Hans Hauner - Academia.edu (original) (raw)

Papers by Hans Hauner

Pediatric research, Jan 15, 2017

Few human studies have explored the role of adiponectin in early life on growth and adipose tissu... more Few human studies have explored the role of adiponectin in early life on growth and adipose tissue development. High molecular weight (HMW) and total adiponectin levels from 141 cord blood samples and plasma blood samples from 40 3-y-old children were analyzed. Associations between adiponectin levels in cord blood and child plasma, and infant/child growth and fat mass measurements up to the age of 5 y were assessed using linear regression models. HMW cord blood adiponectin was positively associated with weight, BMI percentiles, and lean body mass at birth only. At 3 and 4 y, positive associations were found with cord blood adiponectin and sum of four skinfold thickness measures and percentage of body fat following adjustment for maternal and child covariates, but did not persist at 5 y. There was no significant evidence of an association between child plasma HMW adiponectin and growth or body composition characteristics at 3-5 y. Our results do not support the hypothesis that HMW co...

BMC Genomics, 2014

Background: Previously we have examined the effect of maternal dietary n-3 long-chain polyunsatur... more Background: Previously we have examined the effect of maternal dietary n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on offspring fat mass. Considering the involvement of the placenta in fetal programming, we aimed to analyze the sex-specific gene expression in human term placenta and its response to the n-3 LCPUFA intervention, as well as their correlations to offspring adiposity. Results: Placental gene expression was assessed in a control and n-3 LCPUFA intervention group by DNA microarrays, biological pathway analyses and RT-qPCR validation. Expression data were correlated with sex steroid hormone levels in placenta and cord plasma, and offspring anthropometric data. Transcriptome data revealed sexually dimorphic gene expression in control placentas per se, whereas in intervention placentas sex-specific expression changed, and more n-3 LCPUFA-regulated genes were found in female than male placentas. Sexually dimorphic gene expression and n-3 LCPUFAresponsive genes were enriched in the pathway for cell cycle and its associated modulator pathways. Significant mRNA expression changes for CDK6, PCNA, and TGFB1 were confirmed by RT-qPCR. CDK6 and PCNA mRNA levels correlated with offspring birth weight and birth weight percentiles. Significantly reduced placental estradiol-17β/testosterone ratio upon intervention found in female offspring correlated with mRNA levels for the 'Wnt signaling' genes DVL1 and LRP6. Conclusions: Overall, human placentas show sexually dimorphic gene expression and responsiveness to maternal n-3 LCPUFA intervention during pregnancy with more pronounced effects in female placentas. The absence of correlations of analyzed placental gene expression with offspring adipose tissue growth in the first year is not mutually exclusive with programming effects, which may manifest later in life, or in other physiological processes.

BMC Pregnancy and Childbirth, 2014

Background: Maternal obesity and gestational diabetes mellitus (GDM) may independently influence ... more Background: Maternal obesity and gestational diabetes mellitus (GDM) may independently influence offspring fat mass and metabolic disease susceptibility. In this pilot study, body composition and fat distribution in offspring from obese women with and without GDM and lean women were assessed within the 1st year of life, and maternal and newborn plasma factors were related to offspring adipose tissue distribution. Methods: Serum and plasma samples from pregnant obese women with (n = 16) or without (n = 13) GDM and normoglycemic lean women (n = 15) at 3rd trimester and offspring cord plasma were used for analyzing lipid profiles, insulin and adipokine levels. At week-1 and 6, month-4 and year-1, offspring anthropometrics and skinfold thickness (SFT) were measured and abdominal subcutaneous (SCA) and preperitoneal adipose tissue (PPA) were determined by ultrasonography. Results: Cord insulin was significantly increased in the GDM group, whereas levels of cord leptin, total and high molecular weight (HMW) adiponectin were similar between the groups. Neonates of the GDM group showed significantly higher SFT and fat mass until week-6 and significantly increased SCA at week-1 compared to the lean group that persisted as strong trend at week-6. Interestingly, PPA in neonates of the GDM group was significantly elevated at week-1 compared to both the lean and obese group. At month-4 and year-1, significant differences in adipose tissue growth between the groups were not observed. Multiple linear regression analyses revealed that cord insulin levels are independently related to neonatal PPA that showed significant relation to PPA development at year-1. Maternal fasted C-peptide and HMW adiponectin levels at 3rd trimester emerged to be determinants for PPA at week-1. Conclusion: Maternal pregravid obesity combined with GDM leads to newborn hyperinsulinemia and increased offspring fat mass until week-6, whereas pregravid obesity without GDM does not. This strongly suggests the pivotal role of GDM in the adverse offspring outcome. Maternal C-peptide and HMW adiponectin levels in pregnancy emerge to be predictive for elevated PPA in newborns and might be indicative for the obesity risk at later life. Altogether, the findings from our pilot study warrant evaluation in long-term studies.

