Center for Fetal Programming

Copenhagen, Denmark

Center for Fetal Programming

Copenhagen, Denmark
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Nalla A.,University of Southern Denmark | Nalla A.,Center for Fetal Programming | Ringholm L.,Copenhagen University | Sostrup B.,Center for Fetal Programming | And 7 more authors.
Acta Obstetricia et Gynecologica Scandinavica | Year: 2014

Results Late gestational pregnancy serum significantly increased proliferation of rat beta cells compared with early pregnancy and nonpregnancy. The mitogenic active serum fractions contained proteins and peptides derived from kininogen-1, fibrinogen-α, α1-antitrypsin, apolipoprotein-A1, placental lactogen, angiotensinogen and serum albumin.Conclusion Pregnancy serum is able to stimulate proliferation of rat beta cells. We have identified several circulating factors that may contribute to beta cell adaptation to pregnancy. Further studies are needed to elucidate their possible role in glucose homeostasis in the mother and her offspring.Objective Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors.Samples Serum samples from nonpregnant and pregnant women.Methods The effect of serum from pregnant women on the proliferation of rat beta cells was studied using [3H]thymidine incorporation and 5-ethynyl-2-deoxyuridine proliferation assays. In addition, serum from pregnant and nonpregnant women was fractionated by gel filtration and high performance liquid chromatography. The fractionated serum was screened for mitogenic activity in INS-1E cells. Proteins and peptides in mitogenic active serum fractions were identified by amino acid sequencing and mass spectrometry.Main outcome measures Presence of circulating beta cell proliferating factors. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.


Strom M.,Center for Fetal Programming | Strom M.,Statens Serum Institute | Halldorsson T.I.,Center for Fetal Programming | Halldorsson T.I.,University of Iceland | And 8 more authors.
Annals of Nutrition and Metabolism | Year: 2014

Background: Vitamin D is obtained from dietary sources and synthesized in the skin during exposure to ultraviolet B radiation in sunlight. During pregnancy, vitamin D is transported from mother to fetus through the placenta in the form of 25-hydroxyvitamin D [25(OH)D]. There is evidence that vitamin D influences neuronal differentiation, endocrine functions, and fetal brain growth. Animal studies indicate alterations in the offspring brain as a consequence of vitamin D deficiency during pregnancy. In humans, maternal vitamin D insufficiency has been linked to impaired child language development. Using data from a prebirth cohort with up to 22 years of follow-up, we examined the association of vitamin D status with proxies of offspring neurodevelopmental outcomes. During 1988-1989, pregnant women were recruited for the DaFO88 cohort (n = 965) in Aarhus, Denmark. Maternal concentrations of 25(OH)D were quantified in serum from week 30 of gestation via the LC-MS/MS method (n = 850). Offspring were followed up through national registries until the age of 22 years. We evaluated the association of the maternal concentration of 25(OH)D with offspring neurodevelopmental outcomes defined as first admission diagnosis or prescription of medication for (1) ADHD, (2) depression, and (3) scholastic achievement based on the mean grade on standardized written examinations in the 9th grade (final exams after 10 years of compulsory school in Denmark). Key Messages: Maternal concentrations of 25(OH)D were higher compared to current levels (median 76 nmol/l; 5th to 95th percentiles 23-152). There was a direct association between maternal vitamin D status and offspring depression (ptrend = 0.01); for ADHD there was no association. Scholastic achievement was slightly higher for offspring of mothers with a vitamin D status in the range of >50-125 nmol/l, but this nonlinear association was not statistically significant. Conclusions: Our analyses based on biomarker measurement of 25(OH)D from a cohort of 850 pregnant women combined with long-term follow-up showed no support for a beneficial fetal programming effect of vitamin D status with regard to behavioral and affective disorders and scholastic achievement. © 2014 S. Karger AG, Basel.


