Lipid metabolism in the Aromatase Knock-out Mouse (ArKO)

Funded Activity 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, 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.

Funded Activity Details

Start Date: 01-01-2001

End Date: 01-01-2003

Funding Scheme: NHMRC Project Grants

Funding Amount: $408,055.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Nutritional science

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

Adiposity and obesity | Android obesity of post-menopausal women | Aromatase knock-out mice - targetted gene disruption | Hypercholesterolaemia | Insulin resistance | Regulation of cholesterol metabolism by oestrogens | Regulation of lipid metabolism by oestrogens | Regulation of oxidative metabolism by oestrogens | Role of oestrogens in adipocyte differentiation | Sexually - dimorphic adipose distribution

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