Annals of Nutrition and Metabolism, 2009

Recent observational studies suggest that mean birth weight and body fat growth in the first year... more Recent observational studies suggest that mean birth weight and body fat growth in the first year of life have increased continuously over the last decades. Both elevated birth weight and early fat mass are potential risk factors for childhood obesity. Experimental and limited clinical data suggest that the dietary ratio of n–6 to n–3 fatty acids (FAs) during pregnancy is critical for early adipose tissue growth. The aim of this randomized controlled study is to examine the effect of the supplementation with n–3 long-chain polyunsaturated FAs and reduction in the n–6/n–3 ratio in the diet of pregnant women/breast-feeding mothers on adipose tissue growth in their newborns using various methods for the assessment of body fat mass. Measurement of skinfold thickness in the newborn is the primary outcome parameter. Two hundred and four pregnant women will be recruited before the 15th week of gestation and randomly assigned to either active intervention or an isocaloric control diet. This...

The American Journal of Clinical Nutrition, 2013

Childhood obesity is increasing worldwide, and all previous attempts to stop this epidemic have s... more Childhood obesity is increasing worldwide, and all previous attempts to stop this epidemic have shown little success. There is now growing evidence that the risk of childhood obesity is strongly influenced by perinatal determinants, including prepregnancy body mass index (BMI), gestational weight gain, and-at least in animal studiesdietary factors during pregnancy and lactation. This review addresses the issue of whether modulation of fat intake and its composition in this early-life period has a potential for primary prevention of childhood obesity. Of particular interest is the question of whether supplementation with n-3 long-chain PUFAs (LC-PUFAs) may exert an antiobesity effect. Retrospective analysis of human randomized controlled trials with fish-oil intervention during pregnancy and lactation gave inconsistent results concerning BMI and obesity development in offspring. A recent prospective human intervention study aimed at reducing the n-6:n-3 LC-PUFA ratio did not show an effect on adipose tissue growth in offspring up to the age of 1 y. Therefore, there is currently little evidence to support the hypothesis that dietary intervention to modify fat composition during pregnancy and lactation would be a promising strategy to prevent childhood obesity in humans, but more research is clearly needed to address the question if and how the risk of developing obesity can be modified by dietary intervention early in life.

The American Journal of Clinical Nutrition, 2011

Background: The composition of long-chain PUFAs (LCPUFAs) in the maternal diet may affect obesity... more Background: The composition of long-chain PUFAs (LCPUFAs) in the maternal diet may affect obesity risk in the mother's offspring. Objective: We hypothesized that a reduction in the n26 (omega-6): n23 (omega-3) LCPUFA ratio in the diet of pregnant women and breastfeeding mothers may prevent expansive adipose tissue growth in their infants during the first year of life. Design: In a randomized controlled trial, 208 healthy pregnant women were randomly assigned to an intervention (1200 mg n23 LCPUFAs as a supplement per day and a concomitant reduction in arachidonic acid intake) or a control diet from the 15th wk of pregnancy to 4 mo of lactation. The primary outcome was infant fat mass estimated by skinfold thickness (SFT) measurements at 4 body sites at 3-5 d, 6 wk, and 4 and 12 mo postpartum. Secondary endpoints included sonographic assessment of abdominal subcutaneous and preperitoneal fat, fat distribution, and child growth. Results: Infants did not differ in the sum of their 4 SFTs at 1 y of life [intervention: 24.1 6 4.4 mm (n = 85); control: 24.1 6 4.1 mm (n = 80); mean difference: 20.0 mm (95% CI: 21.3, 1.3 mm)] or in growth. Likewise, longitudinal ultrasonography showed no significant differences in abdominal fat mass or fat distribution. Conclusions: We showed no evidence that supplementation with n23 fatty acids and instructions to reduce arachidonic acid intake during pregnancy and lactation relevantly affects fat mass in offspring during the first year of life. Prospective long-term studies are needed to explore the efficacy of this dietary approach for primary prevention. This trial was registered at clinicaltrials.gov as NCT00362089.

