| 1. |
- Alimohammadi, Mohammad, 1978-
(författare)
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Molecular Targets in Autoimmune Polyendocrine Syndrome Type1 and Their Clinical Implications
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Autoimmunity is known to cause a wide range of disorders, and is suspected to be responsible for many more. Most autoimmune disorders are chronic and cause severe morbidity for the patients, and are also costly for society. A majority of these disorders are today considered as complex diseases with incompletely known etiology. Hence, model systems for studying the pathogenesis of autoimmunity are important to unravel its causes. Autoimmune Polyendocrine Syndrome Type 1 (APS-1), (OMIM 240300), is a rare autoimmune disorder. Patients with APS-1 progressively develop multiple organ-specific autoimmune lesions involving both endocrine and non endocrine tissues. Typical autoimmune disease components in APS-1 are hypoparathyroidism, Addison’s disease, vitiligo, alopecia and type 1 diabetes. The gene preventing APS-1 has been identified and designated Autoimmune Regulator (AIRE). It has been shown that mutations of AIRE cause loss of tolerance to self-structures, resulting in organ-specific autoimmunity. Although APS-1 is a rare syndrome occurring mainly in genetically isolated populations, the disease components of APS-1 are, in isolated forms, not unusual in the general population and affect many patients. Hence, APS-1 is an attractive model disease for studies of molecular mechanisms underlying organ-specific autoimmunity. This thesis concerns investigations in which two novel autoantigens are identified in APS-1 and used in serological diagnosis of the disease. NALP5, is identified as a parathyroid autoantigen - an important finding since autoimmune hypoparathyroidism is one of the cardinal symptoms of APS-1. Additionally, KCNRG is identified as a bronchial autoantigen in APS-1 patients with respiratory symptoms. Finally, studies that compare the immune response in APS-1 patients and the mouse model for APS-1 are presented.
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| 2. |
- Alvehus, Malin, 1975-
(författare)
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Obesity-associated inflammation in adipose tissue
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Excess body fat, particularly in the visceral depot, is linked to increased mortality and morbidity, including the development of diseases such as type 2 diabetes, cardiovascular disease, and cancer. Chronic low-grade inflammation in adipose tissue may be a key mediator of obesity-associated diseases. Importantly, specific pro-inflammatory cytokines have been shown to influence adipose tissue function and could therefore be a link to metabolic disorders. Circulating cytokine levels may also be increased in obesity and metabolic diseases. However, although fat distribution and inflammation are clearly linked to metabolic disorders, inflammatory gene expression in the different abdominal adipose depots has not been investigated in detail. The menopausal transition is followed by a centralization of body fat and increased adiposity. Notably, inflammatory changes in fat during the menopausal transition have not been characterized. Finally, there is a lack of studies investigating the long-term effects of weight loss on low-grade inflammation. The aim of this thesis was to characterize differences between fat depots and investigate putative changes in low-grade inflammation in adipose tissue and circulation following menopause or weight loss. Materials & Methods: The expression of inflammation-related genes was investigated in abdominal adipose tissue depots obtained from women with varying adiposity, before and after menopause or weight loss induced by surgery or dietary intervention. Circulating cytokine levels were analyzed using immunoassays. Results: Visceral fat displayed a distinct and adverse inflammatory profile compared with subcutaneous adipose tissues, and the higher gene expression in visceral fat was associated with adiposity. Postmenopausal women exhibited a higher expression of pro-inflammatory genes than premenopausal women that associated with central fat accumulation. There was also a menopause-related increase in circulating cytokine levels in postmenopausal women. After surgery-induced weight loss, there was a dramatic reduction in inflammatory gene expression followed by increased insulin sensitivity. We observed no alterations in circulating cytokine levels. Long-term dietary intervention, associated with weight loss, had favorable effects on inflammation in both adipose tissue and serum. Conclusion: Fat accumulation is linked to low-grade inflammation in abdominal adipose tissue. The unique inflammatory pattern of visceral fat suggests a distinct role in adipose tissue inflammation that is aggravated with increasing adiposity. In postmenopausal women, the adverse adipose inflammatory profile was associated with central fat accumulation, while higher circulating cytokine levels correlated with menopausal state/age. Our data from severely obese women undergoing surgery-induced weight loss clearly supports a link between adipose inflammation and insulin resistance. The long-term beneficial effects of weight loss were also demonstrated by the improved inflammatory profile after dietary intervention. In summary, excess body fat is clearly linked to adipose tissue inflammation. Long-term weight loss is accompanied by improved metabolic profile and reduced low-grade inflammation in fat.