Li S.,National Health Research Institute | Zhu Y.,National Health Research Institute | Chavarro J.E.,Harvard University | Bao W.,National Health Research Institute | And 10 more authors.
Hypertension | Year: 2016

Women who developed gestational diabetes mellitus represent a high-risk population for hypertension later in life. The role of diet in the progression of hypertension among this susceptible population is unknown. We conducted a prospective cohort study of 3818 women with a history of gestational diabetes mellitus in the Nurses' Health Study II as part of the ongoing Diabetes & Women's Health Study. These women were followed-up from 1989 to 2011. Incident hypertension was identified through self-administered questionnaires that were validated previously by medical record review. Adherence scores for the alternative Healthy Eating Index 2010, the alternative Mediterranean diet, and the Dietary Approaches to Stop Hypertension were computed for each participant. Cox proportional hazard models were used to evaluate the associations between dietary scores and hypertension while adjusting for major risk factors for hypertension. We documented 1069 incident hypertension cases during a median of 18.5 years of follow-up. After adjustment for major risk factors for hypertension, including body mass index, alternative Healthy Eating Index 2010, alternative Mediterranean diet, and Dietary Approaches to Stop Hypertension scores were significantly inversely associated with the risk of hypertension; hazard ratio and 95% confidence interval comparing the extreme quartiles (highest versus lowest) were 0.76 (0.61-0.94; P for linear trend =0.03) for AHEI score, 0.72 (0.58-0.90; P for trend =0.01) for Dietary Approach to Stop Hypertension score, and 0.70 (0.56-0.88; P for trend =0.002) for alternative Mediterranean diet score. Adherence to a healthful dietary pattern was related to a lower subsequent risk of developing hypertension among women with a history of gestational diabetes mellitus. © 2016 American Heart Association, Inc.


Knudsen V.K.,Statens Serum Institute | Knudsen V.K.,Technical University of Denmark | Heitmann B.L.,Copenhagen University | Halldorsson T.I.,Statens Serum Institute | And 4 more authors.
British Journal of Nutrition | Year: 2013

Dietary glycaemic index and glycaemic load (GL) have been related to obesity and other health outcomes. The objective of the present study was to examine the associations between maternal dietary GL and gestational weight gain, birth weight, the risk of giving birth to a child large-for-gestational age (LGA) or small-for-gestational age and postpartum weight retention (PPWR). Data were derived from the Danish National Birth Cohort (1996-2002), including data on gestational and lifestyle factors in pregnancy and 18 months postpartum. Dietary data were collected using a validated FFQ. Information on birth outcome was obtained through registers. A total of 47 003 women were included. The associations between the GL and birth outcome, gestational weight gain, assessed between weeks 12 and 30 of gestation, and PPWR were analysed by linear and logistic regression. Birth weight increased by 36 g from the lowest to highest GL quintile (95 % CI 19, 53 g), and an increased risk of LGA of 14 % was detected in the highest GL quintile compared with the lowest GL quintile. Among normal-weight and overweight women, higher gestational weight gain rates were detected in the highest GL quintile (26 g/week (95 % CI 19, 34) and 30 g/week (95 % CI 13, 46), respectively). The association between the GL and PPWR was most pronounced among pre-pregnant obese women, with an increase in weight retention of 1·3 (95 % CI 0·2, 2·8) kg from the lowest to highest GL quintile. The GL may play a role for excessive gestational weight gain and PPWR, which may be more pronounced among overweight and obese women. © 2012 The Authors.


Hou L.,Copenhagen University | Hou L.,Center for Fetal Programming | Hellgren L.I.,Center for Fetal Programming | Hellgren L.I.,Technical University of Denmark | And 6 more authors.
Acta Physiologica | Year: 2014