Breast care (Basel, Switzerland), 2014

Epidemiological data suggest a close link between obesity and breast cancer, the most frequently ... more Epidemiological data suggest a close link between obesity and breast cancer, the most frequently occurring cancer in women. The metabolic syndrome is typically associated with abdominal obesity and comprises disturbances in glucose and/or lipid metabolism and/or hypertension. Recent studies have established a specific association between the metabolic syndrome - as well as its components - and breast cancer, indicating both an increased risk of developing breast cancer and a poorer prognosis. In premenopausal women, obesity might have a protective effect only on receptor-positive tumors, whereas a positive association was observed between obesity/abdominal obesity and an increased risk of triple-negative breast cancer (TNBC). Overall survival and disease-free survival were reported to be significantly shorter in premenopausal obese women with TNBC compared to non-obese women, but these results are still inconsistent and need further research. The metabolic syndrome is characterized ...

Biomolecular detection and quantification, 2017

The process of adipogenesis is controlled in a highly orchestrated manner, including transcriptio... more The process of adipogenesis is controlled in a highly orchestrated manner, including transcriptional and post-transcriptional events. In developing 3T3-L1 pre-adipocytes, this program can be interrupted by all-trans retinoic acid (ATRA). To examine this inhibiting impact by ATRA, we generated large-scale transcriptomic data on the microRNA and mRNA level. Non-coding RNAs such as microRNAs represent a field in RNA turnover, which is very important for understanding the regulation of mRNA gene expression. High throughput mRNA and microRNA expression profiling was performed using mRNA hybridisation microarray technology and multiplexed expression assay for microRNA quantification. After quantitative measurements we merged expression data sets, integrated the results and analysed the molecular regulation of in vitro adipogenesis. For this purpose, we applied local enrichment analysis on the integrative microRNA-mRNA network determined by a linear regression approach. This approach inclu...

The Journal of Clinical Endocrinology & Metabolism, 2001

American Journal of Physiology-Endocrinology and Metabolism, 2009

Obesity is associated with a state of chronic low-grade inflammation. Immune cells accumulate in ... more Obesity is associated with a state of chronic low-grade inflammation. Immune cells accumulate in white adipose tissue (WAT). The vascular endothelium plays an interactive role in these infiltration and inflammatory processes. Mature and hypertrophic adipocytes are considered as the major adipogenic cell type secreting proinflammatory cytokines in WAT. In contrast, the proinflammatory capacity of preadipocytes and their role in endothelial cell activation have been neglected so far. To gain new insights into this molecular and cellular cross-talk, we examined the proinflammatory expression and secretion of normoxia, hypoxia, and TNFα-treated human preadipocytes and adipocytes (SGBS cells) and their impact on human microvascular endothelial cell (HMEC-1) function. In this study, stimulation of HMEC-1 with conditioned media (CM) from preadipocytes increased endothelial ICAM-1 expression and monocyte adhesion but not adipocyte-CM. After hypoxia and TNFα stimulation of SGBS cells, adipoc...

International Journal of Obesity, 1998

OBJECTIVE: In differentiating human preadipocytes glucose uptake in the presence of insulin is a ... more OBJECTIVE: In differentiating human preadipocytes glucose uptake in the presence of insulin is a prerequisite for lipid accumulation. The aim of this study was to characterize the insulin-regulated glucose transport system during and after differentiation. DESIGN AND METHODS: Human adipocyte precursor cells kept in primary culture were allowed to differentiate into fat cells under serum-free hormone-supplemented conditions. 2-Deoxy-glucose uptake was measured as a functional parameter of the glucose transport system, the amount of GLUT1 and GLUT4 protein was determined by Western blotting. RESULTS: In the undifferentiated state, cells did not increase 2-deoxy-glucose uptake in response to insulin. On day 16, when cells have acquired the adipocyte phenotype, there was a 3±4-fold stimulation of glucose transport by insulin compared to basal rates, whereas basal glucose uptake was dramatically diminished. Measurement of GLUT4 protein in cell extracts, showed a marked increase in the amount of this insulin-regulated transporter isoform during the differentiation period. On average, the amount of GLUT4 was 16.7-fold greater after than before differentiation. In contrast, the amount of GLUT1 protein decreased during differentiation to almost undetectable levels on day 16. When newly developed adipocytes were maintained in culture for another 14 d, the stimulation of glucose uptake and the amount of GLUT4 remained stable. CONCLUSION: Differentiating human fat cells in primary culture develops an insulin-responsive glucose transport system which exhibits a high stability, thereby providing a valuable model for long-term studies of glucose transport and GLUT4 expression in human adipocytes.

