| 1. |
- García, Maria C, et al.
(författare)
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Mature-onset obesity in interleukin-1 receptor I knockout mice.
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:5, s. 1205-13
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI(-/-) mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5- to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI(-/-) mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young pre-obese IL-1RI(-/-) mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in pre-obese IL-1RI(-/-) mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity.
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| 2. |
- Andersson, Niklas, 1970, et al.
(författare)
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Investigation of central versus peripheral effects of estradiol in ovariectomized mice
- 2005
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Ingår i: J Endocrinol. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 187:2, s. 303-9
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Tidskriftsartikel (refereegranskat)abstract
- It is generally believed that estrogens exert their bone sparing effects directly on the cells within the bone compartment. The aim of the present study was to investigate if central mechanisms might be involved in the bone sparing effect of estrogens. The dose-response of central (i.c.v) 17beta-estradiol (E2) administration was compared with that of peripheral (s.c.) administration in ovariectomized (ovx) mice. The dose-response curves for central and peripheral E2 administration did not differ for any of the studied estrogen-responsive tissues, indicating that these effects were mainly peripheral. In addition, ovx mice were treated with E2 and/or the peripheral estrogen receptor antagonist ICI 182,780. ICI 182,780 attenuated most of the estrogenic response regarding uterus weight, retroperitoneal fat weight, cortical BMC and trabecular bone mineral content (P<0.05). These findings support the notion that the primary target tissue that mediates the effect of E2 on bone is peripheral and not central.
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| 3. |
- Andersson, Niklas, 1970, et al.
(författare)
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Variants of the interleukin-1 receptor antagonist gene are associated with fat mass in men
- 2009
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 33:5, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- Context: Immune functions seem to have connections to variations in body fat mass. Studies of knockout mice indicate that endogenous interleukin (IL)-1 can suppress mature-onset obesity. Objective: To systematically investigate our hypotheses that single- nucleotide polymorphisms (SNPs) and/or haplotypes variants in the IL-1 gene system are associated with fat mass. Subjects: The Gothenburg osteoporosis and obesity determinants (GOOD) study is a population-based cross-sectional study of 18-20 year-old men (n = 1068), from Gothenburg, Sweden. Major findings were confirmed in elderly men (n = 3014) from the Swedish part of the osteoporotic fractures in men (MrOS) multicenter population-based study. Main Outcome Measure: The genotype distributions and their association with body fat mass in different compartments, measured with dual-energy X-ray absorptiometry (DXA). Results: Out of 15 investigated SNPs in the IL-1 receptor antagonist (IL1RN) gene, a recently identified 30 untranslated region C4T (rs4252041, minor allele frequency 4%) SNP was associated with the primary outcome total fat mass (P = 0.003) and regional fat masses, but not with lean body mass or serum IL-1 receptor 1 (IL1RN) levels. This SNP was also associated with body fat when correcting the earlier reported IL1RN_2018 T4C (rs419598) SNP (in linkage disequilibrium with a well-studied variable number tandem repeat of 86 bp). The association between rs4252041 SNP and body fat was confirmed in the older MrOS population (P = 0.03). The rs4252041 SNP was part of three haplotypes consisting of five adjacent SNPs that were identified by a sliding window approach. These haplotypes had a highly significant global association with total body fat (P < 0.001). None of the other investigated members of the IL-1 gene family displayed any SNPs that have not been described previously to be significantly associated with body fat. Conclusions: The IL1RN gene, shown to enhance obesity by suppressing IL-1 effects in experimental animals, have no previously described gene polymorphisms and haplotypes that are associated with fat, but not lean mass in two populations of men. International Journal of Obesity (2009) 33, 525-533; doi: 10.1038/ijo.2009.47; published online 17 March 2009
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| 4. |
- Eriksson, Anna-Lena, 1971, et al.
(författare)
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SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:12, s. 5029-37
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men.
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| 5. |
- Lorentzon, Mattias, 1970, et al.
(författare)
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Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study.
