Lipid Metabolism In The Aromatase Knock-out Mouse (ArKO)
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermi ....Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermineralisation of the bones, intra-abdominal obesity, hypercholesterolaemia and insulin resistance. We are addressing the mechanisms of all of those phenotypes but in the present application we focus on the abnormalities in lipid metabolism. Thus we will seek to understand the increase in adiposity by examining the role of oestrogen in lipid synthesis, oxidation and breakdown in adipose tissue from intra-abdominal sites. We will also examine the role that oestrogen plays in cholesterol uptake, synthesis and catabolism by the liver as well as fatty acid synthesis and oxidation by the liver. These studies will be correlated with whole body parameters such as feeding behaviour, physical activity, energy expenditure, glucose and fat oxidation rates. We will also examine the effect of feeding a high cholesterol or a high fat diet on lipid metabolism in the oestrogen deficient animals, and we will determine the effect of oestradiol and isoflavone replacement on the phenotype. In this way we aim to reach a better understanding of the multiplicity of roles that oestrogens play in the regulation of lipid and cholesterol metabolism in both males and females. The results of such studies will be the development of better strategies to deal with pathologies resulting from disturbances in cholesterol and lipid metabolism.Read moreRead less
Over a research career currently spanning 44 years, the single unifying theme of my research has been the regulation of steroid hormone biosynthesis. Since 1993, the focus of my laboratory has been oestrogen biosynthesis. We study three main areas: i) the
Predictors Of Cardiovascular Disease Mortality In The Melbourne Collaborative Cohort Study
Funder
National Health and Medical Research Council
Funding Amount
$350,544.00
Summary
The Melbourne Collaborative Cohort Study was set up in the early 1990s to investigate prospectively the role of diet and other lifestyle factors in causing common chronic diseases including common cancers and cardiovascular disease. Between 1990 and 1994, 41,500 people, aged 40-69 were recruited into the MCCS. About 30% of the cohort are southern European migrants to Australia who were deliberately over-sampled to extend the range of dietary and lifestyle exposures. Migrants from southern Europe ....The Melbourne Collaborative Cohort Study was set up in the early 1990s to investigate prospectively the role of diet and other lifestyle factors in causing common chronic diseases including common cancers and cardiovascular disease. Between 1990 and 1994, 41,500 people, aged 40-69 were recruited into the MCCS. About 30% of the cohort are southern European migrants to Australia who were deliberately over-sampled to extend the range of dietary and lifestyle exposures. Migrants from southern Europe have an adverse risk factor profile in relation to obesity, body fat distribution, physical activity patterns, diabetes, smoking, blood pressure and cholesterol levels, yet their death rates from heart disease are 30-40% lower than the Australian average. A major objective of this study is to investigate the possibility that particular aspects of the diet and cuisine of migrants from southern Europe (olive oil as the major dietary fat, and high intakes of a variety of vegetables and fruit) protect against heart disease and stroke by providing high levels of a wide range of natural antioxidants. It represents the most comprehensive prospective study of diet and cardiovascular disease mortality ever conducted in Australia. A particularly powerful feature is the combination of detailed self-reported dietary intake, the very wide range of exposures to dietary factors implicated in CVD (as risk factors or protective agents), and the objective markers of dietary intake (biochemical markers of dietary intake patterns in blood collected at recruitment, body weight, body fat and body fat distribution). The data should provide a strong rationale for specific dietary recommendations as part of population-based strategies to reduce the incidence of premature mortality from heart disease and stroke in the Australian population.Read moreRead less