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Adipocyte-derived hormones and cardiovascular disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is increasing globally and related to major changes in lifestyle. This increase is associated with an increased risk of cardiovascular disease (CVD). Knowledge about adipose tissue as a metabolic-endocrine organ has increased during the last few decades. Adipose tissue produces a number of proteins with increased body weight, many of which are important for food intake and satiety, insulin sensitivity, and vessel integrity, and aberrations have been related to atherosclerosis. Notably, the risk for developing CVD over the course of a lifetime differs between men and women. In Northern Sweden, men have a higher risk for myocardial infarction (MI). However, the incidence is declining in men but not in women. These sex differences could be due to functional and anatomical differences in the fat mass and its functions.

The primary aim of this thesis was to evaluate associations between the adipocyte-derived hormones leptin and adiponectin, and fibrinolysis and other variables associated with the metabolic syndrome, and particularly whether these associations differ between men and women. Another aim was to evaluate these associations during physical exercise and pharmacological intervention (i.e. enalapril). Finally, whether leptin and adiponectin predict a first MI or sudden cardiac death with putative sex differences was also investigated.

The first study used a cross-sectional design and included 72 men and women  recruited from the WHO MONICA project. We found pronounced sex differences in the associations with fibrinolytic variables. Leptin was associated with fibrinolytic factors in men, whereas insulin resistance was strongly associated with all fibrinolytic factors in women. The second study was an experimental observational study with 20 men exposed to strenuous physical exercise. During exercise, leptin levels decreased and adiponectin levels increased, and both were strongly associated with an improved fibrinolytic capacity measured as decreased PAI-1 activity. Changes in insulin sensitivity were not associated with changing adiponectin levels. The third study was a randomised, double-blind, single centre clinical trial including 46 men and 37 women who had an earlier MI. The study duration was one year, and participating subjects were randomised to either placebo or ACE inhibitor (i.e. enalapril). Circulating leptin levels were not associated with enalapril treatment. During the one-year study, changes in leptin levels were associated with changes in circulating levels of tPA mass, PAI-1 mass, and tPA-PAI complex in men, but not vWF. These associations were found in all men and men on placebo treatment. In women on enalapril treatment there was an association between changes in leptin and changes in vWF. In the fourth study, the impact of leptin, adiponectin, and their ratio on future MI risk or sudden cardiac death was tested in a prospective nested casecontrol study within the framework of the WHO MONICA, Västerbotten Intervention Project (VIP), and Västerbotten  Mammary Screening Program (MSP). A total 564 cases (first-ever MI or sudden cardiac death) and 1082 matched controls were selected. High leptin, low adiponectin, and a high leptin/adiponectin ratio independently predicted a first-ever MI, possibly with higher risk in men in regards to leptin. The association was found for non-fatal cases with ST-elevation MI. Subjects with low adiponectin levels had their MI earlier than those with high levels.

In conclusion, the adipocyte-derived hormones leptin and adiponectin are related to the development of CVD with a sex difference, and fibrinolytic mechanisms could be possible contributors to CVD risk.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2010. , 110 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1358
Keyword [en]
leptin, adiponectin, fibrinolysis, vWF, myocardial infarction, sex differences, physical activity, risk factors
Identifiers
URN: urn:nbn:se:umu:diva-36679ISBN: 978-91-7459-041-8 (print)OAI: oai:DiVA.org:umu-36679DiVA: diva2:355615
Public defence
2010-10-29, Tandläkarhögskolan Sal B, Umeå universitet, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-10-11 Created: 2010-10-07 Last updated: 2010-10-11Bibliographically approved
List of papers
1. Sex-related differences in the associations between hyperleptinemia, insulin resistance and dysfibrinolysis
Open this publication in new window or tab >>Sex-related differences in the associations between hyperleptinemia, insulin resistance and dysfibrinolysis
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2008 (English)In: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 19, no 7, 625-632 p.Article in journal (Refereed) Published
Abstract [en]

