Metabolic and ovarian consequences of perinatal sex steroid programming

Endocrine and metabolic disturbances in adulthood may stem from insults such as nutritional and hormonal alterations that occur at critical periods in pre- or postnatal life – a process known as programming. This means that suboptimal conditions in utero and early life may contribute to adult reproductive and metabolic impairments such as type 2 diabetes, insulin resistance, and dyslipidemia. The aims of this thesis were 1) to identify the potential metabolic and ovarian programming effects of early postnatal sex steroid exposure in adult female rats, and 2) to utilize data collected by the Swedish Twin Registry to investigate, in a large cohort of dizygotic twins, the potential effects of prenatal androgen exposure on metabolism and anthropometry in adult women with a male twin. The main findings of this thesis were: A single early postnatal dose of testosterone or estradiol caused insulin resistance and an increase in mesenteric adipocyte size in adult female rats. Testosterone exposure also resulted in dyslipidemia and estradiol exposure in elevated triglyceride levels. Rats exposed to estradiol displayed more pronounced insulin resistance than rats exposed to testosterone or dihydrotestosterone. Testosterone-injected rats exhibited increased mesenteric adipose tissue. Dihydrotestosterone-injected rats exhibited reduced insulin sensitivity only. Estradiol administration directly after birth altered ovarian morphology and expression of genes involved in follicle development. Estradiol exposure also decreased the weight of parametrial adipose tissue, increased parametrial adipose tissue lipoprotein lipase activity, and altered parametrial adipose tissue expression of genes involved in adipose tissue metabolism. In addition, reduced insulin sensitivity in postnatal estradiol-exposed rats was accompanied by an increase in the serum levels of inflammatory markers, and skeletal muscle alterations in the expression of immune-related genes and genes involved in the regulation of glucose and lipid metabolism. Adult women with at twin brother exhibited increased weight and BMI, and a higher risk of being overweight compared to women from same-sex twin pairs. The differences in BMI and weight between the groups were observed in women of 60 years and older, but not in those below 60 years of age. Dyslipidemia, but not type 2 diabetes mellitus, was more common in women with a male twin. In summary, perinatal exposure to sex steroids affected the developing organism, predisposing to reproductive and endocrine abnormalities and features of the metabolic syndrome at adult age. Changes in insulin sensitivity, lipid profile, adipose tissue distribution, cellularity and metabolism, as well as in ovarian morphology, are factors that can be programmed perinatally with health consequences in adulthood. Our observations of dyslipidemia and increased BMI and body weight in opposite-sex female twins are consistent with the results of animal experiments, indicating that the programming effects of early androgen exposure are of relevance also for humans

Ekonomistyrning i förändring - Lunds Energi AB

Syfte: Syftet är att beskriva och analysera en traditionell, resultatansvarsindelad ekonomistyrning, samt att sätta den i relation till en modernt orienterad styrning. Metod: Vår uppsats är en enskild fallstudie med en kvalitativ ansats av enheten Energiprodukter inom Lunds Energi AB. Vi har genomfört ett antal intervjuer i fallföretaget. Empirin är analyserad med hjälp av relevant teori, främst Lindvalls Verksamhetsstyrning, Källströms Uppdrag Styreffekt och Anthony & Govindarajans Management Control Systems. Slutsatser: Lunds Energi AB har flera inslag av modern verksamhetsstyrning i sin traditionella, resultatansvarsindelade ekonomistyrning. Styrningen har enligt vår mening vissa samordningsbrister, då varje enhet inom företaget har självständiga resultatmål. Vi har även identifierat potentiella förbättringsområden, exempelvis gällande informationshantering, kundkontakter, rekryteringsförfarande samt miljöpolicy

Postnatal testosterone exposure results in insulin resistance, enlarged mesenteric adipocytes, and an atherogenic lipid profile in adult female rats: comparisons with estradiol and dihydrotestosterone.

