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

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 5909-5918 ◽  
Author(s):  
Malgorzata Wamil ◽  
Ruth Andrew ◽  
Karen E. Chapman ◽  
Jonathan Street ◽  
Nicholas M. Morton ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Diabetes Type 2 ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
Intracellular Enzyme ◽  
Increased Risk ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Reaction Direction

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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11β-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-HC). Here, we report that 11β-HSD1 catalyzes the reduction of 7KC to 7β-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7β-HC. Approximately 73% of added 7KC was reduced to 7β-HC within 24 h; this conversion was prevented by selective inhibition of 11β-HSD1. Oxysterol and glucocorticoid conversion by 11β-HSD1 was competitive and occurred with a physiologically relevant IC50 range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11β-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7β-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 7β-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11β-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11β-HSD1. Thus, the activity and reaction direction of adipose 11β-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.

scholarly journals Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2539-2543 ◽  
Author(s):  
Kylie N. Hewitt ◽  
Elizabeth A. Walker ◽  
Paul M. Stewart
Keyword(s):  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Pentose Phosphate ◽  
Intact Cells ◽  
The Metabolic Syndrome ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract Hexose-6-phosphate dehydrogenase (H6PDH) is a microsomal enzyme that is able to catalyze the first two reactions of an endoluminal pentose phosphate pathway, thereby generating reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is distinct from the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses. It has been proposed to be a NADPH regenerating system for steroid hormone and drug metabolism, specifically in determining the set point of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11β-HSD1 is a bidirectional enzyme, but in intact cells displays predominately oxo-reductase activity, a reaction requiring NADPH and leading to activation of glucocorticoids. However, in cellular homogenates or in purified preparations, 11β-HSD1 is exclusively a dehydrogenase. Because H6PDH and 11β-HSD1 are coexpressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11β-HSD1 with NADPH, thus promoting oxo-reductase activity in vivo. Recently, several studies have confirmed this functional cooperation, indicating the importance of intracellular redox mechanisms for the prereceptor control of glucocorticoid availability. With the increased interest in 11β-HSD1 oxo-reductase activity in the pathogenesis and treatment of several human diseases including insulin resistance and the metabolic syndrome, H6PDH represents an additional novel candidate for intervention.

scholarly journals Different mechanisms of regulation of nuclear reduced nicotinamide–adenine dinucleotide phosphate-dependent 3-oxo steroid 5α-reductase activity in rat liver, kidney and prostate

1974 ◽  
Vol 142 (2) ◽  
pp. 273-277 ◽  
Author(s):  
Jan-Åke Gustafsson ◽  
Åke Pousette
Keyword(s):  
Testosterone Propionate ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Female Rats ◽  
Male Rats ◽  
Regulatory Mechanisms ◽  
Oestradiol Benzoate ◽  
Liver And Kidney ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Hydroxy Steroid

The regulatory mechanisms involved in the control of the nuclear NADPH-dependent 3-ketosteroid 5α-reductase (5α-reductase) activity were studied in liver, kidney and prostate. The substrate used was [1,2-3H]androst-4-ene-3,17-dione (androstenedione) (for liver and kidney) or [4-14C]androstenedione (for prostate). The hepatic nuclear 5α-reductase activity was greater in female than in male rats, was greater in adult than in prepubertal female rats, increased after castration of male rats, but was not affected by treatment with testosterone propionate or oestradiol benzoate. These regulatory characteristics are in part different from those previously described for the hepatic microsomal 5α-reductase. The renal nuclear metabolism of androstenedione, i.e. 5α reduction and 17β-hydroxy steroid reduction, was relatively unaffected by sex, age, castration and treatment with testosterone propionate. However, treatment of castrated male rats with oestradiol benzoate led to a significant increase in the 5α-reductase activity and a significant decrease in the 17β-hydroxy steroid reductase activity. Finally, the nuclear 5α-reductase activity in prostate was androgen-dependent, decreasing after castration and increasing after treatment with testosterone propionate. In conclusion, the nuclear 5α-reductase activities in liver, kidney and prostate seem to be under the control of distinctly different regulatory mechanisms. The hypothesis is presented that whereas the prostatic nuclear 5α-reductase participates in the formation of a physiologically active androgen, 5α-dihydrotestosterone, this may not be the true function of the nuclear 5α-reductase in liver and kidney. These enzymes might rather serve to protect the androgen target sites in the chromatin from active androgens (e.g. testosterone) by transforming them into less active androgens (e.g. 5α-androstane-3,17-dione and/or 5α-dihydrotestosterone).