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| 3. |
- Andersson, Jonas, 1969-
(författare)
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Adipose tissue as an active organ : blood flow regulation and tissue-specific glucocorticoid metabolism
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Andersson, Therése, 1978-
(författare)
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Estrogen and Glucocorticoid Metabolism
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cardiovascular disease (CVD) is the leading cause of death among women in Sweden. The risk of CVD increases rapidly after the menopause. A major contributing factor may be the redistribution of adipose tissue, from the peripheral to central depots, associated with menopause. This change in body composition is commonly attributed to declining estrogen levels but may also be affected by tissue-specific alterations in exposure to other steroid hormones, notably glucocorticoids – mainly cortisol in humans. Indeed, adipose tissue-specific overexpression of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) induces central obesity, insulin resistance and hypertension in mice. Interestingly, estrogen may regulate this enzyme. The aim of this thesis was to investigate putative links between estrogen and glucocorticoid activation by 11βHSD1. Materials and Methods: 11βHSD1 expression and/or activity in adipose tissue and liver, and adipose estrogen receptor α and β (ERα and ERβ) gene expression, were investigated in lean pre- and postmenopausal women and ovariectomized rodents with and without estrogen supplementation. In lean women measures of 11βHSD1 were correlated to risk markers for CVD. The association between adipose 11βHSD1 and ER mRNA expression was investigated in both lean women and rats and in an additional cohort of obese premenopausal women. In vitro experiments with adipocyte cell lines were used to explore possible pathways for estrogen regulation of 11βHSD1. Results: Subcutaneous adipose tissue transcript levels and hepatic activity of 11βHSD1 were higher in postmenopausal vs. premenopausal women. In rodents, estrogen treatment to ovariectomized rats decreased visceral adipose tissue 11βHSD1, resulting in a shift towards higher subcutaneous (vs. visceral) 11βHSD1 mRNA expression/activity. Increased adipose and hepatic 11βHSD1 were associated with increased blood pressure and a disadvantageous blood lipid profile in humans. We found significant positive associations between 11βHSD1 and ERβ transcript levels in adipose tissue. The in vitro experiments showed upregulation of 11βHSD1 mRNA expression and activity with estrogen or ERβ-agonist treatment at low (corresponding to physiological) concentrations. Conclusions: Our studies show for the first time increased local tissue glucocorticoid activation with menopause/age in women. This may contribute to an increased risk of CVD. Estrogen treatment in rodents induces a shift in 11βHSD1 activity towards the subcutaneous adipose tissue depots, which may direct fat accumulation to this metabolically “safer” depot. The in vitro studies suggest that low-dose estrogen treatment upregulates 11βHSD1 via ERβ. In summary, estrogen - glucocorticoid metabolism interactions may be key in the development of menopause-related metabolic dysfunction and in part mediate the beneficial effects of postmenopausal estrogen treatment on body fat distribution.
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| 5. |
- Bergman, Frida, 1984-
(författare)
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Active workstations : a NEAT way to prevent and treat overweight and obesity?