Postnatal events contribute to features of the metabolic syndrome in adulthood. In this study, postnatally administered testosterone reduced insulin sensitivity and increased the mesenteric fat depot, the size of mesenteric adipocytes, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and the atherogenic index in adult female rats. To assess the involvement of estrogen and androgen receptors in these programming effects, we compared testosterone-exposed rats to rats exposed to estradiol or dihydrotestosterone (DHT). Estradiol-treated rats had lower insulin sensitivity than testosterone-treated rats and, like those rats, had enlarged mesenteric adipocytes and increased triglyceride levels. DHT also reduced insulin sensitivity but did not mimic the other metabolic effects of testosterone. All treated rats were probably anovulatory, but only those treated with testosterone had reduced testosterone levels. This study confirms our previous finding that postnatal administration of testosterone reduces insulin sensitivity in adult female rats and shows that this effect is accompanied by unfavorable changes in mesenteric fat tissue and in serum lipid levels. The findings in the estradiol and DHT groups suggest that estrogen receptors exert stronger metabolic programming effects than androgen receptors. Thus, insults such as sex hormone exposure in early life may have long-lasting effects, thereby creating a predisposition to disturbances in insulin sensitivity, adipose tissue, and lipid profile in adulthood

A single early postnatal estradiol injection affects morphology and gene expression of the ovary and parametrial adipose tissue in adult female rats.

Events during early life can affect reproductive and metabolic functions in adulthood. We evaluated the programming effects of a single early postnatal estradiol injection (within 3h after birth) in female rats. We assessed ovarian and parametrial adipose tissue morphology, evaluated gene expression related to follicular development and adipose tissue metabolism, and developed a non-invasive volumetric estimation of parametrial adipose tissue by magnetic resonance imaging. Estradiol reduced ovarian weight, increased antral follicle size and number of atretic antral follicles, and decreased theca interna thickness in atretic antral follicles. Adult estradiol-injected rats also had malformed vaginal openings and lacked corpora lutea, confirming anovulation. Estradiol markedly reduced parametrial adipose tissue mass. Adipocyte size was unchanged, suggesting reduced adipocyte number. Parametrial adipose tissue lipoprotein lipase activity was increased. In ovaries, estradiol increased mRNA expression of adiponectin, complement component 3, estrogen receptor alpha, and glucose transporter 3 and 4; in parametrial adipose tissue, expression of complement component 3 was increased, expression of estrogen receptor alpha was decreased, and expression of leptin, lipoprotein lipase, and hormone-sensitive lipase was unaffected. These findings suggest that early postnatal estradiol exposure of female rats result in long-lasting effects on the ovary and parametrial adipose tissue at adult age

Prenatal exposure to interleukin-6 results in hypertension and alterations in the renin–angiotensin system of the rat

Cytokines are emerging as important in developmental processes. They may induce alterations in normal gene expression patterns, activate angiotensinogen transcription, or alter expression of the renin–angiotensin system (RAS). To determine whether prenatal exposure to interleukin-6 (IL-6) influences gene expression of the intrarenal RAS and contributes to renal dysfunction and hypertension in adulthood, we exposed female rats to IL-6 early (EIL-6 females) and late (LIL-6 females) in pregnancy and analysed blood pressure in the offspring at 5–20 weeks of age. Renal fluid and electrolyte excretion was assessed in clearance experiments, mRNA expression by real-time PCR, and protein levels by Western blot. Systolic pressure was increased at 5 weeks in IL-6 females and at 11 weeks in males. Circulatory RAS levels were increased in all IL-6 females, but angiotensin-1-converting enzyme (ACE) activity was increased only in LIL-6 females. LIL-6 males and IL-6 females showed decreased urinary flow rate and urinary sodium and potassium excretion. Dopamine excretion was decreased IL-6 females. In adult renal cortex, renin expression was increased in all IL-6 females, but angiotensinogen mRNA was increased only in LIL-6 females; AT1 receptor (AT1-R) mRNA and protein levels were increased in LIL-6 females, whereas AT2 receptor (AT2-R) levels were decreased in LIL-6 females and EIL-6 males. In adult renal medulla, AT1-R protein levels were increased in LIL-6 females, and AT2-R mRNA and protein levels were decreased in EIL-6 males and LIL-6 females. Prenatal IL-6 exposure may cause hypertension by altering the renal and circulatory RAS and renal fluid and electrolyte excretion, especially in females