In the last decade there has been a substantial increase in the number of overweight and obese individuals. Obesity is now a major public health issue in Australia and, along with its associated disorders of type 2 diabetes and heart disease, incurs significant health care costs. There is a widespread awareness of the problem, but it has proved difficult to bring this obesity epidemic under control, and unless we can understand the underlying causes, the trend seems set to continue. This researc ....In the last decade there has been a substantial increase in the number of overweight and obese individuals. Obesity is now a major public health issue in Australia and, along with its associated disorders of type 2 diabetes and heart disease, incurs significant health care costs. There is a widespread awareness of the problem, but it has proved difficult to bring this obesity epidemic under control, and unless we can understand the underlying causes, the trend seems set to continue. This research proposal seeks to define the mechanisms which lead to the development of obesity. Evidence from a large range of clinical and population-based studies has shown that infants who are exposed to an increased supply of nutrients before birth have an increased risk of being overweight or obese as children and adults. It is not however, fully understood why this occurs. In normal adults, factors released by fat cells play an important role in the maintenance of energy balance, and changes in the levels of these factors in the fat cell or in the circulation can lead to increased weight gain and the development of poor sensitivity of the body's tissues to the actions of hormones, such as insulin. Fat cells develop before birth, and therefore changes in nutrient supply to the fetus have the potential to alter the functional properties of fat cells for life. In this proposal, we will investigate the effect of being exposed to an increased supply of nutrients in fetal life on the properties of fat cells after birth and define how such changes explain the development of obesity in these individuals. Understanding the mechanisms which link the risk of obesity to events before birth will allow clinicians of the future to provide children who are born to overweight, glucose-intolerant or diabetic mothers with a healthy start to life.Read moreRead less
Mechanisms Responsible For Hypertension Caused By Perinatal Omega-3 Fatty Acid Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$280,650.00
Summary
Does the nourishment we receive as babies, or even before birth, affect our adult health? The recent findings from Barker, Meaney, Langley-Evans and their co-workers, has established that intra-uterine and early post-natal factors, particularly nutrition, influence adult neural development and cardiovascular function. It appears that the dietary intake of omega-3 fatty acids in early life may be a critical factor in the development of hypertension. We reported (Nature Medicine 2001, 7: 258-259) ....Does the nourishment we receive as babies, or even before birth, affect our adult health? The recent findings from Barker, Meaney, Langley-Evans and their co-workers, has established that intra-uterine and early post-natal factors, particularly nutrition, influence adult neural development and cardiovascular function. It appears that the dietary intake of omega-3 fatty acids in early life may be a critical factor in the development of hypertension. We reported (Nature Medicine 2001, 7: 258-259) for the first time that the essential omega-3 fatty acid, alpha-linolenic acid (ALA), supplied in the early developmental period, affects blood pressure later in life. The work showed that moderate omega-3 fatty acid deficiency in the perinatal period resulted in hypertension, despite reversal of the deficiency at a time months before the assessment of blood pressure. These findings are suggestive of a critical period, during which time the development of normal blood pressure control mechanisms appears, at least partially, dependent upon the supply of omega-3 fatty acids. These findings suggest that omega-3 deficiency early in life may affect fatty acid metabolism, transport or uptake systems, such that re-feeding of the nutrients is functionally ineffective. Alternatively, deficiency of omega-3 fatty acids early in life may arrest development of one or more of the key signalling pathways in the control of blood pressure, such as the Brain Angiotensin System. The influence of dietary omega-3 fatty acid supply, relative to the critical period, on expression of genes involved in the control of blood pressure as well as in fatty acid metabolism, will be defined. Also, the role of the brain angiotensin system in omega-3 fatty acid deficiency-induced hypertension will be determined. We expect that the results of this study will profoundly affect hypertension research, as well as nutrition, particularly that for infants.Read moreRead less
The Role Of Hypoxia In The Developmental Programming Of The Kidney
Funder
National Health and Medical Research Council
Funding Amount
$651,276.00
Summary
We aim to understand how inadequate oxygen supply to the fetus during pregnancy can affect development of the kidney. Many babies do not get enough oxygen whilst developing in the womb. This can be due to a poorly formed placenta or the mother smoking. This can interfere with normal growth and formation of the kidney. Our knowledge may help babies get the best start to life.