International Journal of Obesity, 2006

International Journal of Obesity, 1998

BACKGROUND: Recent studies show an increased adipose production of tumor necrosis factor-alpha (T... more BACKGROUND: Recent studies show an increased adipose production of tumor necrosis factor-alpha (TNF-a) in human obesity. It was hypothesized from this ®nding and other data, that TNF-a may be a mediator of obesity-linked insulin resistance. OBJECTIVE: The aim of this study was to measure plasma concentrations of the two soluble TNF-a receptors, together with those of TNF-a in subjects with severe obesity with and without type 2 diabetes mellitus, in comparison to a lean control group, to examine whether plasma concentrations re¯ect an up-regulation of the TNF system in adipose tissue. PATIENTS AND METHODS: Plasma concentrations of the two soluble TNF-a receptors were measured in 49 obese subjects (mean body mass index (BMI): 44.9 kgam 2 , 95% con®dence intervals (CI) 42.3 ± 47.5 kgam 2 , including 19 type 2 diabetic individuals) and 28 lean controls, by using a highly sensitive enzyme-linked immunoassay (ELISA) technique. TNF-a concentrations were determined in 28 obese (10 with diabetes) and 23 lean subjects. RESULTS: The obese subjects showed signi®cantly higher plasma concentrations of the soluble p60 and p80 TNF receptor, respectively, compared to the lean control group, independent of the presence of diabetes. Multiple regression analysis, with the p80 TNF receptor as dependent variable, revealed that BMI and log insulin signi®cantly affected the plasma concentration of this soluble receptor subtype, explaining 46% of the variance, whereas for the p60 TNF receptor, only BMI turned out to in¯uence plasma concentrations. TNF-a plasma concentrations were not different between the three groups (Kruskal-Wallis test: P 0.34), but due to the low power of the test, an effect of obesity on TNF-a is not excluded. CONCLUSION: These data indicate that plasma concentrations of both soluble TNF receptors are elevated in obesity and insulin resistance, possibly as a function of excess body fat. The reported adipose overexpression of TNF-a does not seem to be re¯ected by elevated plasma concentrations, suggesting a primarily local role of the cytokine.

International Journal of Obesity, 2004

Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinoly... more Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-a and transforming growth factor-b, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT 1receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease.

Molecular Psychiatry, 2003

Journal of Clinical Investigation, 1989

The Journal of Clinical Endocrinology & Metabolism, 2007

Context: Adipocytes are known to release a variety of factors that may contribute to the proinfla... more Context: Adipocytes are known to release a variety of factors that may contribute to the proinflammatory state characteristic for obesity. This secretory function is considered to provide the basis for obesity-related complications such as type 2 diabetes and atherosclerosis. Patients and Methods Materials Collagenase was obtained from Biochrom (Berlin, Germany). Culture media were purchased from Life Technologies, Inc.

Journal of Biological Chemistry, 2001

Tumor necrosis factor-␣ (TNF-␣) is a pleiotropic cytokine with a proposed role in obesity-related... more Tumor necrosis factor-␣ (TNF-␣) is a pleiotropic cytokine with a proposed role in obesity-related insulin resistance. This could be mediated by increased lipolysis in adipose tissue resulting in elevated free fatty acid levels. The early intracellular signals entailed in TNF-␣mediated lipolysis are unknown but may involve members of the mitogen-activated protein kinase (MAPK) family. We investigated the possible contribution of MAPK in TNF-␣-induced lipolysis in human preadipocytes. TNF-␣ activated the three mammalian MAPK, p44/ 42, JNK, and p38, in a distinct time-and concentrationdependent manner. TNF-␣ also induced a concentrationdependent stimulation of lipolysis with a more than 3-fold increase at the maximal dose. Lipolysis was completely inhibited by blockers specific for p44/42 (PD98059) and JNK (dimetylaminopurine) but was not affected by the p38 blocker SB203580. Use of receptorspecific TNF-␣ mutants showed that activation of MAPK is entirely mediated by the TNFR1 receptor. The results in human preadipocytes differed from those obtained in murine 3T3-L1 adipocytes in which all three MAPK were constitutively active. Thus, studies of intracellular signaling pathways obtained in different cellular contexts should be interpreted with caution. In conclusion, although TNF-␣ activates all three known MAPK in human preadipocytes, only p44/42 and JNK appear to be involved in the regulation of lipolysis. Obesity, peripheral insulin resistance, and non-insulin-dependent diabetes mellitus are closely related clinical conditions with an almost epidemically increasing prevalence in industrialized countries (1). The molecular mechanisms underlying this close association are still not clear but are thought to involve, among others, factors produced by the adipose tissue. A wealth of studies in recent years has implicated tumor necrosis factor-␣ (TNF-␣) 1 in this process (2). TNF-␣ was first