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Modern society is triggering sedentary behaviours in different domains. Different strategies can be used to reduce the time spent sitting and increase physical activity in the office environment, which is one domain where sedentary time is often high. One such strategy could be to install treadmill workstations. With these, the office workers can walk on a treadmill while performing their usual work tasks at the computer. However, the long-term effects of these workstations are not known. Aim: The overall aim of this thesis was to investigate the long-term effects on sedentary behaviour, physical activity and associated health factors of installing treadmill workstations in offices compared to regular office work.Method: In this randomized controlled trial, 80 sedentary, middle-aged, healthy office workers with overweight or obesity were individually randomized into either an intervention or a control group. Those in the intervention group had a treadmill workstation installed at their sit-stand desk, to use for at least one hour per day for 13 months. They further received boosting e-mails at four time-points during the study. Participants in the control group continued to work as normal at their sit-stand office desk. All participants also received a health consultation at the beginning of the study, where they got to discuss physical activity and diet recommendations. Measurements reported include physical activity and sedentary behaviour, anthropometric measurements, body composition, metabolic outcomes, stress, depression and anxiety, cognitive function, structural brain images and interview data. Linear mixed models were used for the main statistical analyses of the quantitative data. An exploratory approach was also undertaken, using orthogonal partial least squares regression on the baseline data. Finally, interview data from participants in the intervention group were analysed using a modified Grounded Theory approach.Results: The intervention group increased their daily walking time and their number of steps at all follow-ups compared to the control group. Concomitantly, a decrease in moderate-to-vigorous intensity physical activity (MVPA) was observed within both groups, mainly during weekends. No intervention effects were observed on any of the body, cognitive or brain volume measurements. Our exploratory analyses revealed a significant association between smaller hippocampal volume and percentage sitting time among participants over 51 years of age. From the interview data, we discovered a core category, “The Capacity to Benefit”. The categories were described as the ideal types the Convinced, the Competitive, the Responsible and the Vacillating, based on the principal characteristics of the participants representing their different motivational status and strategies to reach the goal of benefitting from the intervention. Conclusion: It is possible to increase daily physical activity in office environments by introducing treadmill workstations. Future interventions should adapt strategies for the individuals based on their motivational level, but should also workwith the social and physical environment and with factors within the organization to gain the best effects of these interventions.
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| 6. |
- Blomquist, Caroline, 1966-
(författare)
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Metabolic consequences of a Paleolithic diet in obese postmenopausal women
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundObesity, in particular abdominal adiposity, is associated with elevated fatty acids and pro-inflammatory adipokines, which are linked to ectopic fat storage and insulin resistance. During menopause, there is a redistribution of fat from the peripheral to abdominal depots. This transition is associated with an increased risk of type 2 diabetes and cardiovascular diseases. We hypothesized that a Paleolithic diet, with high proportions of lean meat, fish, vegetables, fruits, and oils, but devoid of dairy products and cereals, might have long-term beneficial effects on inflammation, fat metabolism, and circulating fatty acids. These effects might potentially reduce the risk of metabolic complications in postmenopausal women that are obese. MethodsPostmenopausal women with obesity were studied before, after six months, and after 24 months of one of two specified ad libitum diets. One diet was a Paleolithic diet, in which approximately 30% of the total energy (E%) was protein, 30 E% was fat, and 40 E% was carbohydrate. The other diet was a prudent control diet, consistent with Nordic Nutrition recommendations of 15 E% protein, 25 E% fat, and 55 E% carbohydrate. Dietary intakes of polyunsaturated fatty acids and protein were validated objectively by measuring circulating and urinary biomarkers. Anthropometrics and diet reports were analyzed, and abdominal subcutaneous fat samples were evaluated for the expression of proteins key in inflammation and fat metabolism and for lipoprotein lipase mass and activity. In addition, blood samples were analyzed to determine concentrations of specific serum proteins, serum lipids, and the fatty acids carried in cholesterol esters.ResultsThe Paleolithic diet group reported reduced intakes of saturated fatty acids and carbohydrates and elevated intakes of protein and unsaturated fatty acids, compared to baseline. The elevated intakes of polyunsaturated fatty acids and protein were objectively verified for this group. After 24 months, both diets were found to have beneficial effects on the expression of inflammation-related genes in adipose tissue and pro-inflammatory factors in the circulation. Compared to the control group, the Paleolithic diet group exhibited more pronounced reductions of circulating cardiometabolic risk factors, including the ratio of triglycerides to high density lipoprotein, lipogenic index, specific fatty acids, and indices of desaturase activities. After six months, the Paleolithic group also exhibited more pronounced reductions in lipogenesis-promoting factors, including the expression of key proteins in fat synthesis, the activity of lipoprotein lipase, and the activity of stearoyl-CoA desaturase 1, compared to the control group.ConclusionLong-term weight loss in postmenopausal obese women was accompanied by reductions in low-grade inflammation in adipose tissue and in the circulation. In addition, a Paleolithic diet, with a high content of unsaturated fatty acids and a low content of refined carbohydrates, appeared to provide greater reductions in cardiometabolic risk factors associated with insulin resistance and lipogenesis, compared to a prudent control diet.
