Metabolic diseases such as diabetes and fatty liver disease are major health concerns worldwide, with Australia being one of the most affected countries. Diabetes increases cardiovascular risk at least 3-fold, it is associated with accelerated atherosclerosis and linked to premature mortality. We are interested in studying the underlying mechanisms that contribute to the development of these metabolic disorders. Further understanding of the pathophysiology of diabetes, fatty liver disease and atherosclerosis will help us develop more effective therapeutic approaches for these metabolic diseases.
While the causes remain complex, there are three molecules that have been recognized as key players in the development of metabolic diseases: i) an enzyme called AMP-activated kinase (AMPK), ii) Salt-Inducible Kinases (SIKs) and iiI) the neuropeptide Y (NPY) system.
i) AMPK in health & disease
AMPK is a key regulator of whole-body energy metabolism, including lipid oxidation, cholesterol synthesis and glucose homeostasis. It plays a crucial role in controlling the balance between energy production and energy storage. AMPK is activated by metabolic stresses or hormonal changes that signal low energy conditions and acts to inhibit anabolic and promote catabolic pathways. The suppression of AMPK activity under conditions of chronic over-nutrition has been shown to be a key factor contribute to the development of metabolic diseases. We have developed a sophisticated suite of research tools such as mice that carry mutations in specific parts of the AMPK enzyme to determine the precise role of AMPK in metabolic regulation. We aim to clarify the exact contribution that AMPK makes to the development of metabolic diseases such as diabetes and atherosclerosis in order to find new and more effective ways of treating it.
ii) SIKs in health & disease
The SIK family belongs to a subfamily of serine/threonine protein kinases and contains 3 isoforms: SIK1, SIK2 and SIK3. The SIK family has been implicated in the regulation of a wide range of physiological processes such as circadian rhythm, bone development, lipid metabolism and glucose homeostasis, primarily by regulating gene expression. Our lab is interested in studying the role of SIKs in the regulation of energy metabolism and pancreatic b-cell function. We have developed several tissue-specific transgenic mouse models which will allow us to determine the precise role of SIKs in metabolic regulation and understanding how these protein kinases contribute to the development of diabetes, obesity and fatty liver disease.
iI) The NPY system in metabolic cross-talk
The NPY system is one of the most important regulators of appetite and energy balance. The NPY family consists of 3 ligands [NPY, Peptide YY (PYY) and pancreatic polypeptide (PP)] and 5 receptors (Y1, Y2, Y4, Y5 and y6). While NPY centrally promotes feeding and reduces energy expenditure, PYY and PP mediate satiety. Recent research has uncovered additional functions for these peptides that go beyond the simple feeding/satiety circuits and indicate a more extensive role in controlling other physiological functions such as pancreatic islet function. By using unique mouse models and cutting-edge techniques, my group aims to uncover new physiological role of the NPY system in the regulation of beta-cell functions and hepatic lipid metabolism and its implications in diabetes and fatty liver disease.
Stemming from dyslipidemia and maladaptive inflammatory responses, atherosclerosis precedes and predicts the development of cardiovascular complications including stroke and myocardial infarction, which account for more than 30% of all deaths worldwide. AMP-activated kinase (AMPK) is a key regulator of whole body energy metabolism, including lipid metabolism, glucose uptake and mitochondrial biogenesis. It has been shown that the suppression of AMPK activity under conditions of chronic over-nutrition may contribute to the development of metabolic diseases. We have recently shown that activation of the regulatory enzyme AMPK reduces cholesterol production in a way similar to statin therapy (Loh et.al 2019 Hepatology Communications). The main objective of this project is to study how AMPK controls cholesterol production in the liver and macrophages. AMPK’s activation in response to exercise is thought to be part of the protective mechanism against the development of heart disease. We aim to investigate whether by changing the activity of AMPK, using drugs that currently in clinical trial, we can augment the body’s natural control mechanisms and significantly reduce the development of atherosclerosis. Since reduction of AMPK activity was found in response to hyperglycemia, the project also aims to shed light on whether impairment of AMPK signaling responsible toward the pathology of diabetes-associated atherosclerosis. We hypothesize that pharmacological activation of the signaling cascade which culminates in AMPK activation may serve as an alternative cholesterol lowering therapy and reducing atherosclerosis development.
Current efforts to enhance β-cell function focus mostly on the pathways that stimulate insulin release, very little is known about the inhibitory mechanisms that terminate insulin secretion. Improving β-cell function by inhibiting the counter-regulatory pathway that suppresses the release of insulin remains largely unexplored as a therapeutic option. Peptide YY has been shown to activate neuropeptide Y1 receptor to attenuate insulin secretion in mouse pancreatic islets. We have identified that the neuropeptide Y1 receptor is also expressed in the β-cells in humans. Our recent published studies (Loh et.al 2017 Nature Communications) have shown that pharmacological inhibition of this receptor using a Y1 receptor specific antagonist, BIBO3304, significantly enhanced β-cell function in human islets. Despite this, the beneficial effects of Y1 inhibition in improving β-cell function and glycemic control in type 2 diabetes remain to be examined. We will now extend our published work with a detailed exploration of Y1 receptor inhibition in type 2 diabetes models. We aim to investigate whether pharmacological inhibition of Y1 receptor signalling will enhance β-cell function and improve glucose homeostasis in type 2 diabetes.