Pediatric research, Jan 15, 2017

Few human studies have explored the role of adiponectin in early life on growth and adipose tissu... more Few human studies have explored the role of adiponectin in early life on growth and adipose tissue development. High molecular weight (HMW) and total adiponectin levels from 141 cord blood samples and plasma blood samples from 40 3-y-old children were analyzed. Associations between adiponectin levels in cord blood and child plasma, and infant/child growth and fat mass measurements up to the age of 5 y were assessed using linear regression models. HMW cord blood adiponectin was positively associated with weight, BMI percentiles, and lean body mass at birth only. At 3 and 4 y, positive associations were found with cord blood adiponectin and sum of four skinfold thickness measures and percentage of body fat following adjustment for maternal and child covariates, but did not persist at 5 y. There was no significant evidence of an association between child plasma HMW adiponectin and growth or body composition characteristics at 3-5 y. Our results do not support the hypothesis that HMW co...

BMC Genomics, 2014

Background: Previously we have examined the effect of maternal dietary n-3 long-chain polyunsatur... more Background: Previously we have examined the effect of maternal dietary n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on offspring fat mass. Considering the involvement of the placenta in fetal programming, we aimed to analyze the sex-specific gene expression in human term placenta and its response to the n-3 LCPUFA intervention, as well as their correlations to offspring adiposity. Results: Placental gene expression was assessed in a control and n-3 LCPUFA intervention group by DNA microarrays, biological pathway analyses and RT-qPCR validation. Expression data were correlated with sex steroid hormone levels in placenta and cord plasma, and offspring anthropometric data. Transcriptome data revealed sexually dimorphic gene expression in control placentas per se, whereas in intervention placentas sex-specific expression changed, and more n-3 LCPUFA-regulated genes were found in female than male placentas. Sexually dimorphic gene expression and n-3 LCPUFAresponsive genes were enriched in the pathway for cell cycle and its associated modulator pathways. Significant mRNA expression changes for CDK6, PCNA, and TGFB1 were confirmed by RT-qPCR. CDK6 and PCNA mRNA levels correlated with offspring birth weight and birth weight percentiles. Significantly reduced placental estradiol-17β/testosterone ratio upon intervention found in female offspring correlated with mRNA levels for the 'Wnt signaling' genes DVL1 and LRP6. Conclusions: Overall, human placentas show sexually dimorphic gene expression and responsiveness to maternal n-3 LCPUFA intervention during pregnancy with more pronounced effects in female placentas. The absence of correlations of analyzed placental gene expression with offspring adipose tissue growth in the first year is not mutually exclusive with programming effects, which may manifest later in life, or in other physiological processes.

BMC Pregnancy and Childbirth, 2014

Background: Maternal obesity and gestational diabetes mellitus (GDM) may independently influence ... more Background: Maternal obesity and gestational diabetes mellitus (GDM) may independently influence offspring fat mass and metabolic disease susceptibility. In this pilot study, body composition and fat distribution in offspring from obese women with and without GDM and lean women were assessed within the 1st year of life, and maternal and newborn plasma factors were related to offspring adipose tissue distribution. Methods: Serum and plasma samples from pregnant obese women with (n = 16) or without (n = 13) GDM and normoglycemic lean women (n = 15) at 3rd trimester and offspring cord plasma were used for analyzing lipid profiles, insulin and adipokine levels. At week-1 and 6, month-4 and year-1, offspring anthropometrics and skinfold thickness (SFT) were measured and abdominal subcutaneous (SCA) and preperitoneal adipose tissue (PPA) were determined by ultrasonography. Results: Cord insulin was significantly increased in the GDM group, whereas levels of cord leptin, total and high molecular weight (HMW) adiponectin were similar between the groups. Neonates of the GDM group showed significantly higher SFT and fat mass until week-6 and significantly increased SCA at week-1 compared to the lean group that persisted as strong trend at week-6. Interestingly, PPA in neonates of the GDM group was significantly elevated at week-1 compared to both the lean and obese group. At month-4 and year-1, significant differences in adipose tissue growth between the groups were not observed. Multiple linear regression analyses revealed that cord insulin levels are independently related to neonatal PPA that showed significant relation to PPA development at year-1. Maternal fasted C-peptide and HMW adiponectin levels at 3rd trimester emerged to be determinants for PPA at week-1. Conclusion: Maternal pregravid obesity combined with GDM leads to newborn hyperinsulinemia and increased offspring fat mass until week-6, whereas pregravid obesity without GDM does not. This strongly suggests the pivotal role of GDM in the adverse offspring outcome. Maternal C-peptide and HMW adiponectin levels in pregnancy emerge to be predictive for elevated PPA in newborns and might be indicative for the obesity risk at later life. Altogether, the findings from our pilot study warrant evaluation in long-term studies.