The adipocyte-derived hormone leptin is associated with insulin resistance and reduced fibrinolytic status--or dysfibrinolysis--in humans. As leptin associates differentially to the development of cardiovascular disease and diabetes in men and women, we hypothesized that leptin and insulin sensitivity are related to dysfibrinolysis in a sex-dependent manner. Thirty-two men and 40 women were recruited from the Monitoring of trends and determinants in Cardiovascular disease (MONICA) population sample, representing the highest and lowest quartiles of fasting insulin levels. Lipids, fibrinolytic status [plasminogen activator inhibitor 1 (PAI-1) activity, tissue plasminogen activator (tPA) mass and activity, and tPA-PAI complex], leptin, testosterone and sex-hormone-binding globulin were measured. Insulin sensitivity was estimated using the euglycaemic clamp technique. Body composition was determined by bioimpedance. Determinants for circulating levels of fibrinolytic factors were explored in a multivariate linear regression analysis. Levels of fibrinolytic variables and estimated insulin sensitivity did not differ between men and women. Leptin was independently associated with reduced fibrinolytic status (high PAI-1 activity, low tPA activity, high tPA mass, and high tPA-PAI complex) in men (P < 0.001-0.002). In women, fat mass and/or insulin sensitivity were related to these factors (P < 0.001-0.03), and leptin only to reduced tPA activity (P = 0.002). Hyperleptinemia, dysfibrinolysis, insulin sensitivity and androgenicity associate differentially in men and women.

Keyword
androgens; dysfibrinolysis; hyperleptinemia; insulin resistance; sex
Identifiers
urn:nbn:se:umu:diva-18465 (URN)10.1097/MBC.0b013e3283099046 (DOI)18832901 (PubMedID)
Available from: 2009-02-10 Created: 2009-02-10 Last updated: 2017-12-14Bibliographically approved
2. Improved fibrinolytic activity during exercise may be an effect of the adipocyte-derived hormones leptin and adiponectin
Open this publication in new window or tab >>Improved fibrinolytic activity during exercise may be an effect of the adipocyte-derived hormones leptin and adiponectin
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2008 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 122, no 5, 701-708 p.Article in journal (Refereed) Published
Abstract [en]
Introduction

Physical activity is associated with improved fibrinolytic activity and reduced risk for cardiovascular disease. High levels of leptin and low levels of adiponectin, both adipocyte-derived hormones, or adipokines, are related to dysfibrinolysis and risk for cardiovascular disease. In this study, we explored if improved fibrinolytic activity during exercise could be linked to changes in leptin and adiponectin levels.

Materials and methods

Twenty healthy men (mean age 36 years) participated in a 14-day long skiing expedition in the Swedish mountains. They were randomly assigned to either a 40% or a 30% fat-based diet. Anthropometry, lipids, fibrinolytic activity (PAI-1 activity, tPA activity and mass) and adipokines (leptin and adiponectin) were measured before, during and six weeks after the expedition.

Results

PAI-1 activity and circulating levels of leptin decreased whereas levels of adiponectin increased during exercise. The fall in PAI-1 activity showed a strong linear association with changes in leptin and adiponectin levels (p = 0.001 and p < 0.001, respectively). Changes in leptin and adiponectin levels were independent of decreasing waist circumference. However, the association between anthropometric measures and adipokines changed considerably during the expedition. Adiponectin was weakly and negatively associated with BMI at baseline. In contrast, there was a strong positive association between adiponectin and BMI after two weeks of exercise, whereas the association between leptin and BMI became less pronounced. In addition, increasing leptin and decreasing adiponectin levels were associated with increasing PAI-1 activity during the six weeks following the expedition. After six weeks of normal activity, fibrinolytic activity and hormone levels returned towards baseline levels.

Conclusion

Heavy exercise induced improved fibrinolytic activity, which was associated independently with changes in circulating levels of the adipocyte-derived hormones leptin and adiponectin. Improved fibrinolytic activity (and reduced risk for cardiovascular disease) related to physical activity could possibly be mediated by leptin and adiponectin.

Keyword
Fibrinolytic activity; Adipocyte-derived hormones; Leptin; Adiponectin; Healthy men; Physical activity; Clinical experiment; Repeated measures
Identifiers
urn:nbn:se:umu:diva-10470 (URN)10.1016/j.thromres.2008.01.010 (DOI)18387655 (PubMedID)
Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2017-12-14Bibliographically approved
3. Leptin levels are not associated with enalapril treatment after an uncomplicated myocardial infarction, but associate strongly with changes in fibrinolytic variables in men
Open this publication in new window or tab >>Leptin levels are not associated with enalapril treatment after an uncomplicated myocardial infarction, but associate strongly with changes in fibrinolytic variables in men
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(Swedish)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-36676 (URN)
Available from: 2010-10-07 Created: 2010-10-07 Last updated: 2010-10-11Bibliographically approved
4. Leptin and adiponectin predict independently a first-ever myocardial infarction with a sex difference: data from a large prospective Swedish nested case-referent study
Open this publication in new window or tab >>Leptin and adiponectin predict independently a first-ever myocardial infarction with a sex difference: data from a large prospective Swedish nested case-referent study
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-36677 (URN)
Available from: 2010-10-07 Created: 2010-10-07 Last updated: 2015-04-29Bibliographically approved

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