Aim: Determine the impacts of pre- and early-post-natal nutrition on selected markers of hepatic glucose and fat metabolism. Methods: Twin-bearing ewes were fed 100% (NORM) or 50% (LOW) of protein and energy requirements during the last 6-weeks of gestation. Twin-lambs received either a high-carbohydrate high-fat (HCHF) or conventional (CONV) diet from 3 days to 6 months of age (around puberty), whereafter lambs from the four subgroups were slaughtered (16 males/3 females). Remaining lambs (19 females) were fed a moderate diet and slaughtered at 2 years of age (young adults). Results: Pre-natal LOW nutrition was associated with increased hepatic triglyceride, ceramide and free fatty acid content in adulthood (not observed in lambs), which was accompanied by up-regulated early-stage insulin signalling as reflected by increased INSRβ and PI3K-p110 protein expression. The HCHF diet increased hepatic triglyceride content in lambs, associated with down-regulated expressions of energy-metabolism-related genes (GLUT1, PPARα, SREBP1c, PEPCK). These post-natal effects were not observed in adult HCHF sheep, after they had received a moderate (body-fat correcting) diet for 1.5 years. Interestingly, pre-natal LOW nutrition induced permanent alterations in hepatic phospholipids' fatty acid composition. Thus, the amount of linoleic acid (C18: 2 {increment}9,12) was significantly increased and composition of rumen-derived fatty acids were altered, indicating changed composition of rumenal microbiota. Conclusion: Hepatic insulin signalling and linoleic and microbial-derived fatty acid content in phospholipids are targets of foetal programming induced by late-gestation undernutrition. Future studies are required to explain their cause-effect associations with increased risks of developing hepatic steatosis and insulin insensitivity in adulthood. © 2013 Scandinavian Physiological Society.


Nielsen M.O.,Copenhagen University | Nielsen M.O.,Center for Fetal Programming | Hou L.,Copenhagen University | Hou L.,Center for Fetal Programming | And 11 more authors.
Clinical Nutrition Experimental | Year: 2016

Background & aims: Previous studies have shown that fetal life malnutrition affects preferences for fat deposition in the body thereby predisposing for visceral adipocity and associated disorders in glucose-insulin regulation. In this study, we aimed to test the hypotheses that late-gestation undernutrition 1) has long-term differential impacts on development, expandability and metabolic features in subcutaneous as compared to perirenal and mesenteric adipose tissues, which 2) will predispose for visceral obesity upon exposure to an obesogenic diet in early postnatal life. Methods: Twin-bearing last trimester ewes received diets supplying 100% (NORM) or 50% (LOW) of protein and energy requirements. Lambs received moderate, low-fat (CONV) or high-carbohydrate-high-fat (HCHF) diets from 3-days until 6-months of age (just after puberty), and then half the lambs (including all males) were sacrificed. Remaining animals (exclusively females) received a low-fat, grass-based diet until sacrificed at 2-years of age (adulthood). In subcutaneous, perirenal and mesenteric fat, energy metabolism related gene expressions and fatty acid composition were determined. Histological evaluations were performed of subcutaneous and perirenal fat. The late-gestation undernutrition reduced whole-body insulin sensitivity and increased the risk of obesity-induced mesenteric adiposity in the sheep used in the experiment. Results: A deviating morphology of subcutaneous adipose tissue with greater occurrence of very small adipocytes (<40 μm in diameter) and collagen infiltration was observed in the non-obese LOW/CONV lambs, and after dietary correction (and associated body fat loss) it became apparent in all adult LOW sheep. LOW lambs deposited more fat in visceral compared to subcutaneous fat when exposed to the obesogenic HCHF diet. Prenatal undernutrition had differential impacts in subcutaneous versus perirenal fat on expressions of glucose-insulin signaling and lipid metabolism genes and on fatty acid composition, but these prenatal impacts were not sustained into adulthood, except to a limited extent in perirenal fat, where C14:0 was decreased in LOW sheep. Conclusions: The present study showed that greater preponderance of very small adipocytes, increased collagen infiltration and reduced subcutaneous lipid accumulation ability, as well as altered perirenal fat preferences for accumulation of C14:0 can have a fetal origin. Disturbance of normal (subcutaneous) adipose tissue development may play a key role in linking fetal malnutrition to disease risk later in life. © 2016 The Authors.


Nielsen J.H.,Copenhagen University | Nielsen J.H.,Center for Fetal Programming | Haase T.N.,Copenhagen University | Haase T.N.,Center for Fetal Programming | And 22 more authors.
Acta Obstetricia et Gynecologica Scandinavica | Year: 2014

The global epidemic of diabetes is a serious threat against health and healthcare expenses. Although genetics is important it does not explain the dramatic increase in incidence, which must involve environmental factors. Two decades ago the concept of the thrifty phenotype was introduced, stating that the intrauterine environment during pregnancy has an impact on the gene expression that may persist until adulthood and cause metabolic diseases like obesity and type 2 diabetes. As the pancreatic beta cells are crucial in the regulation of metabolism this article will describe the influence of normal pregnancy on the beta cells in both the mother and the fetus and how various conditions like diabetes, obesity, overnutrition and undernutrition during and after pregnancy may influence the ability of the offspring to adapt to changes in insulin demand later in life. The influence of environmental factors including nutrients and gut microbiota on appetite regulation, mitochondrial activity and the immune system that may affect beta cell growth and function directly and indirectly is discussed. The possible role of epigenetic changes in the transgenerational transmission of the adverse programming may be the most threatening aspect with regard to the global diabetes epidemics. Finally, some suggestions for intervention are presented. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.


