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Adipose tissue as an active organ:  blood flow regulation and tissue-specific glucocorticoid metabolism
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Despite advances in the treatment of atherosclerosis, cardiovascular disease is the leading cause of death worldwide. With the population getting older and more obese, the burden of cardiovascular disease may further increase. Premenopausal women are relatively protected against cardiovascular disease compared to men, but the reasons for this sex difference are partly unknown. Redistribution of body fat from peripheral to central depots may be a contributing factor. Central fat is associated with hyperlipidemia, hyperglycemia, hypertension, and insulin resistance. Two possible mediators of these metabolic disturbances are tissue-specific production of the stress hormone cortisol and adipose tissue blood flow (ATBF). The aim of this thesis was to determine the adipose tissue production of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and to investigate the regulation of ATBF.

Materials and Methods: Cortisol release was estimated by labeled cortisol infusions and tissue-specific catheterizations of subcutaneous and visceral adipose tissue (VAT) in men. We investigated ATBF by 133Xe-washout and its relation to autonomic activity, endothelial function, adipose tissue distribution, and adipokines in different groups of women. We further investigated the effect of two diets and of weight loss on ATBF in women.

Results: We demonstrated significant cortisol release from subcutaneous adipose tissue in humans. Splanchnic cortisol release was accounted for entirely by the liver. Cortisol release from VAT (to the portal vein) was not detected. ATBF decreased according to increasing weight and postmenopausal status, and the level of blood flow was associated with nitric oxide (NO) activity and autonomic activity. ATBF was also highly associated with leptin levels and both subcutaneous adipose tissue and VAT areas. After 6 months of diet and weight reduction, a significant difference in ATBF was observed between diet groups.

Conclusions: Our data for the first time demonstrate the contributions of cortisol generated from subcutaneous adipose tissue, visceral tissues, and liver by 11β-HSD1. ATBF is linked to autonomic activity, NO activity, and the amount of adipose tissue (independent of fat depot). Postmenopausal overweight women exhibited a loss of ATBF flexibility, which may contribute to the metabolic dysfunction seen in this group. Weight loss in a diet program could not increase the ATBF, although there were ATBF differences between diet groups. The results will increase understanding of adipose tissue biology and contribute to the development of treatment strategies targeting obesity and obesity-related disorders.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2011. , 87 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1444
Keyword [en]
11β-hydroxysteroid dehydrogenase type 1, adipose tissue, autonomic nervous system, blood flow, cortisol, nitric oxide, weight loss.
National Category
Other Clinical Medicine
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-48415ISBN: 978-91-7459-280-1 (print)OAI: oai:DiVA.org:umu-48415DiVA: diva2:449158
Public defence
2011-11-11, Hörsal Betula, byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2011-10-21 Created: 2011-10-19 Last updated: 2011-10-21Bibliographically approved
List of papers
1. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans
Open this publication in new window or tab >>Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans
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2009 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, no 1, 46-53 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from cortisone. 11beta-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11beta-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11beta-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo.

RESEARCH DESIGN AND METHODS: Six healthy men underwent 9,11,12,12-[(2)H](4)-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein.

RESULTS: Significant cortisol and 9,12,12-[(2)H](3)-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol . min(-1) . 100 g(-1) adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[(2)H](3)-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected.

CONCLUSIONS: Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11beta-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32405 (URN)10.2337/db08-0969 (DOI)18852329 (PubMedID)
Available from: 2010-03-11 Created: 2010-03-11 Last updated: 2017-12-12Bibliographically approved
2. Dysregulation of subcutaneous adipose tissue blood flow in overweight postmenopausal women
Open this publication in new window or tab >>Dysregulation of subcutaneous adipose tissue blood flow in overweight postmenopausal women
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2010 (English)In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 17, no 2, 365-371 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:: A putative link between abdominal obesity and metabolic-vascular complications after menopause may be due to a decreased adipose tissue blood flow (ATBF). The present work aimed to analyze possible changes in ATBF with being overweight and menopausal and its putative link to endothelial dysfunction and autonomic nervous system balance.