- 2005
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 0884-0431 .- 1523-4681. ; 20:8, s. 1334-41
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we evaluated the predictive roles of sex steroids for skeletal parameters in young men (n = 1068) at the age of peak bone mass. Serum free estradiol was a negative predictor, whereas free testosterone and SHBG were positive predictors of cortical bone size. INTRODUCTION: Previous studies have shown that free estradiol in serum is an independent predictor of areal BMD (aBMD) in elderly men. The aim of this study was to determine whether sex steroids are predictors of volumetric BMD (vBMD) and/or size of the trabecular and cortical bone compartments in young men at the age of peak bone mass. MATERIALS AND METHODS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men, 18.9 +/- 0.6 years of age. Serum levels of testosterone, estradiol, and sex hormone binding globulin (SHBG) were measured, and free levels of testosterone and estradiol were calculated. The size of the cortical bone and the cortical and trabecular vBMDs were measured by pQCT. RESULTS: Regression models including age, height, weight, free estradiol, and free testosterone showed that free estradiol was an independent negative predictor of cortical cross-sectional area (tibia beta = -0.111, p < 0.001; radius beta = -0.125, p < 0.001), periosteal circumference, and endosteal circumference, whereas it was a positive independent predictor of cortical vBMD (tibia beta = 0.100, p < 0.003; radius beta = 0.115, p = 0.001) in both the tibia and radius. Free testosterone was an independent positive predictor of cortical cross-sectional area (tibia beta = 0.071, p = 0.013; radius beta = 0.064, p = 0.039), periosteal circumference, and endosteal circumference in both the tibia and radius. Neither cortical nor trabecular vBMD was associated with free testosterone. SHBG was an independent positive predictor of parameters reflecting the size of the cortical bone, including cross-sectional area (beta = 0.078, p = 0.009), periosteal circumference, and endosteal circumference. CONCLUSIONS: Free estradiol is a negative, whereas free testosterone is a positive, predictor of cortical bone size in young men at the age of peak bone mass. These findings support the notion that estrogens reduce, whereas androgens increase, cortical bone size, resulting in the well-known sexual dimorphism of cortical bone geometry.
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| 6. |
- Sjögren, Klara, 1970, et al.
(författare)
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Elevated Aromatase Expression in Osteoblasts Leads to Increased Bone Mass without Systemic Adverse Effects.
- 2009
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Ingår i: Journal of bone and mineral research. - : Wiley. - 1523-4681 .- 0884-0431. ; 24:7, s. 1263-70
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The stimulatory effects of testosterone (T) on bone can either be via a direct activation of the androgen receptor (AR) or mediated via aromatization of T to estradiol (E2), followed by activation of estrogen receptors (ERs) in bone. Aromatase expression in osteoblasts and reproductive tissues is dependent on different promoters, which are differentially regulated. To investigate the effect of elevated local aromatization of T to E2 in bone, we developed a transgenic mouse model (Coll-1alpha1-Arom) that over-expresses the human aromatase gene under the control of the osteoblast specific rat type I alpha I procollagen promoter. The Coll-1alpha1-Arom mice expressed human aromatase mRNA specifically in bone and had unaffected serum E2 and T levels. Male Coll-1alpha1-Arom mice had clearly increased total body bone mineral density (BMD), trabecular BMD, cortical BMD and cortical thickness associated with elevated osteoprotegerin mRNA levels and reduced number of osteoclasts (p<0.01). Treatment of ovariectomized mice with T increased cortical and trabecular thickness in the Coll-1alpha1-Arom mice (p<0.001) but not in the wild type mice. In conclusion, elevated aromatase expression specifically in osteoblasts results in stimulatory estrogenic effects in bone without increasing serum E2 levels. As osteoblast specific aromatase expression results in an increased ER to AR activation ratio in bone, we propose that activation of ERs results in a more pronounced increase in bone mass than what is seen after activation of the AR. Development of osteoblast specific inducers of aromatase expression might identify substances with stimulatory effects on bone without systemic adverse effects.
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| 7. |
- Strandberg, Louise, 1981, et al.
(författare)
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Interleukin-1 system gene polymorphisms are associated with fat mass in young men.
