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- Andersson, Therése, 1978-, et al.
(författare)
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Estrogen reduces 11beta-hydroxysteroid dehydrogenase type 1 in liver and visceral, but not subcutaneous, adipose tissue in rats
- 2010
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Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-7381. ; 18:3, s. 470-475
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Tidskriftsartikel (refereegranskat)abstract
- Following menopause, body fat is redistributed from peripheral to central depots. This may be linked to the age related decrease in estrogen levels. We hypothesized that estrogen supplementation could counteract this fat redistribution through tissue-specific modulation of glucocorticoid exposure. We measured fat depot masses and the expression and activity of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in fat and liver of ovariectomized female rats treated with or without 17beta-estradiol. 11betaHSD1 converts inert cortisone, or 11-dehydrocorticosterone in rats into active cortisol and corticosterone. Estradiol-treated rats gained less weight and had significantly lower visceral adipose tissue weight than nontreated rats (P < 0.01); subcutaneous adipose weight was unaltered. In addition, 11betaHSD1 activity/expression was downregulated in liver and visceral, but not subcutaneous, fat of estradiol-treated rats (P < 0.001 for both). This downregulation altered the balance of 11betaHSD1 expression and activity between adipose tissue depots, with higher levels in subcutaneous than visceral adipose tissue of estradiol-treated animals (P < 0.05 for both), opposite the pattern in ovariectomized rats not treated with estradiol (P < 0.001 for mRNA expression). Thus, estrogen modulates fat distribution, at least in part, through effects on tissue-specific glucocorticoid metabolism, suggesting that estrogen replacement therapy could influence obesity related morbidity in postmenopausal women.
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| 2. |
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| 3. |
- Andersson, Therése, 1978-, et al.
(författare)
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Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:12, s. e8475-
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Tidskriftsartikel (refereegranskat)abstract
- 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 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11betaHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11betaHSD1 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 11betaHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5alpha-tetrahydrocortisol+5beta-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11betaHSD1 activity. Postmenopausal women had higher 11betaHSD1 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 11betaHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11betaHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.
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| 4. |
- Mattsson, Cecilia, et al.
(författare)
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Combined receptor antagonist stimulation of the HPA axis test identifies impaired negative feedback sensitivity to cortisol in obese men
- 2009
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:4, s. 1347-1352
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Tidskriftsartikel (refereegranskat)abstract
- Context: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone, but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR). Objective: To use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity. Design: Double blind, placebo-controlled randomized cross-over study. Setting: Clinical research facility. Participants: 15 lean (BMI 22.0+/-1.6 kg/m(2)) and 16 overweight/obese (BMI 30.1+/-3.5 kg/m(2)) men. Intervention: Subjects attended on four occasions for blood and saliva sampling every 30 minutes between 1800h and 2200h. At 1100h and 1600h before visits subjects took either 200mg spironolactone, 400mg RU38486, 200mg spironolactone + 400mg RU38486, or placebo orally. Main outcome measures: serum cortisol levels following drug or placebo. Results: Cortisol levels did not differ between lean and obese following placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by <50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, moreso in lean than obese men (2.9(0.3) vs 2.2(0.3) fold elevation, p=0.002). Conclusions: Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.