Annals of Nutrition and Metabolism, 2009

Recent observational studies suggest that mean birth weight and body fat growth in the first year... more Recent observational studies suggest that mean birth weight and body fat growth in the first year of life have increased continuously over the last decades. Both elevated birth weight and early fat mass are potential risk factors for childhood obesity. Experimental and limited clinical data suggest that the dietary ratio of n–6 to n–3 fatty acids (FAs) during pregnancy is critical for early adipose tissue growth. The aim of this randomized controlled study is to examine the effect of the supplementation with n–3 long-chain polyunsaturated FAs and reduction in the n–6/n–3 ratio in the diet of pregnant women/breast-feeding mothers on adipose tissue growth in their newborns using various methods for the assessment of body fat mass. Measurement of skinfold thickness in the newborn is the primary outcome parameter. Two hundred and four pregnant women will be recruited before the 15th week of gestation and randomly assigned to either active intervention or an isocaloric control diet. This...

The American Journal of Clinical Nutrition, 2013

Childhood obesity is increasing worldwide, and all previous attempts to stop this epidemic have s... more Childhood obesity is increasing worldwide, and all previous attempts to stop this epidemic have shown little success. There is now growing evidence that the risk of childhood obesity is strongly influenced by perinatal determinants, including prepregnancy body mass index (BMI), gestational weight gain, and-at least in animal studiesdietary factors during pregnancy and lactation. This review addresses the issue of whether modulation of fat intake and its composition in this early-life period has a potential for primary prevention of childhood obesity. Of particular interest is the question of whether supplementation with n-3 long-chain PUFAs (LC-PUFAs) may exert an antiobesity effect. Retrospective analysis of human randomized controlled trials with fish-oil intervention during pregnancy and lactation gave inconsistent results concerning BMI and obesity development in offspring. A recent prospective human intervention study aimed at reducing the n-6:n-3 LC-PUFA ratio did not show an effect on adipose tissue growth in offspring up to the age of 1 y. Therefore, there is currently little evidence to support the hypothesis that dietary intervention to modify fat composition during pregnancy and lactation would be a promising strategy to prevent childhood obesity in humans, but more research is clearly needed to address the question if and how the risk of developing obesity can be modified by dietary intervention early in life.

The American Journal of Clinical Nutrition, 2011

Background: The composition of long-chain PUFAs (LCPUFAs) in the maternal diet may affect obesity... more Background: The composition of long-chain PUFAs (LCPUFAs) in the maternal diet may affect obesity risk in the mother's offspring. Objective: We hypothesized that a reduction in the n26 (omega-6): n23 (omega-3) LCPUFA ratio in the diet of pregnant women and breastfeeding mothers may prevent expansive adipose tissue growth in their infants during the first year of life. Design: In a randomized controlled trial, 208 healthy pregnant women were randomly assigned to an intervention (1200 mg n23 LCPUFAs as a supplement per day and a concomitant reduction in arachidonic acid intake) or a control diet from the 15th wk of pregnancy to 4 mo of lactation. The primary outcome was infant fat mass estimated by skinfold thickness (SFT) measurements at 4 body sites at 3-5 d, 6 wk, and 4 and 12 mo postpartum. Secondary endpoints included sonographic assessment of abdominal subcutaneous and preperitoneal fat, fat distribution, and child growth. Results: Infants did not differ in the sum of their 4 SFTs at 1 y of life [intervention: 24.1 6 4.4 mm (n = 85); control: 24.1 6 4.1 mm (n = 80); mean difference: 20.0 mm (95% CI: 21.3, 1.3 mm)] or in growth. Likewise, longitudinal ultrasonography showed no significant differences in abdominal fat mass or fat distribution. Conclusions: We showed no evidence that supplementation with n23 fatty acids and instructions to reduce arachidonic acid intake during pregnancy and lactation relevantly affects fat mass in offspring during the first year of life. Prospective long-term studies are needed to explore the efficacy of this dietary approach for primary prevention. This trial was registered at clinicaltrials.gov as NCT00362089.

