The Effect Of Ghrelin, Leptin And Orexins On The Function Of Pituitary Somatotropes In Rat, Mouse And Human.
Funder
National Health and Medical Research Council
Funding Amount
$447,000.00
Summary
Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Cont ....Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Contradictory results have however been reported. Mechanisms of action of these three hormones are not clear and the interrelationship between metabolic regulatory hormones and intrinsic GH regulatory system is unknown. We propose to clarify this issue by investigating the effect of in vivo treatment of mice and in vitro treatment of cultured pituitary cells with leptin, ghrelin, and orexins. GH secretion, GH and GH-regulatory hormones' receptor synthesis in pituitary somatotropes will be measured. We will also use GH-GFP transgenic mice, in which somatotropes are specifically marked with green fluorescent signal, to study morphological change of somatotropes in mouse pituitary glands after in vivo treatment. By completing this project, we will be able (1) to clarify the physiological role of metabolic regulatory hormones in control of GH levels and (2) to clarify the pathological role of metabolic regulatory hormones in GH deficiency occurred in malnutritional conditions.Read moreRead less
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.
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
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.
Adiponectin - Multimerization, Secretion And Action
Funder
National Health and Medical Research Council
Funding Amount
$478,844.00
Summary
Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules ....Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules and a higher weight form (HMW adiponectin) made up of large numbers of adiponectin molecules complexed together. We and others have shown that the HMW adiponectin is particularly beneficial. This projects aims to understand the processes regulating the production of differing types of adiponectin by fat cells. It will also examine how the different types of adiponectin have their effects in different tissues such as liver and muscle. The information gained will increase our understanding of how illnesses such as diabetes are associated with obesity. It may also lead to the development of treatments aimed at increasing adiponectin levels - particulalry HMW adiponectin - which may be of benefit in patients with diabetes and cardiovascular disease.Read moreRead less
Role Of Non-classical Actions Of Androgens In Musculoskeletal Physiology
Funder
National Health and Medical Research Council
Funding Amount
$703,664.00
Summary
Androgens (male sex hormones) are important for growth-maintenance of muscle and bone. The classical action of androgens is to bind the androgen receptor (AR) and regulate target genes. They can also act via non-classical AR mechanisms through other cellular pathways. To understand the role of non-classical actions in the musculoskeletal system we will study mice in which androgens can only act via this pathway. This knowledge is important for the treatment of osteoporosis and muscle wasting.
Hormone Transport By Alpha-2-Macroglobulin: Novel Roles In Regulating Hormone Activity
Funder
National Health and Medical Research Council
Funding Amount
$602,857.00
Summary
Alpha-2-macroglobulin is a large protein in the blood known to bind and transport numerous hormones in the circulation. Our previous studies published in BLOOD (2009) and JBC (2013) have discovered an important role for this molecule in the transport and regulation of a peptide hormone. The studies proposed in this application have important implications for understanding new roles of alpha-2-macroglobulin in hormone binding and regulating the activity of hormones in disease states.
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