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| 7. |
- Bäcklund, Nils, 1987-
(författare)
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Diagnosing hyper- and hypocortisolism using saliva samples : pitfalls and how to avoid them
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cushing's syndrome (CS) is caused by high cortisol secretion whereas insufficient cortisol secretion is called adrenal insufficiency (AI). Both are rare diseases with substantial diagnostic delay, and high morbidity and mortality even though effective treatment is available. This thesis aims to improve diagnostic tests for CS and AI using analyses of cortisol and its inactive metabolite cortisone in saliva samples.Methods: Papers 1 and 2 are based on a reference cohort including 155 individuals and 22 patients with CS. Salivary samples were collected at late-night (23:00 hours ± 15 minutes) and after a 1-mg overnight dexamethasone suppression test (DST). In Paper 1, reference intervals for salivary cortisol and cortisone analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were established for late-night and post-DST samples. Diagnostic accuracy for CS was calculated using the established reference intervals. Potential effects of age, comorbidities, season, and sampling time point were also studied. In Paper 2, different analytical methods for measurement of salivary cortisol (3 LC-MS/MS and 3 immunoassays) and salivary cortisone (3 LC-MS/MS assays) were compared regarding reference intervals and diagnostic accuracies for CS. Paper 3 elucidated the potential effect of liquorice consumption, blood contamination, and topical hydrocortisone handling prior to sampling on salivary cortisol and cortisone. Paper 4 investigated whether salivary cortisol and cortisone are less affected than plasma cortisol by estrogen-containing oral contraceptive (OCs) in women undergoing a short Synacthen test (SST) by comparing the response in women with (n=41) and without OCs (n=46).Results: Paper 1 established reference intervals for salivary cortisol and cortisone at 23:00 hours and after DST. Using the upper reference limits as cut-offs, the diagnostic tests rendered high diagnostic accuracy for CS using salivary cortisol (sensitivity 90–95 %, specificity 96 %). There was no seasonal variation and no significant difference between samples collected at 22:00 vs 23:00 hours. Salivary cortisone showed a higher diagnostic accuracy for CS (sensitivity 100 % and specificity 94–95 %) and was less affected by other comorbidities compared to salivary cortisol. Paper 2 showed very high agreement between the three LC-MS/MS methods and that measuring salivary cortisol with immunoassays resulted in higher cortisol concentrations than with LC-MS/MS. However, using the newly established reference limits for each method, all had high diagnostic accuracy for CS. Late-night salivary cortisone analyzed with the LC-MS/MS methods and salivary cortisol analyzed with the Roche immunoassay showed the highest diagnostic accuracies. Paper 3 showed that liquorice consumption increased late-night salivary cortisol, which was sustained for up to 6 days, whereas no effect was seen on salivary cortisone. Salivary cortisol, but not cortisone, was increased by contamination of saliva with ≥0.5 % blood, which could be revealed by a clearly visible red discoloration of the saliva. Handling of topical hydrocortisone before saliva sampling affected salivary cortisol to a much higher degree than salivary cortisone. Paper 4 showed that women using OCs have considerably higher plasma cortisol levels during an SST, whereas salivary cortisol and salivary cortisone were lower compared to controls. However, the lower reference limits were not significantly different for salivary measurands, with salivary cortisone slightly more robust, opting for a common cut-off to exclude AI regardless of OCs.Conclusion: Using the reference intervals calculated for several clinically used analytical methods showed high diagnostic accuracy for CS, with cortisone showing the highest accuracy. Analyzing salivary cortisone was not affected by liquorice consumption or blood contamination. Salivary cortisone was least affected by OCs during an SST. In summary, salivary cortisone is very useful in the diagnostic work-up for CS and AI.