Hou L.,Copenhagen University | Hou L.,Center for Fetal Programming | Kongsted A.H.,Copenhagen University | Kongsted A.H.,Center for Fetal Programming | And 11 more authors.
PLoS ONE | Year: 2013

We previously reported that undernutrition in late fetal life reduced whole-body insulin sensitivity in adult sheep, irrespective of dietary exposure in early postnatal life. Skeletal muscle may play an important role in control of insulin action. We therefore studied a range of putative key muscle determinants of insulin signalling in two types of skeletal muscles (longissimus dorsi (LD) and biceps femoris (BF)) and in the cardiac muscle (ventriculus sinister cordis (VSC)) of sheep from the same experiment. Twin-bearing ewes were fed either 100% (NORM) or 50% (LOW) of their energy and protein requirements during the last trimester of gestation. From day-3 postpartum to 6-months of age (around puberty), twin offspring received a high-carbohydrate-high-fat (HCHF) or a moderate-conventional (CONV) diet, whereafter all males were slaughtered. Females were subsequently raised on a moderate diet and slaughtered at 2-years of age (young adults). The only long-term consequences of fetal undernutrition observed in adult offspring were lower expressions of the insulin responsive glucose transporter 4 (GLUT4) protein and peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC1α) mRNA in BF, but increased PGC1α expression in VSC. Interestingly, the HCHF diet in early postnatal life was associated with somewhat paradoxically increased expressions in LD of a range of genes (but not proteins) related to glucose uptake, insulin signalling and fatty acid oxidation. Except for fatty acid oxidation genes, these changes persisted into adulthood. No persistent expression changes were observed in BF and VSC. The HCHF diet increased phospholipid ratios of n-6/n-3 polyunsaturated fatty acids in all muscles, even in adults fed identical diets for 11/2 years. In conclusion, early postnatal, but not late gestation, nutrition had long-term consequences for a number of determinants of insulin action and metabolism in LD. Tissues other than muscle may account for reduced whole body insulin sensitivity in adult LOW sheep. © 2013 Hou et al.


Ingvorsen C.,Technical University of Denmark | Ingvorsen C.,Center for Fetal Programming | Brix S.,Technical University of Denmark | Ozanne S.E.,University of Cambridge | And 2 more authors.
Acta Physiologica | Year: 2015

Maternal obesity during pregnancy increases the child's risk of developing obesity and obesity-related diseases later in life. Key components in foetal programming of metabolic risk remain to be identified; however, chronic low-grade inflammation associated with obesity might be responsible for metabolic imprinting in the offspring. We have therefore surveyed the literature to evaluate the role of maternal obesity-induced inflammation in foetal programming of obesity and related diseases. The literature on this topic is limited, so this review also includes animal models where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS). An LPS challenge results in an immunological response that resembles the obesity-induced immune profile, although LPS injections provoke a stronger response than the subclinical obesity-associated response. Maternal LPS or cytokine exposures result in increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. The cytokine levels might be specifically important for the metabolic imprinting, as cytokines are both transferable from maternal to foetal circulation and have the capability to modulate placental nutrient transfer. However, the immune response associated with obesity is moderate and therefore potentially weakened by the pregnancy-driven immune modulation, dominated by anti-inflammatory Treg and Th2 cells. We know from other low-grade inflammatory diseases, such as rheumatoid arthritis, that pregnancy can improve disease state. If pregnancy is also capable of suppressing the obesity-associated inflammation, the immunological markers might be less likely to affect metabolic programming in the developing foetus than otherwise implied. © 2015 Scandinavian Physiological Society.

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