Biology of Lipid Metabolism Laboratory 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, liver 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. The research streams in our laboratory are: Alterations in adipocyte lipolysis (triglyceride breakdown) are observed in several metabolic disorders oakley minute 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. Basal 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 buy oakley 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 Dotted line = unpublished event. 2.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 resistance Insulin 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: Mechanism 1. Intracellular accumulation of fats leads to insulin resistance in skeletal muscle Fatty acid metabolism is dysregulated in obesity leading to the accumulation of intracellular fatty acid metabolites. Dysregulation of fatty acid metabolism in obesity Lean: Fatty acids derived from adipose tissue lipolysis and dietary intake are transported across the plasma membrane. The majority of fatty acids are directed towards in the mitochondria, where most fatty acids are completely oxidized. A smaller oakley twitch 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. Mechanism 2: Adipose released factors induce insulin resistance in skeletal muscle 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 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 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. We are now actively studying the regulation of metabolism by several adipose as well as liver secreted factors. Borg ML, Andrews ZB, Duh EJ, Zechner R, Meikle PJ, and Watt MJ. Pigment epithelium derived factor regulates lipid metabolism via adipose triglyceride lipase. Diabetes. 60: 1458 66, 2011. Turpin SM, Hoy AJ, Brown RD, Garcia Rudaz C, Honeyman J, Matzaris M, and Watt MJ. Adipose triglyceride lipase is a major regulator of hepatic lipid metabolism, but not insulin sensitivity. Diabetologia 54: 146 156, 2011. Hoy AJ, Bruce CR, Turpin SM, Morris AJ, Febbraio MA, and Watt MJ. Adipose triglyceride lipase null mice are resistant to high fat diet induced insulin resistance despite reduced energy expenditure and ectopic lipid accumulation. Endocrinology 152: 48 58, 2011. Watt MJ and Spriet LL. Triacylglycerol lipases and metabolic control: implications for health and disease. Am J Physiol Endocrinol Metab 299: E162 8, 2010. Crowe S, Wu LE, Economou C, Turpin SM, Matzaris M, Hoehn KL, Hevener AL, James DE, Duh EJ and Watt MJ. Pigment epithelium derived factor contributes to insulin resistance in obesity. Cell Metabolism. 10: 40 47, 2009. Turpin SM, Ryall JG, Sothgate R, Darby I, Hevener AL, Febbraio MA, Kemp BE, Lynch GS and Watt MJ. Examination of in skeletal muscle of high fat fed and ob/ob mice. J Physiol 587: 1593 1605, 2009. Crowe S, Turpin SM, Ke, Kemp BE and Watt MJ. Metabolic remodelling in adipocytes promotes CNTF mediated fat loss in obesity. Endocrinology 149: 2546 2556, 2008. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV, Hevener AL, and Farese RV Jnr. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metabolism. 6: 69 78, 2007. Hevener AL, Olefsky J, Reichart D, Nguyen MTA, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, and Ricote M. Macrophage PPAR is required for normal skeletal muscle and hepatic insulin sensitivity and full anti diabetic effects of TZDs. oakley racing J. Clin Invest. 117: 1658 1669, 2007.
Watt MJ, Dzamko N, Thomas WG, Rose John S, Ernst M, Carling D, Kemp BE, Febbraio MA, and GR Steinberg. Ciliary neurotrophic factor reverses obesity induced insulin resistance by activating skeletal muscle AMPK. Nature Medicine 12: 541 548, 2006.
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