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- 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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| 2. |
- 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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| 3. |
- Olausson, Hanna, 1975-
(författare)
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Nutritional status before and during pregnancy in relation to the maternal insulin-like growth factor-system and health related variables in the offspring
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adequate fetal growth is of importance for health in adulthood. Maternal nutritional status has been suggested to be one major factor influencing fetal development. The nature of how the mother's nutritional status and her metabolic, endocrine and physiological adaptations to pregnancy interact and how these interactions affect fetal growth is unclear. The insulin-like growth factor (IOF)-system has been suggested to be one mediator between maternal nutritional status and fetal growth. Impaired fetal growth may have life-long effects, but little is known about the possibilities to ameliorate intrauterine perturbations postnatally. Oxytocin, an anti-stress hormone, was used as a model to study such possibilities.The aims were: to measure serum levels of IGF-I, IGF-II, IGF-binding protein (IGFBP)-1, IGFBP-3 and protease activity against IOFBP-3 in healthy women before, during and after pregnancy; to study the relationships regarding maternal body weight and composition before and during pregnancy versus components of the maternal IGF-system in serum in healthy women; to study the relationships regarding components of the maternal IGF-system in serum versus infant birth weight; to measure the expression of mRNA for IGF-I and IGF-II in different tissues in guinea pigs and to study how these expressions are altered by gestation and food restriction; to study long-term effects of maternal food restriction during gestation on health related variables in adult rat offspring; to study long-term effects of early postnatal treatment of oxytocin in the adult rat offspring.Healthy women were studied before pregnancy, in weeks 8, 14, 20, 32, 35 of pregnancy and 2 weeks postpartum. Body weight, body composition and serum levels of IGF-I, IGF-II, IGFBP-1, IGFBP-3 and protease activity against IOFBP-3 were measured. Infant body weight and length at birth were obtained from hospital records. The amounts of mRNA for IGF-I and IGF-II in the liver, adipose tissues, muscles, spleen, uterus and placenta were measured in virginal and pregnant guinea pigs, being either ad libitum fed or food restricted. Rat dams were either ad libitum fed or food restricted during gestation. Their offspring received oxytocin or NaCI at day 1-14 of age. Blood pressure, plasma levels of corticosterone, IGF-1, IGFBP-1, and reproductive performance were measured in the adult offspring.All of the studied components of the IGF-system in serum underwent changes during pregnancy. The levels of IGF-1 were reduced in early pregnancy compared to before conception. The lower the body weight or the less amount of body fat before pregnancy, the larger the decrease in IGF-I in early pregnancy. The combination of body weight before pregnancy and the serum level of IGF-I in early pregnancy explained as much as 47 % of the variation in birth weight, indicating that the higher the maternal body weight before pregnancy and the lower the level of IGF-I in early pregnancy, the heavier the infant. From week 20 of pregnancy, maternal levels of IGFBP-I were negatively correlated to birth weight. In late pregnancy, the abundance of IGFBP-I and protease activity in serum together explained 35% of the variation in birth weight, indicating that the lower the IGFBP-I and the higher the protease activity, the higher the birth weight. In guinea pigs, mRNA for IGF-I was expressed in high amounts in adipose tissue and liver, whereas mRNA for IGF-II were highly expressed in placenta and liver. The expression of IGF-I was in general unaffected by food restriction, but doubled during gestation, whereas the expression of IGF-II in the placenta was decreased by food restriction and increased in the liver by gestation. Maternal food restriction during gestation caused increased levels of corticosterone, IGF-I and IGFBP-I, but no elevation in blood pressure, in adult offspring. Early postnatal oxytocin treatment decreased blood pressure and corticosterone, whereas the influence on reproductive performance was dependent on the nutritional status of their dams and the current nutritional experience in adulthood.In conclusion, this thesis confirms that the IGF-system may be one factor mediating the effects of maternal nutritional status on fetal growth. It also supports the suggestion that IGFBP-I in maternal serum may be used as a marker of infant birth weight. Adipose tissue was shown to produce high amounts of IGF-I, indicating endocrine functions during gestation. Postnatal oxytocin treatment ameliorated some of the adverse effects in adult offspring, induced by maternal food restriction.
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