scholarly journals Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus

2003 ◽  
Vol 176 (2) ◽  
pp. 175-184 ◽  
Author(s):  
S Gupta ◽  
N Alfaidy ◽  
AC Holloway ◽  
WL Whittle ◽  
SJ Lye ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Fetal Liver ◽  
Reductase Activity ◽  
Plasma Concentrations ◽  
Hydroxysteroid Dehydrogenase ◽  
Late Gestation ◽  
Concurrent Administration ◽  
Fetal Plasma ◽  
Fetal Organ

In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E(2)) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E(2) are believed to regulate the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11beta-HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E(2) on hepatic 11beta-HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1.35 mg/h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1.44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E(2); concurrent administration of 4-OHA attenuated the increase in plasma E(2) concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11beta-HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E(2) concentrations, significantly increased concentrations of 11beta-HSD1 (34 kDa) and GR (95 kDa) proteins. 11beta-HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [(3)H]cortisone (10(-)(6) M) or [(3)H]cortisol (10(-)(6) M) and NADPH (reductase activity) or NADP(+) (dehydrogenase activity) respectively. 11beta-HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11beta-HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E(2).

scholarly journals DETERMINATION OF GLUTATHIONE REDUCTASE ACTIVITY IN MICROGRAM SAMPLES OF TISSUE, QUANTITATIVE HISTOLOGIC DISTRIBUTION OF THE ENZYME IN THE RAT ADRENAL AND EFFECT OF ADRENOCORTICOTROPIN

1968 ◽  
Vol 16 (3) ◽  
pp. 185-190 ◽  
Author(s):  
NORBERTO A. SCHOR ◽  
DAVID GLICK
Keyword(s):  
Glutathione Reductase ◽  
Nicotinamide Adenine Dinucleotide ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Border Region ◽  
Nicotinamide Adenine ◽  
Subcutaneous Injections ◽  
Glutathione Reductase Activity ◽  
Reduced Nicotinamide Adenine Dinucleotide

A fluorometric method for determination of glutathione reductase activity in microgram samples of tissue, i.e., microtome sections, based on measurement of the decrease of reduced nicotinamide adenine dinucleotide phosphate due to its oxidation on reaction with oxidized glutathione, was developed and applied to the quantitative histologic distribution of the enzyme in the adrenal gland of the rat. Single subcutaneous injections of adrenocorticotropin in saline solution (25 mg/kg) produced little change of enzyme activity in any of the histologic zones, although there was some tendency for the peak activity to shift from fasciculata to the fascicular-reticular border region. The possible interrelationship of glutathione reductase with ascorbic acid and reduced nicotinamide adenine dinucleotide phosphate in adrenal function was considered.

scholarly journals Hexose-6-Phosphate Dehydrogenase and 11β-Hydroxysteroid Dehydrogenase-1 Tissue Distribution in the Rat

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 525-533 ◽  
Author(s):  
Elise P. Gomez-Sanchez ◽  
Damian G. Romero ◽  
Angela F. de Rodriguez ◽  
Mary P. Warden ◽  
Zygmunt Krozowski ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Dehydrogenase Activity ◽  
Leydig Cells ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Interstitial Cells ◽  
Rat Tissues ◽  
Rt Pcr ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
The Brain

Intracellular concentrations of the glucocorticoids cortisol and corticosterone are modulated by the enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD) 1 and 2. 11β-HSD1 is a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent microsomal reductase that converts the inactive glucocorticoids cortisone and 11-dehydrocorticosterone to their active forms, cortisol and corticosterone. Hexose-6-phosphate dehydrogenase (H6PDH) is an enzyme that generates NADPH from oxidized NADP (NADP+) within the endoplasmic reticulum. In the absence of NADPH or H6PDH to regenerate NADPH, 11β-HSD1 acts as a dehydrogenase and inactivates glucocorticoids, as does 11β-HSD2. A monoclonal antibody against H6PDH was produced to study the possibility that 11β-HSD1 in the absence of H6PDH may be responsible for hydroxysteroid dehydrogenase activity in tissues that do not express significant amounts of 11β-HSD2. H6PDH and 11β-HSD1 expression was surveyed in a variety of rat tissues by real-time RT-PCR, Western blot analysis, and immunohistochemistry. H6PDH was found in a wide variety of tissues, with the greatest concentrations in the liver, kidney, and Leydig cells. Although the brain as a whole did not express significant amounts of H6PDH, some neurons were clearly immunoreactive by immunohistochemistry. H6PDH was amply expressed in most tissues examined in which 11β-HSD1 was also expressed, with the notable exception of the renal interstitial cells, in which dehydrogenase activity by 11β-HSD1 probably moderates activation of the glucocorticoid receptor because rat renal interstitial cells do not have significant amounts of mineralocorticoid receptors. This antibody against the H6PDH should prove useful for further studies of enzyme activity requiring NADPH generation within the endoplasmic reticulum.

