Protein chemistry & metabolism
Team Leader, Metabolic Physiology Group
Senior Research Officer
Email: [email protected]
Ms Lisa Murray-Segal
Mr Luke McAloon
2001 Biochemistry graduate (Diploma), University of Tübingen, Germany
2008 PhD, Dept of Biochemistry and Molecular Biology, Monash University
2012 Senior Research Officer, Protein Chemistry and Metabolism Unit, SVI
2002 International Postgraduate Research Scholarship
2002 Monash Graduate Scholarship
We are interested in the molecular mechanisms that control energy metabolism and substrate utilisation in cells and on the whole body level. Body weight is determined by the balance between energy intake and energy expenditure. We seek to understand how nutrients and hormones affect this balance and how energy homeostasis becomes dysregulated during the development of obesity and insulin resistance. We are particularly interested in the mechanisms by which the brain senses the body’s energy status and influences physiological responses such as appetite, physical activity and glucose homeostasis and the role the metabolic enzyme AMP-activated protein kinase (AMPK) plays in this process. The goal of our research is to find new therapeutic targets for the treatment of obesity, type 2 diabetes and cardiovascular disease, which are the leading causes of premature death and illness in Australia.
1) Regulation of ghrelin signalling by AMPK. PhD project.
Ghrelin is a hormone that is mainly produced by the stomach and acts on ghrelin-sensitive cells in the brain to stimulate appetite, food-related reward behaviour and lipid storage in adipose tissue. Importantly, ghrelin is known to mediate the body weight regain that often follows diet-induced weight loss. We have previously shown that regulation of lipid metabolism in the hypothalamus by the energy sensing enzyme AMP-activated protein kinase (AMPK) is required for increases in appetite in response to low energy conditions, such as fasting or cold exposure. Furthermore, we have evidence that this process is mediated by ghrelin and that disrupting AMPK signalling suppresses ghrelin-induced body weight gain. This project will use genetically modified mice to determine whether inhibition of AMPK control of fatty acid metabolism or complete deletion of AMPK from ghrelin-sensitive cells can suppress appetite during low-calorie feeding. The experiments will determine whether specific targeting of ghrelin-AMPK signalling is an effective strategy to prevent rebound weight gain after dieting. The techniques associated with this study will involve comprehensive metabolic analyses in mice including measurements of body composition, energy expenditure, physical activity, metabolic flexibility, food intake behaviour and glucose tolerance. In addition the project will offer training in a range of biochemical and histological techniques, such as analyses of fatty acid synthesis and oxidation, kinase activity, gene expression, immunoblotting, immunohistochemistry and ELISA.
2) Inhibition of microglia inflammation by AMPK for obesity treatment. PhD project.
Consumption of high-calorie diets is associated with the rapid onset of inflammation in the hypothalamus, the main area of the brain involved in the regulation of appetite, energy expenditure and glucose homeostasis. This overnutrition-induced inflammation is mediated by microglia, which are macrophage-like cells that normally protect the brain from pathogens and help with clearance of dead neurons and cell debris. However, when chronically activated in response to saturated fatty acids from the diet, microglia generate an inflammatory environment within the hypothalamus that is toxic for neighbouring neurons and can lead to damage of neuronal circuits that normally control energy homeostasis and hepatic glucose production. We have previously shown that the AMP-activated protein kinase (AMPK) has anti-inflammatory effects in bone marrow derived macrophages and inhibits adipose tissue inflammation associated with a high-fat diet. This project will investigate whether AMPK activation in microglia can suppress hypothalamic inflammation and damage of appetite-regulating neurons resulting in reduced body weight gain with high-fat feeding. The study will involve the isolation and culture of primary microglia and handling of knockout and transgenic mice to investigate hormone signalling pathways, gene expression, whole-body energy homeostasis and hepatic glucose production. Commonly used techniques will include brain immunohistochemistry, confocal microscopy, immunoblotting, Real-time PCR, ELISA, flow cytometry, calorimetry and body composition analyses by NMR.
- Loh K, Tam S, Murray-Segal L, Huynh K, Meikle PJ, Scott JW, van Denderen B, Chen Z, Steel R, LeBlond ND, Burkovsky LA, O'Dwyer C, Nunes JRC, Steinberg GR, Fullerton MD, Galic S*, Kemp BE* (2018) Inhibition of Adenosine Monophosphate-Activated Protein Kinase-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Signaling Leads to Hypercholesterolemia and Promotes Hepatic Steatosis and Insulin Resistance. Hepatol Commun 12;3(1):84-98.
- Galic S, Loh K, Murray-Segal L, Steinberg GR, Andrews ZB, Kemp BE. (2018) AMPK signaling to acetyl-CoA carboxylase is required for fasting- and cold-induced appetite but not thermogenesis. eLife Feb 13;7. pii: e32656.
- Fullerton MD*, Galic S*, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O'Neill HM, Ford RJ, Palanivel R, O'Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin Nature Medicine, 19(12), 1649 – 1654.
- Galic S, Fullerton MD, Schertzer JD, Sikemma S, Marcinko K, Walkley CR, Izon D, Honeyman J, Chen ZP, van Denderen BJ, Kemp BE, Steinberg GR (2011) Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest, 121(12) 4903 – 4915.
- Galic S, Sachithanandan N, Kay TW, Steinberg GR. (2014) Suppressor of cytokine signalling (SOCS) proteins as guardians of inflammatory responses critical for regulating insulin sensitivity. Biochem J. 461(2):177-88
- O'Neill HM, Lally JS, Galic S, Thomas M, Azizi PD, Fullerton MD, Smith BK, Pulinilkunnil T, Chen Z, Samaan MC, Jorgensen SB, Dyck JR, Holloway GP, Hawke TJ, van Denderen BJ, Kemp BE, Steinberg GR. (2014) AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia. 57(8):1693-702.
- Galic S, Oakhill JS, Steinberg GR. (2009) Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 316(2):129-39
- Galic S, Hauser C, Kahn BB, Haj FG, Neel BG, Tonks NK, Tiganis T. (2004) Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Mol Cell Biol. 25(2):819-29.