Monash University
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Lipid metabolism in skeletal muscle: the role of perilipin 5 and adipose triglyceride lipase in regulating metabolism in skeletal muscle

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posted on 2017-02-23, 00:35 authored by Mason, Rachael Ruth
Our understanding of the importance of limiting fats in our diet has grown exponentially, especially with today’s diet and health-food obsessed world. However, the numbers of people who are not only overweight, but obese, grows daily. With this ever increasing problem, our understanding of lipid metabolism has rapidly progressed in the last 30 years. The identification of key proteins, namely perilipin 1 (PLIN1), hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) has provided great insight into the regulation of lipolysis, the process of lipid breakdown. While the primary focus of much lipid metabolism research was in tissue specifically designed for storing lipids, namely adipose tissue, more recently skeletal muscle has been recognised as having a major role in lipid storage and metabolism to provide energy. However, our understandings of the exact mechanisms that regulate skeletal muscle lipolysis remain largely undetermined. The identification of the protein super-family, the Perilipins (PLIN), with at least five members, has seen a resurgence of research in lipid metabolism. It has been hypothesised that each member may have a unique tissue distribution and unique function. As members of the PLIN family exist in skeletal muscle, their function in skeletal muscle is the primary focus of this thesis. Identification of the PLIN family increased the focus of lipid metabolism research in non-adipose tissue. In skeletal muscle, PLIN5 is the most abundant member of the PLIN family. The aim of this thesis was to investigate the role of PLIN5 and ATGL in regulating lipid metabolism in skeletal muscle. Firstly, we used the PLIN5 null mouse to show the role PLIN5 has on maintaining skeletal muscle insulin action and coordinating skeletal muscle triacylglycerol metabolism. Secondly, we showed that PLIN5 null mice were not resistant to diet-induced obesity and had impaired whole body insulin sensitivity similar to that of the low fat diet PLIN5 null mouse. Together, these studies highlight the importance of PLIN5 in skeletal muscle lipid and glucose metabolism. The third aspect of the thesis was to examine the role PLIN5 has in lipid droplets in circumstances of perturbed lipid metabolism. Furthermore, its interaction with other major lipolytic proteins in these situations was also investigated. The rationale behind this approach was previous observations that have shown that PLIN5 associates with lipid droplets and ATGL and CGI-58 in cell culture systems. We demonstrated that PLIN5 was highly colocalised with ATGL and CGI-58 at rest, though acute exercise did not affect this relationship. Lastly, we identified that serine phosphorylation of ATGL site 404 is not increased in skeletal muscle during moderate intensity exercise and that AMPK does not appear to be the activating kinase of the ATGL Ser404 in skeletal muscle. The work in this thesis extends our understanding of the physiological mechanisms of lipid metabolism and the effect it has on glucose metabolism and insulin sensitivity in skeletal muscle.


Principal supervisor

Matthew Watt

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Biomedical Sciences (Monash Biomedicine Discovery Institute)

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Doctor of Philosophy

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Faculty of Medicine Nursing and Health Sciences

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