Tissue-Specific Increases in 11β-Hydroxysteroid Dehydrogenase Type 1 in Normal Weight Postmenopausal Women

With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11βHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11βHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11βHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5α-tetrahydrocortisol+5β-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11βHSD1 activity. Postmenopausal women had higher 11βHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11βHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11βHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women

Weight Loss after Gastric Bypass Surgery in Women Is Followed by a Metabolically Favorable Decrease in 11 beta-Hydroxysteroid Dehydrogenase 1 Expression in Subcutaneous Adipose Tissue

BACKGROUND AND AIMS: The role of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in the pathogenesis of obesity has been elucidated in humans and in various rodent models. Obesity is accompanied by disturbances in glucocorticoid metabolism, circulating adipokine levels, and fatty acid (FA) reesterification. This study was undertaken to evaluate glucocorticoid metabolism in sc fat before and after weight loss and to explore putative associations between 11beta-HSD1 and leptin, adiponectin, and FA recycling.SUBJECTS AND METHODS: Twenty-seven obese (mean body mass index 44.4 + or - 4.4 kg/m(2)) women underwent gastric bypass surgery. Subcutaneous fat biopsies were collected before and 2 yr after surgery. The expression of 11beta-HSD1, leptin, adiponectin, and phosphoenolpyruvate carboxykinase (PEPCK) mRNA was evaluated with real-time PCR. Serum leptin and adiponectin protein levels were estimated by ELISA.RESULTS: Two years after gastric bypass surgery, significant reductions were observed in the mean body mass index (from 44.4 to 30.8 kg/m(2)) and mean waist circumference (from 121.9 to 90.6 cm). After weight loss, 11beta-HSD1 mRNA expression decreased 4-fold (

Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling

The glucocorticoid activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is of major interest in obesity-related morbidity. Alterations in tissue-specific cortisol levels may influence lipogenetic and gluco/glyceroneogenetic pathways in fat and liver. We analyzed the expression and activity of 11betaHSD1 as well as the expression of phosphoenolpyruvate carboxykinase (PEPCK), sterol regulatory element binding protein (SREBP), and fatty acid synthase (FAS) in adipose and liver and investigated putative associations between 11betaHSD1 and energy metabolism genes. A total of 33 obese women (mean BMI 44.6) undergoing gastric bypass surgery were enrolled. Subcutaneous adipose tissue (SAT), omental fat (omental adipose tissue (OmAT)), and liver biopsies were collected during the surgery. 11betaHSD1 gene expression was higher in SAT vs. OmAT (P = 0.013), whereas the activity was higher in OmAT (P = 0.009). The SAT 11betaHSD1 correlated with waist circumference (P = 0.045) and was an independent predictor for the OmAT area in a linear regression model. Energy metabolism genes had AT depot-specific expression; higher leptin and SREBP in SAT than OmAT, but higher PEPCK in OmAT than SAT. The expression of 11betaHSD1 correlated with PEPCK in both AT depots (P = 0.05 for SAT and P = 0.0001 for OmAT). Hepatic 11betaHSD1 activity correlated negatively with abdominal adipose area (P = 0.002) and expression positively with PEPCK (P = 0.003). In human obesity, glucocorticoid regeneration in the SAT is associated with central fat accumulation indicating that the importance of this specific fat depot is underestimated. Central fat accumulation is negatively associated with hepatic 11betaHSD1 activity. A disturbance in peripheral glucocorticoid metabolism is associated with changes in genes involved in fatty acid (FA) recycling in adipose tissue (AT)

Urinary corticosteroid metabolites.

<p>Three women in each premenopausal group were found not to be in the anticipated phase of the menstrual cycle, one woman in follicular phase did not comply with the instructions of the urine collection and two women in luteal and one woman in follicular phase of the menstrual cycle did not collect urine. ^*<i>P</i><0.05 and^***<i>P</i><0.001 <i>vs.</i> follicular phase.</p>†<p><i>P</i><0.05 and ^††<i>P</i><0.01 <i>vs.</i> luteal phase. THF, tetrahydrocortisol; THE, tetrahydrocortisone.</p

Circulating levels of steroids and lipids and adipose aromatase transcript levels.

<p>One woman in follicular phase and three in the luteal phase of the menstrual cycle did not have the biopsy and three women in each premenopausal group were found not to be in the correct menstrual phase. 11βHSD1, 11β-hydroxyteroid dehydrogenase type 1; PPIA, Cyclophilin A; SHBG, Sex hormone-binding globulin; HDL, high-density lipoprotein; LDL low-density lipoprotein; ApoA1, Apolipoprotein A-1; ApoB, Apolipoprotein B. N = 16 for luteal phase blood lipid data.</p>*<p><i>P<</i>0.05, ^**<i>P<</i>0.01 and^***<i>P<</i>0.001 <i>vs.</i> follicular phase.</p>†<p><i>P<</i>0.05, ^††<i>P<</i>0.01 and^†††<i>P<</i>0.001 <i>vs.</i> luteal phase.</p

Bivariate correlations for adipose 11βHSD1 expression and activity, urinary THFs/THE and hepatic 11βHSD1 activity versus anthropometric data, sex steroids, hormones and gene expression of aromatase.

<p>Premenopausal women in follicular phase of the menstrual cycle and postmenopausal women were included. Enzyme activity was measured as percent conversion of cortisol to cortisone after 24 h incubation. Urinary THFs/THE gives a measure of whole body 11βHSD1 activity. Hepatic 11βHSD1 activity was measured as serum cortisol 30 minutes after oral cortisone. 11βHSD1, 11β-hydroxysteroid dehydrogenase type 1; EA, Enzyme activity; THFs/THE, (5α-tetrahydrocortisol+5β-tetrahydrocortisol)/5β-tetrahydrocortione; SBP, systolic blood pressure; DBP, diastolic blood pressure, n.a., not applicable. Data are correlation coefficients (Pearson correlation).</p>*<p><i>P<</i>0.05, ^**<i>P<</i>0.01, and^***<i>P<</i>0.001.</p>‡<p>Association significant after adjusting for waist circumference, BMI, and menopausal group (partial correlation).</p

Subject characteristics.

<p>SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate aminotransferase; ALT alanine aminotransferase; HOMA-IR, Homeostasis Model Assessment for Insulin Resistance.</p>**<p><i>P<</i>0.01 and <i>^***P<</i>0.001 <i>vs.</i> premenopausal women.</p