Characterization Of Sex-Specific Differences In Cardiovascular Adaptation In The First Three Years Of Life
Funder
National Health and Medical Research Council
Funding Amount
$567,725.00
Summary
Male babies born significantly premature are up to twice likely to die than females. The reasons for this are unknown. This study will determine the cardiovascular differences in male and female babies born preterm and will examine how they adapt over the first 5 days. Defining the mechanisms that contribute to the difference in mortality between the sexes will also show how changes starting around birth affect the way the blood pressure system functions for life, a major lifetime stroke risk.
Epigenetic Programming Of The Hypothalmo-Pituitary-Adrenal Axis
Funder
National Health and Medical Research Council
Funding Amount
$550,951.00
Summary
It has been shown that the pattern of nutrition in early pregnancy is important in determining the subsequent health of the fetus and newborn. Interestingly, the nutritional environment of the early embryo, when nutrient demands are minimal has been shown to be important in determining the development of the capacity of the fetus to respond to stress in the womb and the timing of delivery. This proposal seeks to understand the mechanisms that underlie these responses.
Periconceptional Nutrition And The Programming Of Obesity
Funder
National Health and Medical Research Council
Funding Amount
$468,879.00
Summary
Mothers who enter pregnancy with a high body mass index are at risk of developing diabetes in pregnancy and of having a large baby who will be at increased risk of developing obesity in childhood and later life. Heavy mothers therefore have heavy babies and these babies go on to become heavy adults. This grant will determine the separate contributions of exposure of the embryo to high nutrition and exposure of the fetus in late gestation to high maternal nutrition.
Fetal And Genetic Origins Of Polycystic Ovary Syndrome (PCOS) In Young Women
Funder
National Health and Medical Research Council
Funding Amount
$449,073.00
Summary
Polycystic ovary syndrome (PCOS) is a common hormonal condition which emerges at puberty and afflicts up to 10% of women. The cause of PCOS is uncertain. Symptoms include menstrual disorders, acne, obesity, and excess body hair. PCOS is of great significance for women because of the high incidence of infertility and the high risk of other serious diseases, including diabetes mellitus and endometrial cancer. PCOS is probably the most common hormonal condition among young women. The cause of PCOS ....Polycystic ovary syndrome (PCOS) is a common hormonal condition which emerges at puberty and afflicts up to 10% of women. The cause of PCOS is uncertain. Symptoms include menstrual disorders, acne, obesity, and excess body hair. PCOS is of great significance for women because of the high incidence of infertility and the high risk of other serious diseases, including diabetes mellitus and endometrial cancer. PCOS is probably the most common hormonal condition among young women. The cause of PCOS is unknown and the relationship between PCOS and the more common condition of polycystic ovaries, which often features in PCOS, is uncertain. There is evidence that genetic factors contribute to PCOS, but cannot explain certain aspects. There is also striking new evidence that abnormal growth in the womb can alter the metabolism of the baby for life, resulting in increased risks of adult disease, including diabetes and cardiovascular disease. PCOS may be another consequence of abnormal fetal growth, a suggestion that is supported by two recent studies of closely related conditions. To investigate the origins of PCOS, we propose to establish the first international study of the relationships between fetal growth, genetic factors and the presence of PCOS. In this study, we shall trace 3,260 women born in one maternity ward during 1973-75. These women, now young adults, will be invited into our study for an interview, physical examination, and a blood test. We expect 2,200 women will participate. Of this group, some 220 women with PCOS will receive further tests to investigate a range of metabolic problems. The study has the potential to illuminate the path from genetic predisposition and fetal growth, to the emergence of an important reproductive disorder with serious associated diseases in a woman s later life.Read moreRead less
Is Insulin Sensitivity In Children And Their Mothers Programmed By Maternal Blood Glucose?
