An <i>in vivo</i> study of the cortisol–cortisone shuttle in subcutaneous abdominal adipose tissue

Katz, JR; Mohamed‐Ali, Vidya; Wood, Peter; Yudkin, John; Coppack, Simon W.

doi:10.1046/j.1365-2265.1999.00598.x

Cited by 70 publications

(41 citation statements)

References 24 publications

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“…Cell culture media and reagents for reverse transcription of RNA were from Invitrogen (Carlsbad, CA), [1,2,6, H]-cortisol from Amersham Bioscience (Piscataway, NJ), [1,2,6, H]-cortisone from American Radiolabelled Chemicals (St. Louis, MO), the SV total RNA isolation system from Promega (Madison, WI) and reagents for TaqMan realtime PCR from Applied Biosystems (Foster City, CA). Monoclonal antibodies were from Roche Diagnostics (Rotkreuz, Switzerland) and fluorescent antibodies from Molecular Probes (Eugene, OR).…”

Section: Methodsmentioning

confidence: 99%

“…11b-HSD1 is a bidirectional enzyme, catalysing both oxidation and oxoreduction with comparable efficiencies in cell lysates, whereby oxoreduction is less stable and decreases upon preparation of microsomes and purification [2]. Experiments in animals and humans indicated that 11b-HSD1, which is highly expressed in liver and adipose tissue [1] and has been associated with obesity and type 2 diabetes mellitus [3], is predominantly an oxoreductase in vivo [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

et al. 2004

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The impact of hexose-6-phosphate dehydrogenase (H6PDH) on 11b-hydroxysteroid dehydrogenase (11b-HSD) type 1 activity was investigated upon coexpression in HEK-293 cells. Confocal microscopy analysis indicated colocalisation of both enzymes at the lumenal side of the endoplasmic reticulum (ER) membrane. Functional analysis in intact cells revealed fivefold stimulation of 11b-HSD1 oxoreductase activity and sixfold decrease of dehydrogenase activity upon coexpression with H6PDH, without changing kinetic parameters in cell lysates. Thus, H6PDH directly determines the reaction direction of 11b-HSD1 in intact cells as an oxoreductase without changing intrinsic catalytic properties of 11b-HSD1 by regenerating NADPH in the ER-lumen.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

et al. 2004

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“…In biopsies, it has not been possible to correlate 11HSD1 activity or mRNA with cortisol levels or mRNA levels for glucocorticoid-dependent genes (21,22). Previous attempts to measure adipose 11HSD1 in vivo using arteriovenous sampling across abdominal subcutaneous adipose tissue have been inconclusive, perhaps because of variability in measurement (26). Recently, we (27) and others (28) have validated a new approach using deuterated cortisol tracer infusion to measure the turnover of 11HSD activities in vivo.…”

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confidence: 99%

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

et al. 2005

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11␤-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within adipose tissue and liver. 11HSD1 inhibitors may enhance insulin sensitivity in type 2 diabetes and be most efficacious in obesity when 11HSD1 is increased in subcutaneous adipose biopsies. We examined the regeneration of cortisol in vivo in obesity, and the effects of the 11HSD1 inhibitor carbenoxolone. We compared six lean and six obese men and performed a randomized, placebo-controlled crossover study of carbenoxolone in obese men. 11␤-Hydroxysteroid dehydrogenase type 1 (11HSD1) is a microsomal enzyme expressed in many tissues, including liver and adipose tissue (1). It catalyzes the regeneration of the active glucocorticoid cortisol from its inactive 11-keto metabolite cortisone. This intracellular generation of cortisol plays a key role in amplifying glucocorticoid receptor activation independently of the level of cortisol in the circulating plasma. Its potential importance is illustrated in animal models. Transgenic mice that overexpress 11HSD1 by approximately threefold selectively in adipocytes under the AP2 promoter/enhancer (2,3) develop about a twofold increase in intraadipose glucocorticoid levels despite no change in plasma levels, which are controlled by a compensatory fall in ACTH secretion. This results in central obesity together with hyperinsulinemia, hyperglycemia, hyperlipidemia, and hypertension. Mice with similar overexpression of 11HSD1 in liver under the ApoE promoter develop insulin resistance, dyslipidemia, and hypertension without obesity (4). Conversely, 11HSD1 knockout mice on a high-fat diet are protected from obesity, hyperglycemia, and dyslipidemia and redistribute fat to peripheral rather than central fat depots (5-7). Moreover, inbred rodent models of obesity and diabetes show tissue-specific dysregulation of 11HSD1 (2,8,9); most commonly, 11HSD1 is reduced in liver but increased in adipose tissue. These findings substantiate the hypothesis that increased intra-adipose glucocorticoid regeneration by 11HSD1 contributes to obesity and its metabolic complications.Whether increased 11HSD1 levels have a similar importance in human obesity and associated type 2 diabetes is controversial (10). The conventional measure of 11HSD1 is the ratio of urinary cortisol to cortisone metabolites, which is inconsistently altered in obesity (11-16) and diabetes (17)(18)(19). However, this ratio may be confounded by the activity of other enzymes (e.g., 11HSD type 2, 5␣-and 5␤-reductase) that differ in obesity, and is insensitive to the tissue-specific changes in 11HSD1 that have been observed in animals. Hepatic 11HSD1 has been assessed in humans by measuring the conversion of an oral dose of cortisone into cortisol in peripheral plasma after "first pass" metabolism, and is consistently reduced in obesity

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“…The distribution of 11β HSD-1 expression is similar in mice and humans. In vivo measurements using arteriovenous sampling have shown that cortisone is converted into cortisol in human liver [12] and subcutaneous adipose tissue [13], and 11β HSD-1 is the only human enzyme known to catalyse this reaction. Inhibition of 11β HSD-1 with the non-selective inhibitor carbenoxolone results in enhanced insulin sensitivity in the liver [14,15], consistent with the effects of a more selective 11β HSD-1 inhibitor in mice [9,10].…”

mentioning

confidence: 99%

Is ?Cushing?s disease of the omentum? an affliction of mouse and men?

Walker

2004

Diabetologia

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An in vivo study of the cortisol–cortisone shuttle in subcutaneous abdominal adipose tissue

Abstract: We have demonstrated 11 beta-HSD oxo-reductase activity in subcutaneous abdominal adipose tissue, which may be increased in obesity.

Cited by 70 publications

References 24 publications

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

Hexose‐6‐phosphate dehydrogenase determines the reaction direction of 11β‐hydroxysteroid dehydrogenase type 1 as an oxoreductase

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

Is ?Cushing?s disease of the omentum? an affliction of mouse and men?

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