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Alterations in peripheral glucocorticoid metabolism: effects of weight changes
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2011. , 44 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1418
Keyword [en]
11ß Hydroxysteroid dehydrogenase 1, obesity, glucocorticoids, cortisol, phosphoenolpyruvate carboxykinase, adipose tissue, liver
National Category
Endocrinology and Diabetes
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-43160ISBN: 978-91-7459-192-7OAI: oai:DiVA.org:umu-43160DiVA: diva2:412163
Public defence
2011-05-13, Hörsal Betula, NUS, By 6M, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-04-21 Created: 2011-04-20 Last updated: 2011-04-26Bibliographically approved
List of papers
1. Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling
Open this publication in new window or tab >>Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling
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2009 (English)In: Obesity (Silver Spring, Md.), ISSN 1930-7381, Vol. 17, no 11, 1982-1987 p.Article in journal (Refereed) Published
Abstract [en]

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).

Identifiers
urn:nbn:se:umu:diva-32385 (URN)10.1038/oby.2009.99 (DOI)19360009 (PubMedID)
Available from: 2010-03-10 Created: 2010-03-10 Last updated: 2011-04-26Bibliographically approved
2. Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue
Open this publication in new window or tab >>Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue
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2010 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 7, 3527-3531 p.Article in journal (Refereed) Published
Abstract [en]

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.

Identifiers
urn:nbn:se:umu:diva-41447 (URN)10.1210/jc.2009-2472 (DOI)000279589600062 ()20410231 (PubMedID)
Available from: 2011-03-24 Created: 2011-03-24 Last updated: 2011-04-26Bibliographically approved
3. Short- and long-term effects of high-fat diet on 11ßHSD1 expression in subcutaneous adipose tissue and liver of female Sprague-Dawley rats
Open this publication in new window or tab >>Short- and long-term effects of high-fat diet on 11ßHSD1 expression in subcutaneous adipose tissue and liver of female Sprague-Dawley rats
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-43161 (URN)
Available from: 2011-04-20 Created: 2011-04-20 Last updated: 2011-04-26Bibliographically approved

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