scholarly journals Abnormalities of Glucose Homeostasis and the Hypothalamic-Pituitary-Adrenal Axis in Mice Lacking Hexose-6-Phosphate Dehydrogenase

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 5072-5080 ◽  
Author(s):  
Daniela Rogoff ◽  
Jeffrey W. Ryder ◽  
Kelli Black ◽  
Zheng Yan ◽  
Shawn C. Burgess ◽  
...  
Keyword(s):  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hypothalamic Pituitary Adrenal Axis ◽  
Primary Hepatocytes ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Glucose Output ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Pituitary Adrenal Axis

Hexose-6-phosphate dehydrogenase (EC 1.1.1.47) catalyzes the conversion of glucose 6-phosphate to 6-phosphogluconolactone within the lumen of the endoplasmic reticulum, thereby generating reduced nicotinamide adenine dinucleotide phosphate. Reduced nicotinamide adenine dinucleotide phosphate is a necessary cofactor for the reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (EC 1.1.1.146), which converts hormonally inactive cortisone to active cortisol (in rodents, 11-dehydrocorticosterone to corticosterone). Mice with targeted inactivation of hexose-6-phosphate dehydrogenase lack 11β-hydroxysteroid dehydrogenase type 1 reductase activity, whereas dehydrogenase activity (corticosterone to 11-dehydrocorticosterone) is increased. We now report that both glucose output and glucose use are abnormal in these mice. Mutant mice have fasting hypoglycemia. In mutant primary hepatocytes, glucose output does not increase normally in response to glucagon. Mutant animals have lower hepatic glycogen content when fed and cannot mobilize it normally when fasting. As assessed by RT-PCR, responses of hepatic enzymes to fasting are blunted; enzymes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase, tyrosine aminotransferase) are not appropriately up-regulated, and expression of glucokinase, an enzyme required for glycolysis, is not suppressed. Corticosterone has attenuated effects on expression of these enzymes in cultured mutant primary hepatocytes. Mutant mice have increased sensitivity to insulin, as assessed by homeostatic model assessment values and by increased glucose uptake by the muscle. The hypothalamic-pituitary-adrenal axis is also abnormal. Circulating ACTH, deoxycorticosterone, and corticosterone levels are increased in mutant animals, suggesting decreased negative feedback on the hypothalamic-pituitary-adrenal axis. Comparison with other animal models of adrenal insufficiency suggests that many of the observed abnormalities can be explained by blunted intracellular corticosterone actions, despite elevated circulating levels of this hormone.

scholarly journals The Microsomal Enzyme 17β-Hydroxysteroid Dehydrogenase 3 Faces the Cytoplasm and Uses NADPH Generated by Glucose-6-Phosphate Dehydrogenase

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 205-213 ◽  
Author(s):  
Balázs Legeza ◽  
Zoltán Balázs ◽  
Lyubomir G. Nashev ◽  
Alex Odermatt
Keyword(s):  
Cell Model ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Pyridine Nucleotide ◽  
Proteinase K ◽  
Functional Coupling ◽  
293 Cells ◽  
Model Mouse ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Glucose 6 Phosphate Dehydrogenase

Recent studies proposed a functional coupling between 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3)-dependent testosterone formation and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1)-mediated interconversion of glucocorticoids through competition for the luminal pyridine nucleotide pool. To test this hypothesis, we used human embryonic kidney-293 cells transfected with 17β-HSD3 and/or 11β-HSD1, in the absence or presence of hexose-6-phosphate dehydrogenase that generates reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the endoplasmic reticulum and determined enzyme activities. As an endogenous cell model, mouse MA-10 Leydig cells were used. 17β-HSD3-dependent reduction of Δ4-androstene-3,17-dione was affected by neither coexpression with 11β-HSD1 nor overexpression or knockdown of hexose-6-phosphate dehydrogenase. In contrast, knockdown of glucose-6-phosphate dehydrogenase decreased 17β-HSD3 activity, indicating dependence on cytoplasmic NADPH. Upon selective permeabilization of the plasma membrane by digitonin, 17β-HSD3 but not 11β-HSD1 was detected by antibodies against C-terminal epitope tags, suggesting a cytoplasmic orientation of 17β-HSD3. The cytoplasmic orientation was confirmed using proteinase K digestion of microsomal preparations and by analysis of glycosylation of wild-type 17β-HSD3 and chimera in which the N-terminal anchor sequences between 17β-HSD3 and 11β-HSD1 were exchanged. In conclusion, the results demonstrate a cytoplasmic orientation of 17β-HSD3 and dependence on glucose-6-phosphate dehydrogenase-generated NADPH, explaining the lack of a direct functional coupling with the luminal 11β-HSD1-mediated glucocorticoid metabolism.

