Novel Actions Of Leptin In Implantation And Placental Function
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The establishment, growth and function of the placenta is of critical importance to the successful maintenance and completion of pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes and coordination of hormone signals that regulate fetal growth and development. Among these signals the hormone leptin, which is produced primarily by fat cells and regulates food intake, has been identified as a crucial player in the control of f ....The establishment, growth and function of the placenta is of critical importance to the successful maintenance and completion of pregnancy. The placenta is effectively the lifeline of the growing fetus through its supply of nutrients, removal of wastes and coordination of hormone signals that regulate fetal growth and development. Among these signals the hormone leptin, which is produced primarily by fat cells and regulates food intake, has been identified as a crucial player in the control of fetal growth. In human pregnancy, the placenta becomes an additional major source of leptin, and this is secreted into the mother and the fetus. Recent work in animal models also indicates that the process of implantation, whereby the embryo embeds itself in the lining of the uterus and establishes a placenta, cannot proceed in the absence of leptin. But how leptin exerts these critical effects on the implantation process and placental function is not known. In this study we will explore several potential actions of leptin in the uterus and placenta, and examine whether the leptin signaling system is aberrant in cases where the fetus does not grow normally. Of particular interest is the possible interaction of leptin with another group of important signaling molecules called the peroxisome proliferator-activated receptors, or PPARs. One of these, PPAR-gamma, plays an indispensable role in the establishment of the placenta, particularly in relation to the formation of blood vessels, a process that is also a target for leptin action. Several lines of evidence, most notably in fat cells, suggest that both PPAR-gamma and leptin regulate common aspects of cell function. Such interactions provide us with important clues as to how leptin and the PPARs could work together to promote the optimal establishment, growth and function of the placenta, and these will be explored in this project.Read moreRead less
We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons wh ....We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons who are overweight tend to have higher circulating blood levels of leptin and also tend to have denser bones, which suggests that there might be a relationship between blood leptin and bone density or strength. Furthermore, leptin is produced in the bone marrow which is where osteoclasts are produced. Osteoclasts are formed from white blood cells which are present in the bone marrow and the blood. Very recent discoveries have identified a family of new factors which play a key role in the formation of osteoclasts. One of these factors has been called osteoprotegerin and is an inhibitor of osteoclast formation. Mutant mice lacking osteoprotegerin have greatly increased numbers of osteoclasts and severe osteoporosis whereas mutants with too much osteoprotegerin have bones which are much denser than normal. The availability of these factors now allows the generation of human osteoclasts in the laboratory which enables the further study of how the process is regulated. We have found that leptin increases the amount of osteoprotegerin produced by white blood cells and we believe that this is the major way that leptin inhibits osteoclast generation. In this project, we intend to further investigate how and why leptin is able to influence the generation and function of osteoclasts as leptin may be a suitable treatment for osteoporosis and other bone diseases.Read moreRead less
Genetic And Metabolic Determinants Of Spontaneous Physical Activity
Funder
National Health and Medical Research Council
Funding Amount
$67,828.00
Summary
It could be argued that obesity is the most significant public health problem facing Australians today. Almost one in five adult Australians are obese, making them highly susceptible to diabetes, coronary heart disease, high blood pressure, high blood lipid levels, and some cancers, as well as reduced psychosocial health. There is therefore an urgent need to reduce the prevalence of obesity in our society. Unfortunately, attempts to sustain significant weight loss by dieting and exercise are nea ....It could be argued that obesity is the most significant public health problem facing Australians today. Almost one in five adult Australians are obese, making them highly susceptible to diabetes, coronary heart disease, high blood pressure, high blood lipid levels, and some cancers, as well as reduced psychosocial health. There is therefore an urgent need to reduce the prevalence of obesity in our society. Unfortunately, attempts to sustain significant weight loss by dieting and exercise are nearly always unsuccessful and none of the anti-obesity drugs currently on the market are safe to use long-term. Effective treatments for obesity are only likely to be developed once we understand more about what controls body weight regulation. An inactive lifestyle is clearly a risk factor for obesity. Spontaneous physical activity (or activity associated with daily life, as opposed to formal exercise) can play a major role in determining body weight. Recent work suggests that spontaneous physical activity is influenced not only by our environment but by our biological makeup as well (i.e. genetic and metabolic factors). The aim of this study is to investigate what some of these factors are, and whether they are responsible for altering body weight regulation in animal models of obesity. Specifically we will be looking at whether spontaneous physical activity is influenced by circulating hormones (such as leptin, oestrogen, and pancreatic polypeptide) and a messenger molecule (nitric oxide), and we will also identify genes which influence physical activity in a mouse model of obesity. By examining the genetic and metabolic basis of inactivity in obese rodent models, this project will further our understanding of how energy balance is disturbed in obesity in the hope of developing better therapies to treat obesity in the future.Read moreRead less
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