METHODS:: Forty-three healthy women were classified into four groups according to weight and menopause status. The ATBF was measured by xenon washout while fasting and after oral glucose intake. The nitric oxide synthase inhibitor asymmetric dimethylarginine was used as a marker of endothelial function and heart rate variability-estimated autonomic nervous system activity.

RESULTS:: Fasting ATBF was decreased in both overweight groups (P = 0.044 and P = 0.048) versus normal-weight premenopausal women. Normal-weight and overweight postmenopausal women exhibited lower maximum ATBF compared with normal-weight premenopausal women (P = 0.015 and P = 0.001, respectively), and overweight postmenopausal women exhibited lower maximum ATBF compared with normal-weight postmenopausal women (P = 0.003). A negative correlation was found between fasting ATBF and asymmetric dimethylarginine (P = 0.015), whereas maximum ATBF was negatively associated with sympathetic-parasympathetic nervous system balance (ratio of the power of the low frequency to the power of the high frequency; P = 0.002).

CONCLUSIONS:: Loss of ATBF flexibility in overweight postmenopausal women may contribute to the metabolic dysfunction seen in this group of women.

Keyword
Adipose tissue, autonomic nervous system, blood flow, nitric oxide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32514 (URN)10.1097/gme.0b013e3181c12b26 (DOI)19940788 (PubMedID)
Available from: 2010-03-16 Created: 2010-03-16 Last updated: 2017-12-12Bibliographically approved
3. Association of adipose tissue blood flow with fat depot sizes and adipokines in women
Open this publication in new window or tab >>Association of adipose tissue blood flow with fat depot sizes and adipokines in women
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2012 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, no 6, 783-789 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To explore possible associations between adipose tissue (AT) blood flow (ATBF), AT depot sizes and adipocyte-derived hormones (adipokines) in women.

Subjects: In all, 43 healthy women were divided into four groups: normal-weight (n=11) and obese (n=11) pre-menopausal women and normal-weight (n=10) and obese (n=11) post-menopausal women.

Methods: Fasting levels of adipokines were obtained, and a single-slice computed tomography scan at the level of L4-L5 was used to estimate fat depot sizes. ATBF was assessed by xenon washout while in a fasting state and after oral glucose load. We also measured glucose, insulin and non-esterified fatty acids.

Results: Total, subcutaneous and visceral AT areas strongly correlated with ATBF (all P<0.001). Circulating leptin levels strongly and inversely correlated with ATBF (P=0.001), but this association did not remain after adjustment for body mass index. Adiponectin was not associated with blood flow.

Conclusion: ATBF is closely linked to subcutaneous and visceral AT size. Further analyses are needed to determine possible mediators of this association, including mechanistic studies to assess a putative role for leptin as a significant modulator of blood flow. International Journal of Obesity advance online publication, 26 July 2011; doi:10.1038/ijo.2011.152.

Place, publisher, year, edition, pages
Nature Publishing Group, 2012
Keyword
adipose tissue, blood flow, body fat distribution, leptin, women
National Category
Other Clinical Medicine
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-48345 (URN)10.1038/ijo.2011.152 (DOI)000305282400004 ()21792171 (PubMedID)
Available from: 2011-10-19 Created: 2011-10-18 Last updated: 2017-12-08Bibliographically approved
4. Long term effects of a diet intervention on adipose tissue blood flow, heart rate variability and endothelial function: a randomized controlled trial
Open this publication in new window or tab >>Long term effects of a diet intervention on adipose tissue blood flow, heart rate variability and endothelial function: a randomized controlled trial
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(English)Manuscript (preprint) (Other academic)
Keyword
Adipose tissue, blood flow, autonomic nervous system, diet, endothelial function, weight reduction
National Category
Other Clinical Medicine
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-48346 (URN)
Available from: 2011-10-18 Created: 2011-10-18 Last updated: 2014-08-18Bibliographically approved

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