Targeting Ceramide Metabolism To Improve Lipid-induced Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$604,327.00
Summary
We have shown that the buildup of ceramide in muscle plays a key role in the inhibition of normal insulin action when the body is exposed to excessive amounts of fat, which leads to poor control of blood sugar levels and Type 2 diabetes. Using mass spectrometry we will now measure different ceramide types, to investigate which contribute to defects in insulin action. We will also examine whether enzymes involved in ceramide formation or degradation can be targeted to improve insulin responses.
NR4A Orphan Nuclear Receptor Signalling In Skeletal Muscle: Evidence For Crosstalk With The Beta-adrenergic Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$323,749.00
Summary
The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabete ....The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabetes, dyslipidemia, and endocrine disorders (e.g ~15% of the top selling therapeutic compounds target NRs). The NR4A subgroup are stress response genes which are induced by a wide range of physiological stimuli and have been implicated in the response to energy excess (over-eating) and diet induced obesity. The NR4A subgroup are expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of the body mass and energy expenditure. This lean tissue is a major site of fat oxidation, insulin-stimulated glucose utilization and cholesterol metabolism. Therefore this tissue plays a notable role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, muscle has a significant role in the progression of dyslipidemia, diabetes and obesity. Surprisingly, the function of the NR4A subgroup in skeletal muscle metabolism has not been examined. Nevertheless, given the data on NR4A mediated gene regulation, and the potential therapeutic utility for the treatment of metabolic disease, the contribution of skeletal muscle to NR4A action must be defined. Correspondingly, the objective of this proposal is to examine the role of the NR4A subgroup and is relevant to understanding the basis of dyslipidemia and obesity.Read moreRead less
Novel Metabolic Actions Of HDL With Therapeutic Potential For Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$559,471.00
Summary
Our proposal investigates a novel approach to treat type 2 (late onset) diabetes. We have identified an important link between HDL (good) cholesterol and glucose metabolism. The current proposal is to conduct studies in humans to determine whether therapies which increase HDL result in sustained reduction of blood glucose. Given the escalating global prevalence of obesity and type 2 diabetes, this work is potentially of great significance.
Nuclear Receptor 4A3 Signalling In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$475,745.00
Summary
Nuclear receptors regulate hormonal control of reproduction, endocrine physiology, and metabolism, and are very important in human health. NR4A3 function in peripheral tissues remains illusive. However, it is expressed in skeletal muscle, a tissue that (i) modulates blood lipids, insulin sensitivity and energy balance, and (ii) has an imortant role in diabetes and obesity. Understanding NR4A3 function in metabolism provides a potential platform for therapeutic intervention.
Novel Metabolic Actions Of HDL With Potential Therapeutic Implications For Type 2 Diabetes And The Metabolic Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$349,683.00
Summary
There are currently in excess of 170 million patients diagnosed with type 2 (late onset) diabetes in the world and this figure is expected to double by 2030. Almost one in four Australians 25 years and over has either diabetes or a condition of impaired glucose metabolism. These conditions pose significant problems in terms of both individual suffering and economic burden. Poor diet, sedentary lifestyles with resultant weight gain and increased obesity rates underlie the escalating prevalence of ....There are currently in excess of 170 million patients diagnosed with type 2 (late onset) diabetes in the world and this figure is expected to double by 2030. Almost one in four Australians 25 years and over has either diabetes or a condition of impaired glucose metabolism. These conditions pose significant problems in terms of both individual suffering and economic burden. Poor diet, sedentary lifestyles with resultant weight gain and increased obesity rates underlie the escalating prevalence of type 2 diabetes. Our proposal investigates a novel approach to treat these conditions. We have identified an important link between HDL (good) cholesterol and glucose and fat metabolism in human muscle cells. We have shown that HDL increases glucose uptake into muscle cells. This process would be expected to remove glucose from blood vessels where it causes damage which ultimately contributes to heart attack and stroke. Furthermore, we have shown that HDL increases the amount of fat the body uses. HDL may therefore not only remove damaging fat from blood vessels, but also help to reduce body weight. Our study seeks to determine the relevance of these mechanisms in both healthy individuals and patients with type 2 diabetes. At the conclusion of this grant we expect to understand whether HDL raising strategies may be a an effective new therapy for type 2 diabetes. Specifically, we will understand: 1. how HDL exerts its beneficial effects and 2. whether acute and chronic HDL elevation using drugs improves glucose and fat metabolism in humans.Read moreRead less
ERRgamma And Skeletal Muscle: Insights Into Lipid Utilization And Catabolism
Funder
National Health and Medical Research Council
Funding Amount
$357,936.00
Summary
The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the ....The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile, lipid metabolism and obesity. Understanding the functional role of the orphan ERR receptors in skeletal muscle in the context of inflammation, lipid and energy homeostasis is of paramount importance in further understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes and obesity. Identification of novel ERRgamma targets that regulate metabolism in a major mass peripheral tissue, and positively influence the risk factors for cardiovascular disease, provides platforms for potential therapeutic intervention. Cardiovascular disease is the foremost cause of global mortality, and was responsible for >15 million deaths in 2003.Read moreRead less
Genomic And Non-genomic Actions Of Androgens In Regulation Of Fat Mass And Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$395,421.00
Summary
Men have lower amounts of body fat than women, but are more likely to deposit fat around the stomach and abdominal region than women. This increased abdominal fat in men significantly increases the risk of developing type 2 diabetes and heart disease. The differences between men and women suggest that there is hormonal control of fat development; however, little is known regarding how male sex hormones, androgens, control these processes. We will investigate how androgens control fat formation, ....Men have lower amounts of body fat than women, but are more likely to deposit fat around the stomach and abdominal region than women. This increased abdominal fat in men significantly increases the risk of developing type 2 diabetes and heart disease. The differences between men and women suggest that there is hormonal control of fat development; however, little is known regarding how male sex hormones, androgens, control these processes. We will investigate how androgens control fat formation, and the response of fat and muscle tissue to glucose and insulin, using mutant mouse strains. These mouse strains have a mutation in the androgen receptor, a protein which acts as a key-lock mechanism to allow tissues to respond to androgens. This mutation stops the androgen receptor from functioning, so these mice can be used to determine the function of androgens acting through the androgen receptor. We will study three strains of mutant mice: (i) in which the androgen receptor is non-functional in all tissues of the body; (ii) in which the androgen receptor is non-functional only in fat tissue, but normal in all other tissues; and (iii) in which the androgen receptor is non-functional only in skeletal muscle, but is normal in all other tissues. The aim of our research is to determine the effect of the mutations in these three different mouse lines on paramateres including the amount of fat formed, the site of fat deposition, the levels of lipids and insulin in the blood and their response to glucose. The androgen receptor is a master switch that turns on or off other genes. Therefore, we also aim to identify which genes are controlled by the androgen receptor in fat and muscle. This research will identify how androgens control fat development and function, and will identify genes that mediate these actions in fat and muscle. This will provide potential molecules that could be used therapeutically to treat obesity and prevent type 2 diabetes and heart disease.Read moreRead less