The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment ...contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the ‘developmental programming’ of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes.
Maternal obesity is a global problem that increases the risk of short‐ and long‐term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective ...treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet‐induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto‐placental health. Metformin (300 mg kg−1 day−1) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669 ± 568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (P < 0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7 ± 125.4 nmol g−1 in the placenta and 2063 ± 2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk vs. benefits that are weighed in obstetric medical treatments.
Key points
Maternal obesity and gestational diabetes mellitus have detrimental short‐ and long‐term effects for mother and child.
Metformin is commonly used to treat gestational diabetes mellitus in many populations worldwide but the effects on fetus and placenta are unknown.
In a mouse model of diet‐induced obesity and glucose intolerance in pregnancy we show reduced uterine artery compliance, placental structural changes and reduced fetal growth.
Metformin treatment improved maternal metabolic health and uterine artery compliance but did not rescue obesity‐induced changes in the fetus or placenta. Metformin crossed the placenta into the fetal circulation and entered fetal tissue.
Metformin has beneficial effects on maternal health beyond glycaemic control. However, despite improvements in maternal physiology, metformin did not prevent fetal growth restriction or placental ageing. The high uptake of metformin into the placental and fetal circulation highlights the potential for direct immediate effects of metformin on the fetus with possible long‐term consequences postnatally.
figure legend Obesogenic diet during pregnancy leads to impaired metabolic health in the mother and reduced fetal growth and placental pathologies. Maternal metabolic health can be markedly improved by metformin treatment; however, this is not the case for fetal and placental health and metformin reaches the placenta and fetal circulation, which could have direct short‐ and long‐term effects.
Early life nutrition and metabolic programming Fernandez-Twinn, Denise S.; Ozanne, Susan E.
Annals of the New York Academy of Sciences,
November 2010, Letnik:
1212, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Research investigating the early programming of adult metabolic disease has in recent years provided much mechanistic insight into how the early environment impacts on long‐term health. It includes ...studies addressing the roles of intrauterine nutrient availability, which is determined by maternal nutrition, maternal exposure to oxygen, toxic events, and infection; the placental interface; and also the early postnatal environment. This review will explore the epidemiological evidence for programming of metabolic disease and provide an overview of the various studies using animals to model metabolic phenotypic outcome. It will also discuss evidence for the proposed molecular mechanisms and the potential for intervention.
Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white ...adipose tissue (WAT) of 8-week-old male and female mouse offspring.
C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR.
Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (
< 0.05), exaggerated adipocyte hyperplasia (
< 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (
< 0.05) and the mRNA expression of
(
< 0.05). These changes were not observed in female Ob-Met offspring.
Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT.
Key points
In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy, although their effects on the metabolism of the mother, in relation ...to feto‐placental glucose utilization and growth, are unknown.
In the present study, the consumption of an obesogenic HFHS diet compromised maternal glucose tolerance and insulin sensitivity in late pregnancy in association with dysregulated lipid and glucose handling by the dam.
These maternal metabolic changes induced by HFHS feeding were related to altered feto‐placental glucose metabolism and growth.
A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth.
These findings have implications for the health of women and their infants, who consume obesogenic diets during pregnancy.
In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy. However, the impacts of a HFHS diet during pregnancy on maternal insulin sensitivity and signalling in relation to feto‐placental growth and glucose utilization are unknown. The present study examined the effects of a HFHS diet during mouse pregnancy on maternal glucose tolerance and insulin resistance, as well as, on feto‐placental glucose metabolism. Female mice were fed a control or HFHS diet from day (D) 1 of pregnancy (term = D20.5). At D16 or D19, dams were assessed for body composition, metabolite and hormone concentrations, tissue abundance of growth and metabolic signalling pathways, glucose tolerance and utilization and insulin sensitivity. HFHS feeding perturbed maternal insulin sensitivity in late pregnancy; hepatic insulin sensitivity was higher, whereas sensitivity of the skeletal muscle and white adipose tissue was lower in HFHS than control dams. These changes were accompanied by increased adiposity and reduced glucose production and glucose tolerance of HFHS dams. The HFHS diet also disturbed the hormone and metabolite milieu and altered expression of growth and metabolic signalling pathways in maternal tissues. Furthermore, HFHS feeding was associated with impaired feto‐placental glucose metabolism and growth. A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth. These findings have implications for the health of women and their infants, who consume HFHS diets during pregnancy.
