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
Muscle Thermogenesis In Models Of Predisposition To Obesity
Funder
National Health and Medical Research Council
Funding Amount
$469,289.00
Summary
Obesity is a major health crisis, but effective treatments remain elusive. Body weight is determined by a balance of food intake and energy expenditure. Understanding both sides of this equation is essential to combating obesity. This project will show that the rate at which muscle uses energy is an important determinant of energy balance and contributes to the propensity to become obese. The work will define muscle as a target for developing anti-obesity therapies.
MUSCLE METABOLISM AND LEPTIN IN SLEEP-RELATED RESPIRATORY FAILURE - EFFECT OF TREATMENT
Funder
National Health and Medical Research Council
Funding Amount
$165,509.00
Summary
Breathing problems are common during sleep affecting at least 10% of the adult population with major disruptions of sleep patterns and lack of oxygen. These problems range from very heavy snoring to actual repeated obstruction in breathing (obstructive sleep apnea or OSA) through to breathing failure both awake and asleep (hypoventilation syndromes). Sleep-breathing disorders are very common in people with obesity and can be treated with special breathing machines. The study comprises of 2 main ....Breathing problems are common during sleep affecting at least 10% of the adult population with major disruptions of sleep patterns and lack of oxygen. These problems range from very heavy snoring to actual repeated obstruction in breathing (obstructive sleep apnea or OSA) through to breathing failure both awake and asleep (hypoventilation syndromes). Sleep-breathing disorders are very common in people with obesity and can be treated with special breathing machines. The study comprises of 2 main parts. 1. We have found previously a close link between breathing problems during sleep and a certain cluster of health complications in obesity including early diabetes and high blood pressure called the metabolic syndrome. However there is very little information on the how this link develops. We will examine how treatment of sleep apnea, and more severe forms of breathing failure during sleep, changes the following - the circulation of blood in muscle, the amount of fat in the muscle, chemical changes within the muscle and alteration in blood vessel size. All these measurements are related to early risk of diabetes and blood pressure. If treatment of breathing problems during sleep improves muscle metabolism, then we may have new additional treatments for the many people with this metabolic syndrome problem 2. In some recent small studies, we have found that a special chemical messenger called leptin is very high in patients with severe breathing failure during sleep. Leptin is actually a messenger produced by body fat that tells the body how to regulate food intake. Leptin also stimulates breathing in rats. We believe that people with these breathing problems in sleep may have problems in sensing leptin in the brain. We will measure leptin before and after treatment of hypoventilation syndrome to see if the level in the body changes. This research may help us find new leptin-related drug treatments for these breathing disorders.Read moreRead less
Cellular And Molecular Mechanisms Of The Profibrogenic Effect Of Leptin In The Liver.
Funder
National Health and Medical Research Council
Funding Amount
$166,500.00
Summary
Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus, alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of wound-healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being linked to type II diabetes and cardiovascula ....Cirrhosis of the liver in the 7th leading cause of death. Regardless of the underlying cause of liver injury (virus, alcohol, or in affluent countries non-alcoholic steatohepatitis -NASH), the liver repairs damage by forming scar tissue in a pocess similar to wound healing. All chronic liver diseases are associated with repeated rounds of wound-healing leading inevitably to progressive fibrosis and cirrhosis of the liver. Obesity, in addition to being linked to type II diabetes and cardiovascular diseases, is an independent risk factor for liver injury. It is the clinical setting for NASH, the most common liver disorder in western countries. Also the severity of hepatic fibrosis and the risk of progression to fibrosis in most forms of liver diseases (regardless of their cause) are dramatically increased in overweight (>60%) and obese (20% of adult Australian) patients. Leptin is an hormone that primarily controls food intake and energy balance in the body. In addition, leptin has many other functions. It is a modulator of the immune and inflammatory system, it is involved in skin wound healing and increases sclerosis in the kidney. We recently showed that leptin is necessary for fibrosis to develop in the liver and that increased levels of leptin increases the severity of liver fibrosis. It appears that leptin is a fundamental player in the biological processes of hepatic fibrosis. As increased serum levels of leptin is a feature of obesity, leptin is likely to be the missing link between obesity and increased hepatic fibrosis. By understanding the mechanisms by which leptin acts on liver cells to increase fibrosis, this work will lead to new strategies to prevent fibrosis in obese patients and to reverse scarring in the liver. With the endemic obesification in developed countries, prevention and treatment of obesity-associated liver disease will be the main challenge for the hepatologist in the next decades.Read moreRead less
Effects Of Leptin On Follicle Growth And Ovulation
Funder
National Health and Medical Research Council
Funding Amount
$196,470.00
Summary
Leptin is a recently discovered hormone which is very important in controlling body weight. Extremely obese, or extremely underweight women, find it difficult to become pregnant, and leptin is probably the connection between weight and fertility. This may be a particularly important factor in polycystic ovary syndrome (PCOS), a distressing condition which affects 5% of women and causes both obesity and infertility. Exciting new research suggests that leptin also affects the immune system, and pr ....Leptin is a recently discovered hormone which is very important in controlling body weight. Extremely obese, or extremely underweight women, find it difficult to become pregnant, and leptin is probably the connection between weight and fertility. This may be a particularly important factor in polycystic ovary syndrome (PCOS), a distressing condition which affects 5% of women and causes both obesity and infertility. Exciting new research suggests that leptin also affects the immune system, and previous NH and MRC funding has enabled us to demonstrate that the immune system plays a crucial role in maintaining normal ovarian function. The nutritional status of the body, the immune system and the reproductive system all interact, and leptin appears to be the connecting link between these three major systems. We propose that leptin plays a major role in the ovary, and wish to determine how leptin mediates the effects of bodyweight and the immune system on ovarian function. Laboratory rats will be treated with leptin, their food intake and weight recorded, and a few weeks later the rats will have their ovaries removed. We will find out whether ovaries respond to leptin, or whether the ovarian response changes according to the menstrual cycle: perhaps leptin is very important just before ovulation, but it does not affect menstruation? Do any ovarian cells make leptin? Will leptin stimulate ovaries to produce more oestrogen or progesterone, or ovulate more eggs? We will also identify immune system cells in the ovary, and note whether leptin affects them. We will be able to relate all this data to weight and diet. Increased understanding of leptins' effect on the ovary has the potential to lead to new, improved treatments for PCOS or for unexplained cases of infertility. It is also possible that in the future a weight-loss regime might be developed which takes a womans monthly cycle into account, therefore making weight-loss more efficient and attainable.Read moreRead less