The Role Of Muscle Fatty Acid Oxidation In Regulating Intramyocellular Lipid Accumulation.
Funder
National Health and Medical Research Council
Funding Amount
$169,695.00
Summary
Obesity and the subsequent accumulation of fat in muscle leads to reduced insulin action and an increased risk of type 2 diabetes. This project will investigate the metabolic processes that influence fat accumulation and oxidation primarily in skeletal muscle, the tissue responsible for most fuel utilization in the body. This information will help design therapeutic strategies to prevent the development of type 2 diabetes.
Inhibition Of Glucose-stimulated Insulin Secretion By Protein Kinase C Epsilon
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
Type 2 diabetes is a chronic disease which occurs when the pancreas is unable to produce enough insulin for the body to cope with rising blood glucose levels after a meal, and is strongly linked to obesity. We have discovered that fat oversupply activates an enzyme in the pancreas causing defects in insulin release due to glucose. Inhibiting this enzyme helps overcome diabetes, through poorly defined mechanisms that we aim to clarify here. Our work could lead to new therapies for diabetes.
Genetic Programs Induced By The Nuclear Hormone Receptor PPARdelta In Muscle: Control Of Lipid And Energy Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of d ....Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of dyslipidemia by mediating cholesterol efflux from tissues. In contrast, the LDLs accumulate in the arterial wall leading to atherosclerosis. Physiological maintenance of lipid homeostasis requires a dynamic balance between metabolic signalling cascades, diet, lifestyle etc. PPPARs are nuclear hormone receptors that function as fatty acid activated transcription factors that regulate lipid and cholesterol homeostasis. PPARs are bona fide targets for the development of therapeutic compounds useful in the treatment of lipid disorders. PPAR delta is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Muscle is a major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile and lipid metabolism. Understanding the functional role of PPAR delta in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body lipid homeostasis. Understsanding these receptors may provide a pharmaceutical solution for the prevention of hyper-lipidemia--cholesterolemia, and atherogenic disease. Moreover, it may lead to the identification of agents that influence a major mass tissue in terms of lipid absorption, and increased fatty acid oxidation, and consequently normalize the blood lipid profile.Read moreRead less
Dilinoleoyl Phosphatidic Acid As A Novel Mediator Of Insulin Resistance In Muscle
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
We have identified a novel fat molecule in muscle which may play an important role in causing insulin resistance during obesity, a major factor in the development of Type 2 diabetes. We will now examine whether depletion of this molecule, dilinoleoyl-phosphatidic acid, can improve insulin action in muscles and in obese mice, and investigate the mechanisms by which it may act. This work may indicate new strategies for the treatment of diabetes.
Interactions Between Fetal Programming And Postnatal Diet In Development Of The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$445,578.00
Summary
More than 50,000 Australians die annually from cardiovascular disease, accounting for almost 40% of all deaths. Obesity and high blood pressure are both key risk factors for cardiovascular disease, and so it is crucial that we understand the underlying causes of these conditions and how lifestyle changes, such as diet, can prevent them. We now know that several adult-onset diseases, including high blood pressure, obesity and diabetes, are influenced by how well we grow and develop as a fetus. Th ....More than 50,000 Australians die annually from cardiovascular disease, accounting for almost 40% of all deaths. Obesity and high blood pressure are both key risk factors for cardiovascular disease, and so it is crucial that we understand the underlying causes of these conditions and how lifestyle changes, such as diet, can prevent them. We now know that several adult-onset diseases, including high blood pressure, obesity and diabetes, are influenced by how well we grow and develop as a fetus. This effect, known as 'fetal programming', means that if we have a poor environment as a fetus (eg, maternal undernutrition), we are more likely to develop health problems such as high blood pressure many years later. In this study we are interested in how the events in fetal life 'program' these later health problems, and how we might reverse the adverse effects by lifestyle changes after birth. We have developed an animal model in which high blood pressure and problems with fat and muscle function that can lead to obesity and diabetes. These detrimental effects on adult health can be completely prevented in our model by placing offspring on a diet rich in omega-3 fats from the time of birth. These fats are commonly found in fish oil and are well known for their beneficial effects on cardiovascular function. The present proposal will extend these findings by determining whether omega-3 fatty acids can reverse the adverse programming outcomes after they have emerged in adult life. We will also investigate whether fetal programming effects are made even worse by the consumption of excess total dietary fat during development to adulthood, and if this effect can also be overcome by supplementation of the diet with omega-3 fats.Read moreRead less
Leptin And The Regulation Of Substrate Partitioning
Funder
National Health and Medical Research Council
Funding Amount
$349,876.00
Summary
The prevalence of obesity is increasing with currently 18% of adult Australians being classified as obese. Obesity, particularly abdominal obesity, is associated with high blood lipid levels and blood pressure, and type 2 diabetes. In Australia, the cost of obesity is estimated to be $830 million per year. The ultimate aim of any obesity treatment programme is to reduce body fatness by burning off fat and to prevent further fat storage and so studies which focus on developing strategies to achie ....The prevalence of obesity is increasing with currently 18% of adult Australians being classified as obese. Obesity, particularly abdominal obesity, is associated with high blood lipid levels and blood pressure, and type 2 diabetes. In Australia, the cost of obesity is estimated to be $830 million per year. The ultimate aim of any obesity treatment programme is to reduce body fatness by burning off fat and to prevent further fat storage and so studies which focus on developing strategies to achieve these goals are very important. We have found that subjects who fail to keep weight off after being on a weight-reducing diet are bad fat burners. These people also have low levels of leptin, a hormone made by fat cells which helps to regulate food intake. The first aim of this study is to show that leptin increases the burning of fat by regulating the production and activity of factors which decide whether fat is used for energy or is stored in the body. The second aim is to find ways in which leptin levels can be changed so that fat burning is increased. Some of the ways in which we will change leptin levels are by changing the fat content of the diet, or by drugs, or by giving leptin itself. These studies will be performed in animal models of obesity and will help us to develop strategies for the treatment and prevention of obesity in humans.Read moreRead less