Breast care (Basel, Switzerland), 2014

Epidemiological data suggest a close link between obesity and breast cancer, the most frequently ... more Epidemiological data suggest a close link between obesity and breast cancer, the most frequently occurring cancer in women. The metabolic syndrome is typically associated with abdominal obesity and comprises disturbances in glucose and/or lipid metabolism and/or hypertension. Recent studies have established a specific association between the metabolic syndrome - as well as its components - and breast cancer, indicating both an increased risk of developing breast cancer and a poorer prognosis. In premenopausal women, obesity might have a protective effect only on receptor-positive tumors, whereas a positive association was observed between obesity/abdominal obesity and an increased risk of triple-negative breast cancer (TNBC). Overall survival and disease-free survival were reported to be significantly shorter in premenopausal obese women with TNBC compared to non-obese women, but these results are still inconsistent and need further research. The metabolic syndrome is characterized ...

Biomolecular detection and quantification, 2017

The process of adipogenesis is controlled in a highly orchestrated manner, including transcriptio... more The process of adipogenesis is controlled in a highly orchestrated manner, including transcriptional and post-transcriptional events. In developing 3T3-L1 pre-adipocytes, this program can be interrupted by all-trans retinoic acid (ATRA). To examine this inhibiting impact by ATRA, we generated large-scale transcriptomic data on the microRNA and mRNA level. Non-coding RNAs such as microRNAs represent a field in RNA turnover, which is very important for understanding the regulation of mRNA gene expression. High throughput mRNA and microRNA expression profiling was performed using mRNA hybridisation microarray technology and multiplexed expression assay for microRNA quantification. After quantitative measurements we merged expression data sets, integrated the results and analysed the molecular regulation of in vitro adipogenesis. For this purpose, we applied local enrichment analysis on the integrative microRNA-mRNA network determined by a linear regression approach. This approach inclu...

The Journal of Clinical Endocrinology & Metabolism, 2001

American Journal of Physiology-Endocrinology and Metabolism, 2009

Obesity is associated with a state of chronic low-grade inflammation. Immune cells accumulate in ... more Obesity is associated with a state of chronic low-grade inflammation. Immune cells accumulate in white adipose tissue (WAT). The vascular endothelium plays an interactive role in these infiltration and inflammatory processes. Mature and hypertrophic adipocytes are considered as the major adipogenic cell type secreting proinflammatory cytokines in WAT. In contrast, the proinflammatory capacity of preadipocytes and their role in endothelial cell activation have been neglected so far. To gain new insights into this molecular and cellular cross-talk, we examined the proinflammatory expression and secretion of normoxia, hypoxia, and TNFα-treated human preadipocytes and adipocytes (SGBS cells) and their impact on human microvascular endothelial cell (HMEC-1) function. In this study, stimulation of HMEC-1 with conditioned media (CM) from preadipocytes increased endothelial ICAM-1 expression and monocyte adhesion but not adipocyte-CM. After hypoxia and TNFα stimulation of SGBS cells, adipoc...

International Journal of Obesity, 1998

OBJECTIVE: In differentiating human preadipocytes glucose uptake in the presence of insulin is a ... more OBJECTIVE: In differentiating human preadipocytes glucose uptake in the presence of insulin is a prerequisite for lipid accumulation. The aim of this study was to characterize the insulin-regulated glucose transport system during and after differentiation. DESIGN AND METHODS: Human adipocyte precursor cells kept in primary culture were allowed to differentiate into fat cells under serum-free hormone-supplemented conditions. 2-Deoxy-glucose uptake was measured as a functional parameter of the glucose transport system, the amount of GLUT1 and GLUT4 protein was determined by Western blotting. RESULTS: In the undifferentiated state, cells did not increase 2-deoxy-glucose uptake in response to insulin. On day 16, when cells have acquired the adipocyte phenotype, there was a 3±4-fold stimulation of glucose transport by insulin compared to basal rates, whereas basal glucose uptake was dramatically diminished. Measurement of GLUT4 protein in cell extracts, showed a marked increase in the amount of this insulin-regulated transporter isoform during the differentiation period. On average, the amount of GLUT4 was 16.7-fold greater after than before differentiation. In contrast, the amount of GLUT1 protein decreased during differentiation to almost undetectable levels on day 16. When newly developed adipocytes were maintained in culture for another 14 d, the stimulation of glucose uptake and the amount of GLUT4 remained stable. CONCLUSION: Differentiating human fat cells in primary culture develops an insulin-responsive glucose transport system which exhibits a high stability, thereby providing a valuable model for long-term studies of glucose transport and GLUT4 expression in human adipocytes.

