GI

Early malnutrition and programming of adult diseases : experimental, epidemiological and preventive studies

Higher life expectancy and changing lifestyles have led to an increasing incidence of chronic illnesses such as diabetes, obesity and cardiovascular diseases. The key to reducing the burden of these degenerative diseases on society and improving the quality of life of the individual may be in improving the nutrition of the unborn child. Indeed, foetal growth is a complex, dynamic process depending on a continuous supply of nutrients from the mother. Epidemiological and experimental data reveal that deficient foetal nutrition, even over a brief period of time, may lead to irreversible changes in the offspring and to degenerative diseases in adulthood. This programming not only results from malnutrition due to poverty and social deprivation, but also from nutritional imbalances in affluent populations.

Aim…
is to provide the scientific basis to the concept of foetal origin of degenerative diseases such as glucose intolerance, diabetes, obesity, hypertension and cardiovascular diseases (the components of syndrome X) at the physiological, cellular and molecular level and to identify key nutrients required for normal foetal development by combining animal and human studies. This project will focus on the endocrine pancreas, adipocytes, hepatocytes, vascular and smooth muscle cells. Ultimately, we aim to formulate nutritional recommendations to pregnant and nursing mothers to improve long-term quality of life and to propose preventive and therapeutic nutritional supplements.
The objectives …
  • to better understand how nutrition of the pregnant and lactating mother affects early development by using three animal models of decreasing nutritional deficiency (global food restriction, protein restriction and folate restriction)
  • to evaluate the relative importance of nutritional factors versus genetic factors in foetal programming by comparing genetic growth restriction models with the nutritional models
  • to establish the link between experimental and human studies
  • to identify key nutrients which serve as sensors of dietary deficiency and which, ultimately, may serve for preventive and therapeutic purpose
The Workpackages

WP 1 : General Food Restriction (GFR)
1. To understand the nutritional and mechanistic basis of the alterations of ß-cell development observed after maternal food restriction in rat (50% of ad libitum intake during the last week of pregnancy until the end of lactation and ad libitum feeding from weaning onwards).
2. To establish if they are associated with cellular dysfunctions in the pancreas and the major target tissues for insulin : liver, adipose tissue and skeletal muscle.

WP 2 : Protein restriction (PR)
1. To understand the mechanisms responsible for the reduced ß-cell mass observed in early life in the offspring of mother fed on a protein restricted diet (PR, 8% instead of 20% during the entire pregnancy and until weaning).
2. To investigate the impact of the PR diet on the programming and early development of insulin target cells : hepatocytes and adipocytes.

WP 3 : Folate restriction (FR)
To identify critical time windows of folic acid requirement to yield information which can be used to provide advice to both pregnant women and the general population regarding their diet.

WP 4 : Genetic growth restriction (GGR)
To understand the mechanistic basis of the deleterious effects of postnatal catch-up growth on the long-term health of the adult. This will be addressed using two animal models, one of genetic origin and one produced by maternal dietary manipulation.

WP 5 : Nutritional regulation of genes
To determine the effects of specific nutrient deficiencies on the growth and differentiation of foetal hepatocytes and adipocytes.

WP 6 : Human pancreas development (HP)
1. To investigate whether similar alterations in the programming of ß-cell development also occur in human foetuses born with IUGR and characterise the cellular mechanisms involved : differentiation, proliferation and apoptosis.
2. To examine the role of glucocorticoids on human pancreas development by studying the expression of the receptor.

WP 7 : Epidemiological analysis in human
To identify factors in the diet consumed during pregnancy with an impact on fœtal growth.

WP 8 : Prevention/intervention
1. To investigate whether taurine supplementation also restores ß-cell mass dynamics to normal values, if it prevents the alterations of islet and brain vascularisation and the dysfunctions observed in the peripheral tissues of protein-restricted animals.
2. To understand the mechanisms by which taurine would restore the ß cell mass to normal.