Metabolic diseases such as obesity and diabetes are major health concerns worldwide, with Australia being one of the most affected countries. Diabetes increases cardiovascular risk at least three-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 obesity, diabetes and atherosclerosis will help us develop more effective therapeutic approaches for these diseases.
Specifically, our research program focuses on the discovery and fundamental biology of several key molecules – including Salt-inducible kinase 3 (SIK3), Neuropeptide Y (NPY) and AMP-activated protein kinase (AMPK) – that play crucial roles in the regulation of energy homeostasis, beta-cell biology, glucose and lipid metabolism. These molecules are currently being pursued across the pharmaceutical sector as promising drug targets for chronic diseases such as diabetes, obesity and cardiovascular disease.
We have developed a sophisticated suite of research tools, such as several novel transgenic mouse models, to determine the precise role of these molecules in metabolic regulation. We aim to clarify the exact contribution these molecules make to the development of metabolic diseases – such as obesity, diabetes and atherosclerosis – to find new and more effective treatments.
Current research projects
The role of AMPK in suppressing atherosclerosis
Stemming from dyslipidaemia 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 metabolism, including cholesterol metabolism.
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 hyperglycaemia, the project also aims to shed light on whether impairment of AMPK signalling responsible toward the pathology of diabetes-associated atherosclerosis. We hypothesise that pharmacological activation of the signalling cascade which culminates in AMPK activation may serve as an alternative cholesterol-lowering therapy and reducing atherosclerosis development.Investigating a novel mechanism for improving beta-cell function in type 2 diabetes
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.
We have recently identified that a protein kinase called Salt-inducible kinase 3 (SIK3) is also expressed in the β-cells in humans. Despite this, the physiological role of SIK3 in the regulation of β-cell function and glycaemic control remain unknown. We aim to investigate whether pharmacological manipulation of SIK3 signalling will enhance β-cell function and improve glucose homeostasis in type 2 diabetes.
- Dr Jessie Yang, Research Officer
- Shaktypreya Nadarajah, PhD student
- Danise Ann-Onda, PhD student
- Xiaozhuo Yuan, Honours student
CH Yang, D Ann-Onda, X Lin, S Fynch, S Nadarajah, EG Pappas, X Liu, JW Scott, JS Oakhill, S Galic, YC Shi, A Moreno-Asso, C Smith, T Loudovaris, I Levinger, DL Eizirik, DR Laybutt, H Herzog, HE Thomas, KIM LOH (2022). Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes. Journal: Molecular Metabolism, DOI:10.1016/j.molmet.2021.101413
MKS Lee, OD Cooney, X Lin, S Nadarajah, D Dragoljevic, K Huynh, D Ann-Onda, S Galic, PJ Meikle, T Edlund, MD Fullerton, BE Kemp, AJ Murphy, KIM LOH (2022). Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis. Journal: Molecular Metabolism, DOI:10.1016/j.molmet.2022.101514
KIM LOH, Tam S, Murray-Segal L, Huynh K, Meikle PJ, Scott JW, Chen ZP, Steel R, LeBlond ND, Burkovsky LA, O’Dwyer C, Nunes JRC, Steinberg GR, Fullerton MD, Galic S and Kemp BE (2019). Inhibition of AMPK-HMGCR Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance. Journal: Hepatology Communications, DOI:10.1002/hep4.1279
KIM LOH, Shi YC, Walters S, Bensellam M, Lee KL, Dezaki K, Nakata M, Gurzov E, Thomas HE, Waibel M, Cantley J, Kay TWH, Yada T, Laybutt RD, Grey S and Herzog H (2017). Inhibition of Y1 receptor signaling improves islet transplant outcome. Journal: Nature Communications, DOI:10.1038/s41467-017-00624-2
Yulyaningsih E*, KIM LOH*, Lin S*, Lau J, Zhang L, Shi YC, Berning B, Enriquez R, Driessler F, Macia L, Khor E, Qi Y, Baldock P, Sainsbury A & Herzog H (2014). Pancreatic Polypeptide controls energy homeostasis via Npy6r signaling in the suprachiasmatic nucleus in mice. Journal: Cell Metabolism, DOI:10.1016/j.cmet.2013.11.019 Co-first author
KIM LOH, Fukushima A, Zhang XM, Galic S, Briggs D, Enriori PJ, Simonds S, Weide F, Reichenbach A, Hauser C, Sims NA, Bence KK, Zhang S, Zhang ZY, Kahn BB, Neel BG, Andrews ZB, Cowley MA, and Tiganis T (2011). Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Journal: Cell Metabolism, DOI:10.1016/j.cmet.2011.09.011
ORCID profile: 0000-0003-3781-1926
Google Scholar profile: Kim Loh https://scholar.google.com/citations?user=4v9dnwQAAAAJ&hl=en