- 2006
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:7, s. 2749-54
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: There is growing evidence for interactions between the regulation of body fat and the immune system. Studies of knockout mice indicate that IL-1 has an antiobesity effect. OBJECTIVE: The objective of the study was to investigate our hypothesis that common polymorphisms of the IL-1 system, which are associated with IL-1 activity, also are associated with fat mass. DESIGN, SETTING, AND STUDY SUBJECTS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18- to 20-yr-old men (n = 1068), mostly Caucasian, from the Gothenburg area (Sweden). Three different polymorphisms, IL-1beta +3953 C/T, IL-1beta-31 T/C, and IL-1 receptor antagonist (IL-1RN) variable number tandem repeat of 86 bp, were investigated in relation to body fat mass. MAIN OUTCOME MEASURE: The main outcome measures were genotype distributions and their association with body fat mass in different compartments, measured with dual-energy x-ray absorptiometry. RESULTS: Carriers of the T variant (CT and TT) of the +3953 C to T (F(T) = 0.25) IL-1beta gene polymorphism had significantly lower total fat mass (P = 0.013) and also significantly reduced arm, leg, and trunk fat, compared with CC individuals. IL-1RN*2 carriers with two repeats of the IL-1RN variable number tandem repeat polymorphism had increased total fat (P = 0.036), serum leptin, and fat of trunk and arm as well as serum levels of IL-1RN and IL-1RN production ex vivo. The IL-1beta-31 polymorphism did not correlate with the fat measurements. CONCLUSIONS: The IL-1 system, recently shown to affect fat mass in experimental animals, contains gene polymorphisms that are associated with fat mass in young men.
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| 8. |
- Svensson, Johan, 1964, et al.
(författare)
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Liver-derived IGF1 enhances the androgenic response in prostate.
- 2008
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 199:3, s. 489-97
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Tidskriftsartikel (refereegranskat)abstract
- Both IGF1 and androgens are major enhancers of prostate growth and are implicated in the development of prostate hyperplasia and cancer. The aim of the present study was to investigate whether liver-derived endocrine IGF1 modulates the androgenic response in prostate. Mice with adult, liver-specific inactivation of IGF1 (LI-IGF1(-/-) mice) displayed an approximately 80% reduction in serum IGF1 levels associated with decreased prostate weight compared with control mice (anterior prostate lobe -19%, P<0.05; dorsolateral prostate (DLP) lobe -35%, P<0.01; ventral prostate (VP) lobe -47%, P<0.01). Reduced androgen receptor (Ar) mRNA and protein levels were observed in the VP lobe (-34% and -30% respectively, both P<0.05 versus control mice). Analysis of prostate morphology showed reductions in both the glandular and fibromuscular compartments of the VP and DLP lobes that were proportional to the reductions in the weights of these lobes. Immunohistochemistry revealed reduced intracellular AR immunoreactivity in the VP and DLP lobes. The non-aromatizable androgen dihydrotestosterone increased VP weight to a lesser extent in orchidectomized (ORX) LI-IGF1(-/-) mice than in ORX controls (-40%, P<0.05 versus control mice). In conclusion, deficiency of liver-derived IGF1 reduces both the glandular and fibromuscular compartments of the prostate, decreases AR expression in prostate, and reduces the stimulatory effect of androgens on VP weight. These findings may explain, at least in part, the well-known clinical association between serum IGF1 levels and conditions with abnormal prostate growth.
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| 9. |
- Andersson, Niklas, 1970, et al.
(författare)
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A gene expression fingerprint of mouse stomach ECL cells.
- 2005
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 332:2, s. 404-10
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Tidskriftsartikel (refereegranskat)abstract
- Many of the endocrine cells in the stomach are poorly characterized with respect to physiological significance. In some cases, the anticipated hormone has not yet been identified. Global gene expression analysis of mouse stomach was performed in an attempt to identify the ECL-cell peptide/protein. Specific functional activation (omeprazole-induced hypergastrinaemia) was used as a tool to generate a gene expression fingerprint of the ECL cells. The proposed fingerprint includes 14 genes, among them six are known to be expressed by ECL cells (=positive controls), and some novel ones, which are likely to be ECL-cell-related. The known ECL-cell-related genes are those encoding histidine decarboxylase, chromogranin A and B, vesicular monoamine transporter 2, synaptophysin, and the cholecystokinin-B receptor. In addition, the fingerprint included five genes, which might be involved in the process of secretion and three ESTs with unknown function. Interestingly, parathyroid hormone-like hormone (Pthlh) was identified as a candidate ECL-cell peptide hormone.
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| 10. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
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Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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