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| 8. |
- Eriksson, Maria, 1965-
(författare)
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Adipocyte-derived hormones and cardiovascular disease
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 9. |
- Lennmyr, Fredrik, 1971-
(författare)
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Signal Transduction in Focal Cerebral Ischemia : Experimental Studies on VEGF, MAPK and Src family kinases
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cerebral ischemia elicits a wide range of events, including complex activation of various intracellular signaling pathways. This study aims to investigate the expression of vascular endothelial growth factor (VEGF) and the activation pattern of mitogen-activated protein kinases (MAPK) in reponse to focal cerebral ischemia. Furtermore, the functional roles of the p38 MAPK and the Src family kinases (SFKs) are investigated with specific signal transduction inhibitors in the rat in vivo.VEGF was found upregulated in several cell types including neurons, glia and vascular cells after both permanent and transient cerebral ischemia. VEGF-receptor 1 (VEGFR1) was expressed in a similar manner, while VEGFR2 expression was more restricted and confined to endothelial cells and glia.The main MAPK pathways, including extracellular-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, were differentially activated by cerebral ischemia. ERK activation was present in blood vessels, suggesting a potential role in neovascularization. JNK was also activated in blood vessels in the infarcted hemisphere, possibly reflecting an interaction with ERK, whereas p38 activity was absent in vessels. In neurons, ERK was activated in cortical cells up to days of survival, while no substantial JNK or p38 activation was seen in ischemic neurons. Invading macrophages showed distinct activation of p38 and to some extent also JNK but not ERK. Glia showed activation of all MAPK to a variable extent.Pretreatment with the p38-inhibitor SB203580 before transient cerebral ischemia (ischemia-reperfusion) was investigated with magnetic resonance imaging (MRI). The experiment group suffered worse infarcts and blood-brain barrier (BBB) damage than controls, which contrasts to previous studies. The results might be attributed to interference with protective effects of the vehicle or with preconditioning mechanisms. The SFK-inhibitor PP2 significantly reduced infarct size after cerebral ischemia-reperfusion, which is consistent with previously reported effects in permanent ischemia. Due to the multifunctional role of SFKs, it cannot be easily concluded in exactly what cellular context(s) SFKs are of importance to cerebral ischemia.In conclusion, the VEGF and MAPK systems of extra- and intracellular signaling are activated in focal cerebral ischemia. Manipulation of p38 as well as SFK in vivo can influence the course of transient cerebral ischemia, which may be of significance to the understanding of the pathology of cerebral ischemia and to the development of therapeutic strategies.
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| 10. |
- Mellberg, Caroline, 1979-
(författare)
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Effects of diet intervention on body composition and ectopic fat accumulation in obese postmenopausal women
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Obesity is increasing worldwide and is a major contributor to morbidity and mortality. Notably, abdominal (central) obesity carries a high risk of obesity-related diseases, while peripheral fat accumulation can act in a protective manner. A redistribution of fat from peripheral to central depots is seen after the menopause and is associated with an increasing prevalence of diabetes and cardiovascular disease. A key mediator may be ectopic fat accumulation in the liver. Our hypothesis was that a Palaeolithic-type diet (PD) consumed ad libitum improves body composition and metabolic risk markers, including liver fat and insulin sensitivity, in obese postmenopausal women.Methods In study I the study subjects (n=10) used a PD during 5 weeks. In study II and III (n=70) the effect of a Palaeolithic-type diet (PD) was compared to a diet according to the Nordic Nutrition Recommendations diet (NNR) during a 2-year randomized clinical trial (RCT). Food records and nitrogen excretion in urine validated food intake. Anthropometric measurements were performed in a standardized manner. Body composition was calculated using Dual Energy X-ray Absorptiometry (DXA). Total energy expenditure was calculated by accelerometry (Actiheart®) in combination with indirect calorimetry. Liver and muscle fat content was estimated by magnet resonance spectroscopy (1H-MRS). Insulin sensitivity was measured either with hyperinsulinemic euglycemic clamps (paper I) or oral glucose tolerance tests (OGTTs) (paper III).Results In study I a significant weight loss, linked to improved lipid and blood pressure levels, was associated with a 49% decrease in liver fat. Concomitantly, hepatic insulin sensitivity improved, while peripheral insulin sensitivity (and muscle fat) was unaltered. In study II/III both groups had a significant and sustained weight loss after 2 years. The PD was more effective than the NNR diet regarding loss of weight and fat mass after 6 months, but not after 24 months. Serum triglyceride levels were significantly lower at 24 months in the PD group. Liver fat decreased throughout the study in both groups. Hepatic insulin sensitivity improved during the first 6 months of the study, while peripheral insulin sensitivity did not change. Hepatic insulin sensitivity was associated with liver fat at baseline, but not during the diet intervention. Energy expenditure did not change in any of the study groups.Conclusion Ad libitum diets can have sustained beneficial effects on weight and body composition in obese postmenopausal women, a PD being more effective on short-term than a diet according to the NNR. This is associated with a reduction in liver fat that may reduce the risk of future diabetes and cardiovascular disease. Further studies are needed in order to explore the association between liver fat and metabolic dysfunction, including insulin sensitivity.
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