International Journal of Obesity, 2006

International Journal of Obesity, 1998

BACKGROUND: Recent studies show an increased adipose production of tumor necrosis factor-alpha (T... more BACKGROUND: Recent studies show an increased adipose production of tumor necrosis factor-alpha (TNF-a) in human obesity. It was hypothesized from this ®nding and other data, that TNF-a may be a mediator of obesity-linked insulin resistance. OBJECTIVE: The aim of this study was to measure plasma concentrations of the two soluble TNF-a receptors, together with those of TNF-a in subjects with severe obesity with and without type 2 diabetes mellitus, in comparison to a lean control group, to examine whether plasma concentrations re¯ect an up-regulation of the TNF system in adipose tissue. PATIENTS AND METHODS: Plasma concentrations of the two soluble TNF-a receptors were measured in 49 obese subjects (mean body mass index (BMI): 44.9 kgam 2 , 95% con®dence intervals (CI) 42.3 ± 47.5 kgam 2 , including 19 type 2 diabetic individuals) and 28 lean controls, by using a highly sensitive enzyme-linked immunoassay (ELISA) technique. TNF-a concentrations were determined in 28 obese (10 with diabetes) and 23 lean subjects. RESULTS: The obese subjects showed signi®cantly higher plasma concentrations of the soluble p60 and p80 TNF receptor, respectively, compared to the lean control group, independent of the presence of diabetes. Multiple regression analysis, with the p80 TNF receptor as dependent variable, revealed that BMI and log insulin signi®cantly affected the plasma concentration of this soluble receptor subtype, explaining 46% of the variance, whereas for the p60 TNF receptor, only BMI turned out to in¯uence plasma concentrations. TNF-a plasma concentrations were not different between the three groups (Kruskal-Wallis test: P 0.34), but due to the low power of the test, an effect of obesity on TNF-a is not excluded. CONCLUSION: These data indicate that plasma concentrations of both soluble TNF receptors are elevated in obesity and insulin resistance, possibly as a function of excess body fat. The reported adipose overexpression of TNF-a does not seem to be re¯ected by elevated plasma concentrations, suggesting a primarily local role of the cytokine.

International Journal of Obesity, 2004

Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinoly... more Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-a and transforming growth factor-b, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT 1receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease.

Molecular Psychiatry, 2003

Journal of Clinical Investigation, 1989

The Journal of Clinical Endocrinology & Metabolism, 2007

Context: Adipocytes are known to release a variety of factors that may contribute to the proinfla... more Context: Adipocytes are known to release a variety of factors that may contribute to the proinflammatory state characteristic for obesity. This secretory function is considered to provide the basis for obesity-related complications such as type 2 diabetes and atherosclerosis. Patients and Methods Materials Collagenase was obtained from Biochrom (Berlin, Germany). Culture media were purchased from Life Technologies, Inc.

Journal of Biological Chemistry, 2001

Tumor necrosis factor-␣ (TNF-␣) is a pleiotropic cytokine with a proposed role in obesity-related... more Tumor necrosis factor-␣ (TNF-␣) is a pleiotropic cytokine with a proposed role in obesity-related insulin resistance. This could be mediated by increased lipolysis in adipose tissue resulting in elevated free fatty acid levels. The early intracellular signals entailed in TNF-␣mediated lipolysis are unknown but may involve members of the mitogen-activated protein kinase (MAPK) family. We investigated the possible contribution of MAPK in TNF-␣-induced lipolysis in human preadipocytes. TNF-␣ activated the three mammalian MAPK, p44/ 42, JNK, and p38, in a distinct time-and concentrationdependent manner. TNF-␣ also induced a concentrationdependent stimulation of lipolysis with a more than 3-fold increase at the maximal dose. Lipolysis was completely inhibited by blockers specific for p44/42 (PD98059) and JNK (dimetylaminopurine) but was not affected by the p38 blocker SB203580. Use of receptorspecific TNF-␣ mutants showed that activation of MAPK is entirely mediated by the TNFR1 receptor. The results in human preadipocytes differed from those obtained in murine 3T3-L1 adipocytes in which all three MAPK were constitutively active. Thus, studies of intracellular signaling pathways obtained in different cellular contexts should be interpreted with caution. In conclusion, although TNF-␣ activates all three known MAPK in human preadipocytes, only p44/42 and JNK appear to be involved in the regulation of lipolysis. Obesity, peripheral insulin resistance, and non-insulin-dependent diabetes mellitus are closely related clinical conditions with an almost epidemically increasing prevalence in industrialized countries (1). The molecular mechanisms underlying this close association are still not clear but are thought to involve, among others, factors produced by the adipose tissue. A wealth of studies in recent years has implicated tumor necrosis factor-␣ (TNF-␣) 1 in this process (2). TNF-␣ was first