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| 5. |
- Simonyté, Kotryna, 1979-
(författare)
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Alterations in peripheral glucocorticoid metabolism : effects of weight changes
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: An important role has been suggested for tissue-specific glucocorticoid metabolism in the development of obesity and its complications. 11ß hydroxysteroid dehydrogenase 1 (11ßHSD1) is an enzyme that catalyzes the interconversion of biologically inactive cortisone to active cortisol, thereby regulating its access to glucocorticoid receptors in target tissues. Indeed, an unfavorable metabolic outcome has been associated with increased 11ßHSD1 gene expression and activity in adipose tissue and liver in humans and rodents. Cortisol is an important regulator of phosphoenolpyruvate carboxykinase (PEPCK) a key enzyme in gluconeogenesis and lipid metabolism. In rodents, overexpression of PEPCK in adipose tissue leads to adiposity and increased fatty acid re-esterification. In human obesity, PEPCK has been positively associated with body fat, total cholesterol levels, and plasma triglycerides. However, few studies have addressed the putative reversibility of peripheral cortisol levels and disturbed fatty acid homeostasis that may accompany weight loss. The aim of this thesis was to investigate alterations in peripheral glucocorticoid metabolism in the context of obesity, and putative modulations of glucocorticoid metabolism in the context of weight changes in humans and rodents. Materials & Methods: 11ßHSD1 expression/activity in different adipose tissue depots and liver, the expression of genes involved in adipogenesis and fatty acid homeostasis, and serum levels of adipose tissue-derived adipokines were investigated in severely obese women before and after surgically induced weight loss. The same parameters were measured in female Sprague-Dawley rats fed on high-fat and control diets. Results: In severely obese women, 11ßHSD1 expression was higher in subcutaneous adipose tissue (SAT), while 11ßHSD1 activity and PEPCK expression were higher in the omental depot. In a multivariate analysis, SAT 11ßHSD1 activity was an independent predictor for central fat accumulation. Hepatic 11ßHSD1 activity and levels of intra-abdominal fat storage correlated negatively, while 11ßHSD1 correlated positively with PEPCK in adipose tissue and liver. Weight loss after gastric bypass surgery was followed by significant and metabolically beneficial reductions in subcutaneous 11ßHSD1 and leptin gene expression, as well as reduced circulating leptin and increased adiponectin levels. In contrast, PEPCK gene expression did not change with weight loss. In rats, a high-fat diet did not affect body weight, but was associated with increased serum leptin and decreased adiponectin levels. Short-term, high-fat diet feeding resulted in the up-regulation of SAT 11ßHSD1 expression, while chronic feeding led to its significant down-regulation (compared with the control diet and short-term, high-fat feeding). Interestingly, hepatic 11ßHSD1 expression was constantly downregulated in rats that were fed a high-fat diet. Conclusions: Severe obesity in women was accompanied by a metabolically adverse increase of 11ßHSD1 in adipose tissue, with a concomitant decrease in the liver. Subcutaneous 11ßHSD1 was an independent predictor for central fat accumulation. As weight loss was followed by significant down-regulation of subcutaneous 11ßHSD1, we suggest that up-regulation of this enzyme was a consequence, rather than a cause of obesity. In rodents, a high-fat diet induced dynamic changes in 11ßHSD1 in SAT and liver, both being down-regulated after chronic high-fat feeding without altered weight. In summary, weight changes and alterations in fat and liver glucocorticoid metabolism are closely linked. Moreover, a high-fat diet significantly influences 11ßHSD1 expression/activity in adipose tissue and liver without affecting body weight.
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| 6. |
- Simonyte, Kotryna, 1979-, et al.
(författare)
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Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling.
- 2009
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Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-7381 .- 1930-739X. ; 17:11, s. 1982-7
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Tidskriftsartikel (refereegranskat)abstract
- 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).
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| 8. |
- Simonyte, Kotryna, 1979-, et al.
(författare)
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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
- 2010
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Ingår i: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM. - : Williams & Wilkins Co.. - 0021-972X .- 1945-7197. ; 95:7, s. 3527-3531
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Tidskriftsartikel (refereegranskat)abstract
- 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 (P < 0.001). Both leptin and adiponectin mRNA expression decreased, with concomitantly decreased circulating leptin and increased circulating adiponectin levels. PEPCK mRNA expression did not change. CONCLUSION: Weight loss after gastric bypass surgery was followed by metabolically favorable changes in insulin sensitivity, circulating leptin and adiponectin, and peripheral glucocorticoid metabolism. A significant reduction in 11beta-HSD1 expression was observed in sc adipose tissue after weight loss. This suggests that up-regulation of 11beta-HSD1 is a consequence, rather than a cause, of obesity.
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