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Biology of Lipid Metabolism Laboratory
Matthew J. Watt (Laboratory Head) Associate Professor of Physiology Academic Qualifications: Contact details: Telephone: +61 3 9905 2584 Lab group photo
Current lab members
Research interests
Obesity is a serious medical conditions that has doubled in prevalence over the last 20 years and affects 1 in every 3 Australian adults. Our research is directed towards understanding the molecular and cellular regulation of fat metabolism, in adipose tissue and skeletal muscle, and how aberrations in fat metabolism lead to the development of insulin resistance (precursor to type 2 diabetes) . The outcomes of our research aim to influence the development of preventative and therapeutic strategies for obesity and related metabolic disorders. 1. Regulation of adipocyte lipolysisAlterations in adipocyte lipolysis (triglyceride breakdown) are observed in several metabolic disorders including obesity and insulin resistance, and results in increased release of fatty acids into the circulation. For a long time, adipose tissue lipolysis has been targeted as a therapeutic of these metabolic disorders. Hormone sensitive lipase (HSL) was considered to be the only rate-limiting enzyme for adipocyte lipolysis; however, the cloning of a novel triglyceride lipase termed adipose triglyceride lipase (ATGL) has changed the view of lipolysis. ATGL is highly expressed in white adipose tissue with less expression in skeletal muscle, accounts for 60-70% of triglyceride lipase activity in adipose and appears to be essential for the control of normal weight. Despite the critical role of ATGL in lipid homeostasis, virtually nothing is known regarding the mechanisms of its regulation, or its expression and function in pathological states characterised by defective lipolysis. The central aim of this research stream is to investigate the cellular mechanisms that regulate ATGL and whether defects in adipose tissue ATGL are related to obesity and insulin resistance.
An emerging view of lipolysisBasal lipolysis: Perilipin (Peri A) and CGI-58 form a complex on the LD. ATGL is localised partially to the LD and HSL mostly in the cytoplasm. Stimulated lipolysis: LD fragment and PKA activation results in phosphorylation of HSL and perilipin (denoted by P). Phosphorylation of perilipin releases CGI-58, which binds ATGL to initiate lipolysis. HSL translocates to the LD, associates with perilipin and degrades DG. Dotted line = unpublished event. 2. Deciphering the relationship between obesity and insulin resistanceInsulin resistance is defined as a subnormal response of tissues to insulin action and is a central feature of the pathophysiology of type 2 diabetes. Obesity is a well recognised factor contributing to insulin resistance. The concept that adipocytes become dysfunctional with obesity is now well accepted; however, the mechanisms linking obesity to insulin resistance are still poorly defined. We propose two major defects that lead to obesity-induced insulin resistance:
Fatty acid metabolism is dysregulated in obesity leading to the accumulation of intracellular fatty acid metabolites that interferes with insulin signal transduction (see figure.
Dysregulation of fatty acid metabolism in obesityLean: Fatty acids derived from adipose tissue lipolysis and dietary intake are transported across the plasma membrane. The majority of fatty acids are directed towards β-oxidation in the mitochondria, where most fatty acids are completely oxidized. A smaller fraction of the fatty acids are esterified to form diglyceride and triglyceride and some fatty acids are converted into ceramide. Obese: Increased lipolysis from an enlarged adipose mass increases fatty acid delivery to peripheral tissues. Fatty acid uptake is greater and an increased fraction of the transported fatty acids are directed towards esterification, rather than oxidation. Accordingly, lipid metabolites accumulate in the tissue. A reduced mitochondrial capacity is associated with more incomplete oxidation of fatty acids. Increases in function or content are denoted in green; decreases in red. AMPK, AMP activated protein kinase; ATP, adenosine triphosphate; FA, fatty acid.
Adipose tissue was traditionally considered to be an inert storage depot for triglycerides; however, it is now recognised that the adipocyte produces and secretes a wide variety of hormones and cytokines (termed ‘adipokines’) that influence many biological processes, including substrate metabolism. Adipose tissue uses adipokines as a communication tool to signal changes in its mass and energy status to other organs that control fuel usage, such as skeletal muscle and liver. In obesity and type 2 diabetes there is an accelerated release of adipokines that are known to induce insulin resistance including tumor necrosis factor α, resistin, retinol-binding protein 4, plasminogen activated inhibitory 1 (PAI-1) and visfatin. Conversely, adiponectin, which is the only adipocyte hormone known to induce insulin sensitivity, is decreased. In this way, obesity is associated with a chronic low grade inflammatory state that contributes to insulin resistance. Recent Publications
For a complete list of publications go to http://www.ncbi.nlm.nih.gov/sites/entrez Postdoctoral and PhD PositionsPhD and postdoctoral positions are offered to study the cellular and molecular basis of metabolic disorders. Projects include:
These projects are aimed to understand the cellular and molecular mechanisms underlying the biology these processes. Our laboratory utilizes mammalian systems and genetic manipulation of cultured cells and mice models. We have a strong focus on phenotypic evaluation.
Applications and inquiries should be sent to Matthew Watt (matthew.watt@med.monash.edu.au )
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