scholarly journals 11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver

2000 ◽  
Vol 165 (3) ◽  
pp. 685-692 ◽  
Author(s):  
PM Jamieson ◽  
BR Walker ◽  
KE Chapman ◽  
R Andrew ◽  
S Rossiter ◽  
...  
Keyword(s):  
Rat Liver ◽  
Reductase Activity ◽  
Chronic Administration ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
Rat Plasma ◽  
Male Rat ◽  
Perfused Rat Liver

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1), a regulator of intrahepatocellular glucocorticoid activity, is bidirectional in homogenates but catalyses 11 beta-reduction (regenerating glucocorticoid) in intact primary hepatocytes in culture. To examine this discrepancy at the whole-organ level, we examined 11 beta-HSD-1 activity in the intact bivascularly perfused rat liver. On a single pass through male rat liver, 44+/-5% of 11-dehydrocorticosterone (11-DHC) recovered was 11 beta-reduced to corticosterone, whereas 10+/-1% of corticosterone was 11 beta-dehydrogenated to 11-DHC. 11 beta-Reduction was less in female liver (21+/-2%, P<0.01) and was significantly greater with perfusion of all substrate via the portal vein (50+/-3%) than via the hepatic artery (30+/-2%, P<0.05). 11 beta-Reductase activity was not saturated by 11-DHC (10(-)(9)-10(-)(6) M). Perfusion with carbenoxolone (CBX, 10(-)(6)-10(-)(3 )M) did not alter 11 beta-reduction of 11-DHC. In contrast, pretreatment with CBX in vivo (10 mg/day) for 7 days inhibited 11 beta-reductase (19+/-4% conversion, P<0.01). Concentrations of 11-DHC in male rat plasma were 44+/-6 nM. Thus 11 beta-HSD-1 is predominantly an 11 beta-reductase in the intact rat liver and is only inhibited by chronic administration of CBX. The substantial concentrations of plasma 11-DHC as substrate suggest that 11 beta-HSD-1 activity and its potential selective inhibition could modify glucocorticoid action in vivo.

scholarly journals Acute In Vivo Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans

2006 ◽  
Vol 91 (11) ◽  
pp. 4682-4688 ◽  
Author(s):  
Deborah J. Wake ◽  
Natalie Z. M. Homer ◽  
Ruth Andrew ◽  
Brian R. Walker
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Hydroxysteroid Dehydrogenase ◽  
Saline Infusion ◽  
Whole Body ◽  
Cortisol Metabolism

Abstract Context: Extraadrenal regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) is increased after a mixed meal. It is unknown which tissue is responsible and whether this reflects the complex transcriptional control of 11HSD1 or posttranscriptional control exerted by supply of reduced nicotinamide adenine dinucleotide phosphate from hexose-6-phosphate dehydrogenase. Objective: The objective of this study was to test whether hyperinsulinemia and/or increased serum free fatty acids increase whole-body and intraadipose 11HSD1, and whether adipose 11HSD1 switches from dehydrogenase to reductase activity. Methods: In nine healthy men, we measured whole-body cortisol regeneration (by iv infusion of 9,11,12,12-[2H]4-cortisol) and intra-adipose interconversion of cortisol and cortisone (by sc microdialysis infusion of [3H]4-cortisol and [3H]2-cortisone in separate cannulae) during: 1) a hyperinsulinemic euglycemic clamp; 2) iv lipid infusion (Intralipid 20% fat emulsion); and 3) saline infusion, each for 3.5 h. Results: Hyperinsulinemia increased rate of appearance of 9,12,12-[2H]3-cortisol (19.3 ± 0.8 vs. 16.7 ± 1.1 nmol/min with saline, P &lt; 0.001), indicating increased whole-body 11HSD1. Within adipose, the predominant reaction was reductase conversion of cortisone to cortisol (after 3.5 h of saline infusion, reaching 11.0 ± 2.7% per hour reductase vs. 5.2 ± 1.3 dehydrogenase, P &lt; 0.02); insulin increased reductase (reaching 15.8 ± 3.0, P &lt; 0.05) and tended to increase dehydrogenase activity. Intralipid infusion had no effects on whole-body deuterated cortisol metabolism, but increased both dehydrogenase and reductase (reaching 16.7 ± 1.8, P &lt; 0.01) activities in adipose. Conclusions: Hyperinsulinemia and increased free fatty acids induce acute increases in 11HSD1 activity in adipose tissue that are not attributable to a switch from dehydrogenase to reductase. Hyperinsulinemia also increases systemic cortisol regeneration. These effects may enhance intracellular cortisol concentrations after a meal.

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