believed to supply NADPH for the reductase activity of 11beta-HSD1 in the lumen of the endoplasmic reticulum (ER), where the two enzymes are co-localized. We report here expression and purification of full-length and truncated N-terminal domain (NTD) of H6PDH in a mammalian expression system. Interestingly, both full-length H6PDH and the truncated NTD are secreted into the culture medium in the absence of 11beta-HSD1. Purified full-length H6PDH is a bi-functional enzyme with glucose-6-phosphate dehydrogenase (G6PDH) activity as well as 6-phosphogluconolactonase (6PGL) activity. Using co-immunoprecipitation experiments with purified H6PDH and 11beta-HSD1, and with cell lysates expressing H6PDH and 11beta-HSD1, we observe direct physical interaction between the two enzymes. We also show the modulation of 11beta-HSD1 directionality by H6PDH using overexpression and siRNA knockdown systems. The NTD retains the ability to interact with 11beta-HSD1 physically as well as modulate 11beta-HSD1 directionality indicating that the NTD of H6PDH is sufficient for the regulation of the 11beta-HSD1 activity.
 ...
PMID:H6PDH interacts directly with 11beta-HSD1: implications for determining the directionality of glucocorticoid catalysis. 1912 Dec 82

17Beta-estradiol (E(2)) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E(2) on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E(2) inhibited 11beta-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E(2) on 11beta-HSD1 activity was observed within 5-10 min. Furthermore, acetylation or alpha-epimerization of 17-hydroxy group of E(2) attenuated the inhibitory effect on 11beta-HSD1. These results indicate that the inhibition of 11beta-HSD1 by E(2) depends on neither an ER-dependent route, transcriptional pathway nor non-specific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11beta-HSD1, was unaffected by E(2). A kinetic study revealed that E(2) acted as a non-competitive inhibitor of 11beta-HSD1. The inhibitory effect of E(2) on 11beta-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E(2) inhibits 11beta-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.
 ...
PMID:17Beta-estradiol inhibits 11beta-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes. 1938 Apr 58


1 2 3 Next >>