Funder
National Health and Medical Research Council
Funding Amount
$169,630.00
Summary
Glucose intolerance in pregnancy is associated with the birth of large-for-dates and macrosomic (>4000g) babies. The risk of type 2 diabetes is greater in babies who are small or large at birth compared to those with normal birth weight. This study will determine if treatment of mothers with glucose intolerance in pregnancy (which is intermediate between normal glucose tolerance and diabetes) alters the regulation of glucose tolerance in their children. The mothers were randomised to receive ....Glucose intolerance in pregnancy is associated with the birth of large-for-dates and macrosomic (>4000g) babies. The risk of type 2 diabetes is greater in babies who are small or large at birth compared to those with normal birth weight. This study will determine if treatment of mothers with glucose intolerance in pregnancy (which is intermediate between normal glucose tolerance and diabetes) alters the regulation of glucose tolerance in their children. The mothers were randomised to receive normal antenatal care or to have their blood sugar measured and controlled by diet and insulin as for diabetics. We will measure the insulin sensitivity of the children to a glucose load. We will also measure blood pressure and lipids in these children. Treatment of the mother during pregnancy may alter the deposition of fat in the fetus the effect of which will continue into childhood. Thus the offspring of treated mothers may remain thinner throughout childhood. Each pregnancy increases a woman's chance of developing type 2 diabetes in later life. This risk is further increased by abnormal glucose tolerance during pregnancy. This study will test the long-term benefits of treatment during pregnancy of women with impaired glucose tolerance on the subsequent regulation of glucose tolerance. We shall invite women who took part in the Australian Carbohydrate Study in Pregnancy (ACHOIS) to return and have an intravenous glucose tolerance test. Insulin sensitivity and glucose tolerance will be determined and related to treatment of the impaired glucose tolerance in pregnancy. This study will be the first follow-up of a large randomised trial of treatments of impaired glucose tolerance in pregnancy. The potential long-term benefits are strategies to reduce the future chance of developing risk factors for type 2 diabetes, obesity and abnormal blood lipids in childhood and adult life. The study will establish the benefits or otherwise of tight control of blood glucose in pregnancy.Read moreRead less
Exploring The Physiological, Morphological And Molecular Bases Of Renal Developmental Programming.
Funder
National Health and Medical Research Council
Funding Amount
$422,264.00
Summary
Suboptimal fetal and neonatal development increases our risk of developing a range of diseases in adulthood. The concept that deleterious events during development can influence adult health is termed 'developmental programming'. Obtaining A Healthy Start to Life is a priority research goal of the Australian Government. The kidneys are particularly susceptible to developmental programming. This is in part because the functional units (nephrons) of the kidneys are all formed before birth in human ....Suboptimal fetal and neonatal development increases our risk of developing a range of diseases in adulthood. The concept that deleterious events during development can influence adult health is termed 'developmental programming'. Obtaining A Healthy Start to Life is a priority research goal of the Australian Government. The kidneys are particularly susceptible to developmental programming. This is in part because the functional units (nephrons) of the kidneys are all formed before birth in humans. Thus, if fetal development is suboptimal, babies are at risk of being born with a permanent nephron deficit, with functional and disease consequences. We have shown in male rats that the offspring of a maternal low protein diet have fewer nephrons and lower blood pressure than rats fed a normal diet. These rats display a striking sensitivity in adulthood to the feeding of a high salt diet. We will define the physiological and morphological bases of this sensitivity, and repeat these studies in females, as increasing evidence shows significant sex differences in developmental programming. Defining the molecular mechanisms of developmental programming is the greatest challenge for researchers in the field. We have recently completed the most comprehensive analysis to date of gene expression in the developing mouse kidney, and have shown for the first time that the mouse programmes kidney development. We will use the new techniques of genomics and bioinformatics to study the molecular mechanisms of kidney programming. This mechanistic data will provide an excellent hypothesis engine for future studies on the specific roles of these molecular pathways in developmental programming in all mammalian species.Read moreRead less
The Role Of Nutrition In Disease-linked Epigenetic Inheritance
Funder
National Health and Medical Research Council
Funding Amount
$485,412.00
Summary
This project aims to investigate one mechanism behind fetal programming, in which a suboptimal in utero environment can affect health of offspring in later life. We and others have recently shown that fetal programming can be caused by changes in the way genes behave, and we will examine how many genes are affected by these changes. We will ask whether the changes can increase in frequency with long-term exposure to nutritional stress, and become entrenched within the population.