Key points
In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy, although their effects on the metabolism of the mother, in relation to feto‐placental glucose utilization and growth, are unknown.
In the present study, the consumption of an obesogenic HFHS diet compromised maternal glucose tolerance and insulin sensitivity in late pregnancy in association with dysregulated lipid and glucose handling by the dam.
These maternal metabolic changes induced by HFHS feeding were related to altered feto‐placental glucose metabolism and growth.
A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth.
These findings have implications for the health of women and their infants, who consume obesogenic diets during pregnancy.
The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus ...(GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams' systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.
Aims
Intra-uterine growth restriction (IUGR) followed by accelerated postnatal growth is associated with an increased risk of obesity and type 2 diabetes. We aimed to determine central and peripheral ...insulin sensitivity in mice that underwent IUGR followed by postnatal catch-up growth and investigate potential molecular mechanisms underpinning their physiology.
Methods
We used a C57BL/6J mouse model of maternal diet-induced IUGR (maternal diet, 8% protein) followed by cross-fostering to a normal nutrition dam (maternal diet, 20% protein) and litter size manipulation to cause accelerated postnatal catch-up growth. We performed intracerebroventricular insulin injection and hyperinsulinaemic–euglycaemic clamp studies to examine the effect of this early nutritional manipulation on central and peripheral insulin resistance. Furthermore, we performed quantitative real-time PCR and western blotting to examine the expression of key insulin-signalling components in discrete regions of the hypothalamus.
Results
IUGR followed by accelerated postnatal growth caused impaired glucose tolerance and peripheral insulin resistance. In addition, these ‘recuperated’ animals were resistant to the anorectic effects of central insulin administration. This central insulin resistance was associated with reduced protein levels of the p110β subunit of phosphoinositide 3-kinase (PI3K) and increased serine phosphorylation of IRS-1 in the arcuate nucleus (ARC) of the hypothalamus. Expression of the gene encoding protein tyrosine phosphatase 1B (PTP1B;
Ptpn1
) was also increased specifically in this region of the hypothalamus.
Conclusions/interpretation
Mice that undergo IUGR followed by catch-up growth display peripheral and central insulin resistance in adulthood. Recuperated offspring show changes in expression/phosphorylation of components of the insulin signalling pathway in the ARC. These defects may contribute to the resistance to the anorectic effects of central insulin, as well as the impaired glucose homeostasis seen in these animals.
The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has ...detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.
Obesity and gestational diabetes during pregnancy have multiple short- and long-term consequences for both mother and child. One common feature of pregnancies complicated by maternal obesity and ...gestational diabetes is maternal hyperinsulinaemia, which has effects on the mother and her adaptation to pregnancy. Even though insulin does not cross the placenta insulin can act on the placenta as well affecting placental growth, angiogenesis and lipid metabolism. Obese and gestational diabetic pregnancies are often characterised by maternal hyperglycaemia resulting in exposure of the fetus to high levels of glucose, which freely crosses the placenta. This leads to stimulation of fetal ß-cells and insulin secretion in the fetus. Fetal hyperglycaemia/hyperinsulinaemia has been shown to cause multiple complications in fetal development, such as altered growth trajectories, impaired neuronal and cardiac development and early exhaustion of the pancreas. These changes could increase the susceptibility of the offspring to develop cardiometabolic diseases later in life. In this review, we aim to summarize and review the mechanisms by which maternal and fetal hyperinsulinaemia impact on (i) maternal health during pregnancy; (ii) placental and fetal development; (iii) offspring energy homeostasis and long-term cardiometabolic health; (iv) how interventions can alleviate these effects.
The agouti viable yellow (A
) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. A
expressivity is sensitive to ...a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.
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