Animal models and programming of the metabolic syndrome

Bertram, C.; Hanson, Mark A.

doi:10.1093/bmb/60.1.103

Cited by 273 publications

(162 citation statements)

References 76 publications

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“…Feeding a PR diet to pregnant rats increased glucocorticoid receptor (GR) expression and reduced expression of 11b-hydroxysteroid dehydrogenase type II, the enzyme that inactivates corticosteroids, in the liver, lung, kidney and brain in the offspring (3) . In the liver, increased GR activity up-regulates phosphoenolpyruvate carboxykinase expression and activity and so increases capacity for gluconeogenesis.…”

Section: Phenotype Induction and Altered Transcriptionmentioning

confidence: 99%

Effect of maternal diet on the epigenome: implications for human metabolic disease

Lillycrop

2011

Proc. Nutr. Soc.

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The rapid increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now considerable evidence that the fetal and early postnatal environment also strongly influences the risk of developing such diseases in later life. Human studies have shown that low birth weight is associated with an increased risk of CVD, type II diabetes, obesity and hypertension, although recent studies have shown that over-nutrition in early life can also increase susceptibility to future metabolic disease. These findings have been replicated in a variety of animal models, which have shown that both maternal under-and over-nutrition can induce persistent changes in gene expression and metabolism within the offspring. The mechanism by which the maternal nutritional environment induces such changes is beginning to be understood and involves the altered epigenetic regulation of specific genes. The demonstration of a role for altered epigenetic regulation of genes in the developmental induction of chronic diseases raises the possibility that nutritional or pharmaceutical interventions may be used to modify long-term cardio-metabolic disease risk and combat this rapid rise in chronic non-communicable diseases.Epigenetics: DNA methylation: Fetal development: CVD: ObesityThe incidence of chronic non-communicable disease has risen sharply over the last 20 years with an estimated 18 million people dying from CVD per year (1) . This rise in CVD has been amplified by a rapid rise in the rate of obesity and type II diabetes across the world, which are major risk factors for CVD. This increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now substantial evidence that the fetal and early postnatal environment strongly influences the risk of developing cardio-metabolic disease. Epidemiological studies show that a poor intra-uterine environment induced by maternal diet, placental insufficiency or endocrine factors, such as stress, induces changes in the embryo and fetus, which increase its future risk of a range of non-communicable diseases (2) . These findings have been replicated in animal models where restricted nutrition during pregnancy induces dyslipidaemia, obesity, hypertension, hyperinsulinaemia and hyperleptinaemia in the offspring (3,4) . This association between poor intrauterine growth and increased risk of disease in later life may reflect a mismatch between the future environment 'predicted' by the embryo/fetus, based on signals from the mother during gestation, and the actual environment experienced in later life (5) . The mechanism by which cues about nutrient availability in the postnatal environment are transmitted to the fetus and the process by which different, stable phenotypes are induced are beginning to be understood. A number of recent studies suggest that changes in the epigenetic regulation of genes in the embryo ...

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Section: Phenotype Induction and Altered Transcriptionmentioning

confidence: 99%

Effect of maternal diet on the epigenome: implications for human metabolic disease

Lillycrop

2011

Proc. Nutr. Soc.

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“…Detailed information can be found elsewhere. [7][8][9][10] Only selected examples will be cited here to illustrate the relevance of rodent models of foetal undernutrition.…”

Section: The Programming Of the Metabolic Syndromementioning

confidence: 99%

Programming of obesity and cardiovascular disease

2004

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BACKGROUND: There is evidence that malnutrition in early life induces a growth retardation leading, in adult life, to manifest components of the metabolic syndrome. However, the impact on obesity seems less clearly established. OBJECTIVE: To review the effects of foetal and postnatal malnutrition on the programming of obesity in the context of the metabolic syndrome, as well as the link between central obesity and cardiovascular diseases. METHODS: Included in the review were recent papers exploring the mechanisms linking maternal nutrition with impaired foetal growth and later obesity, cardiovascular disease, hypertension and diabetes in humans and animals. RESULTS: The programming of obesity during foetal and early postnatal life depends of the timing of maternal malnutrition as well as the postnatal environment. Obesity arises principally in offspring submitted to malnutrition during early stages of gestation and which presented early catch-up growth. The programming may involve the dysregulation of appetite control or the hormonal environment leading to a context favourable to obesity development (hypersecretion of corticosteroids, hyperinsulinaemia and hyperleptinaemia and anomalies in the IGF axis). Adipose tissue secretes actively several factors implicated in inflammation, blood pressure, coagulation and fibrinolysis. The programmed development of intra-abdominal obesity after early growth restriction may thus favour higher prevalence of hypertension and cardiovascular diseases. CONCLUSIONS: Abdominal obesity appears in malnourished offspring and is aggravated by early catch-up growth. Higher rates of intra-abdominal obesity observed after growth restriction may participate to hypertension and create atherothrombotic conditions leading to the development of cardiovascular diseases.

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“…Furthermore, small size at birth in human population studies is associated with increased risk of high blood pressure and abnormal glucose tolerance in adulthood (3). These associations can be reproduced in animal models of restricted in utero growth (4). A full understanding of the control of fetal growth would therefore make a significant impact on the burden of common diseases.…”

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confidence: 99%

Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

Sibley

Coan

Ferguson-Smith

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

291

216

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Restricted fetal growth is associated with postnatal mortality and morbidity and may be directly related to alterations in the capacity of the placenta to supply nutrients. We proposed previously that imprinted genes can regulate nutrient supply by the placenta. Here, we tested the hypothesis that the insulin-like growth factor 2 gene (Igf2) transcribed from the placental-specific promoter (P0) regulates the development of the diffusional permeability properties of the mouse placenta. Using mice in which placental-specific Igf2 had been deleted (P0), we measured the transfer in vivo of three inert hydrophilic solutes of increasing size ( 14 C-mannitol, 51 CrEDTA, and 14 C-inulin). At embryonic day 19, placental and fetal weights in P0 conceptuses were reduced to 66% and 76%, respectively, of wild type. In P0 mutants, the permeability⅐surface area product for the tracers at this stage of development was 68% of that of controls; this effect was independent of tracer size. Stereological analysis of histological sections revealed the surface area of the exchange barrier in the labyrinth of the mouse placenta to be reduced and thickness increased in P0 fetuses compared to wild type. As a result, the average theoretical diffusing capacity in P0 knockout placentas was dramatically reduced to 40% of that of wild-type placentas. These data show that placental Igf2 regulates the development of the diffusional exchange characteristics of the mouse placenta. This provides a mechanism for the role of imprinted genes in controlling placental nutrient supply and fetal growth. Altered placental Igf2 could be a cause of idiopathic intrauterine growth restriction in the human.

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Animal models and programming of the metabolic syndrome

Cited by 273 publications

References 76 publications

Effect of maternal diet on the epigenome: implications for human metabolic disease

Effect of maternal diet on the epigenome: implications for human metabolic disease

Programming of obesity and cardiovascular disease

Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

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