Regulation Of Growth Hormone Action By Sex Steroids: Metabolic Implications For Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$353,250.00
Summary
Fitness and health is determined by body composition, the amount of fat and lean tissue in the body. Obesity increases the risk of diabetes, blood pressure and heart attacks, while muscle wasting reduces strength and fitness. Body composition is controlled by hormones such as growth hormone (GH) which reduces body fat by stimulating its metabolism (burning) and increases lean tissue by stimulating protein synthesis. These metabolic actions of GH are exerted through the liver. This proposal seeks ....Fitness and health is determined by body composition, the amount of fat and lean tissue in the body. Obesity increases the risk of diabetes, blood pressure and heart attacks, while muscle wasting reduces strength and fitness. Body composition is controlled by hormones such as growth hormone (GH) which reduces body fat by stimulating its metabolism (burning) and increases lean tissue by stimulating protein synthesis. These metabolic actions of GH are exerted through the liver. This proposal seeks to understand how sex hormones control the amount of body fat and muscle in women and men. Based on previous research in our laboratory, we propose that sex hormones control the action of growth hormone on the liver. We will test the hypothesis that oestrogens impair the ability of the liver to burn fat and build protein in response to GH while male hormones have the opposite effect. The effect of oestrogen occurs only when oestrogen is taken as a tablet because the liver is exposed to high concentrations of this hormone after gut absorption. It causes postmenopausal women to gain fat and lose muscle. Apart from oestrogens, there are many other compounds with oestrogen-like activities such as phytooestrogens (oestrogens found in plants) and SERMs (used for treating osteoporosis). Their effect on the liver and body composition are unknown but important because of their widespread use in the community. The significance of these studies relate to optimising the benefits of oestrogen compounds by defining their metabolic effects on the liver. In men, understanding how male hormones work as anabolic agents may lead to ways of treating protein muscle wasting.Read moreRead less
Oestrogens And The Metabolic Process: Regulatory Interaction With The GH-IGF-system In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Growth hormone (GH) plays a key role in controlling body metabolism, fat and muscle in adult life. The female hormone oestrogen controls how much GH is secreted and how well it acts. Drugs that act like or interfere with the action of oestrogen are used increasing for the treatment of many conditions e.g. growth, cancer and osteoporosis. This proposal examines their impact on cardiovascular and physical health.
Structural And Biomechanical Basis Of Differences In Bone Fragility In Asian And Caucasian Men And Women
Funder
National Health and Medical Research Council
Funding Amount
$188,500.00
Summary
Lay Summary Fractures occur less commonly in males than females because males have greater periosteal apposition than females during ageing. This increases bone size (reducing load per unit area - stress), and reduces net bone loss, more in males than females so that the increase in bone fragility with advancing age seen in both sexes is less in males than females. Few males than females have a fracture risk index for vertebral fractures (FRI or ratio of load-bone strength) above unity. The purp ....Lay Summary Fractures occur less commonly in males than females because males have greater periosteal apposition than females during ageing. This increases bone size (reducing load per unit area - stress), and reduces net bone loss, more in males than females so that the increase in bone fragility with advancing age seen in both sexes is less in males than females. Few males than females have a fracture risk index for vertebral fractures (FRI or ratio of load-bone strength) above unity. The purpose of this study is to define the structural and biomechanical basis responsible for the racial differences in fracture rates between Asians and Caucasians. Following the same biomechanical principles as published in Caucasian males and females, we hypothesise that racial differences in periosteal expansion during aging may contribute, in part, to the racial differences in bone fragility at the spine and hip. A cross-sectional study will be conducted in 500 healthy Chinese men and 500 Chinese women age ranged 18 to 90 years living in Melbourne, Australia. We have recruited larger numbers of Caucasian men and women in our Centre. BMD and bone size will be measured at the spine, hip and total body by using dual x-ray bone densitometer (DXA). Vertebral body width, depth, height, cross-sectional area (CSA), stress (load per unit CSA) and fracture risk index (load-strength) at the third lumbar vertebrae will be measured by PA and lateral scanning. Femoral neck periosteal-endocortical diameter, cortical thickness, cross-section moment of inertia (CSMI), section modulus buckling index will be measured by using hip structural analysis program. Just as insight into bone fragility in women has been obtained by studies in men, we believe that the results of this study will provide important insights into the pathogenesis of bone fragility in both racial groups.Read moreRead less
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