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      The role of adipose triglyceride lipase in lipid and glucose homeostasis: lessons from transgenic mice

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          Abstract

          The ability of mammals to store and draw on fat reserves has been a driving force throughout evolution in an environment with intermittent nutrient availability. The discovery of adipose triglyceride lipase (ATGL) as a triglyceride lipase provided a heightened understanding of the mechanisms governing mobilization of fat reserves from adipose tissue. ATGL catalyses the initial step in adipose triglyceride lipolysis, working in concert with other enzymes to mobilize triglyceride for energy production. In addition to the role of ATGL in adipose tissue triglyceride mobilization, ATGL plays crucial roles in regulating lipid homeostasis in other tissues. These roles have been characterized primarily using transgenic mice with tissue-specific ATGL ablation. For example, the global ATGL knockout induces a severe cardiac defect that results in premature mortality that is mimicked by inducible cardiomyocyte-specific ATGL knockout. Global- and adipose-specific ATGL ablation induces a whole-body shift from lipid metabolism to glucose metabolism to satisfy metabolic demand primarily facilitated by an increase in glucose uptake by skeletal muscle. Generation of liver-specific ATGL knockouts has implicated hepatic lipolysis as a critical component of normal liver function. Analysis of β-cell ATGL knockouts implicates the necessity of pancreatic ATGL in insulin secretion. The objective of this review is to discuss the contributions of ATGL to systemic lipid- and glucose-homeostasis discovered through the study of transgenic mice.

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          Most cited references53

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          Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.

          Mobilization of fatty acids from triglyceride stores in adipose tissue requires lipolytic enzymes. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Until now, hormone-sensitive lipase (HSL) was the only enzyme known to hydrolyze triglycerides in mammalian adipose tissue. Here, we report that a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis. It is interesting that ATGL contains a "patatin domain" common to plant acyl-hydrolases. ATGL is highly expressed in adipose tissue of mice and humans. It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. Inhibition of ATGL markedly decreases total adipose acyl-hydrolase activity. Thus, ATGL and HSL coordinately catabolize stored triglycerides in adipose tissue of mammals.
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            FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling

            Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that “lipolytic signaling” is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
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              Regulation of lipolysis in adipocytes.

              Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes.
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                Author and article information

                Contributors
                (780) 932-0648 , clugston@ualberta.ca
                Journal
                Lipids Health Dis
                Lipids Health Dis
                Lipids in Health and Disease
                BioMed Central (London )
                1476-511X
                22 November 2019
                22 November 2019
                2019
                : 18
                : 204
                Affiliations
                [1 ]GRID grid.17089.37, Department of Physiology, Faculty of Medicine and Dentistry, , University of Alberta, ; Edmonton, Alberta T6G 2H7 Canada
                [2 ]GRID grid.17089.37, Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, , University of Alberta, ; Edmonton, Alberta Canada
                Author information
                http://orcid.org/0000-0003-0264-9594
                Article
                1151
                10.1186/s12944-019-1151-z
                6874817
                31757217
                de300a14-6203-4e2d-823c-645adf62b23f
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 August 2019
                : 7 November 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000035, Institute of Nutrition, Metabolism and Diabetes;
                Award ID: PJT-156226
                Award Recipient :
                Funded by: National science and engineering research council
                Award ID: RGPIN-2017-04710
                Award ID: CGSD3-519194-2018
                Award Recipient :
                Funded by: Alberta Innovates
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Biochemistry
                adipose triglyceride lipase (atgl),glucose metabolism,lipid metabolism,transgenic mice,triglyceride (tg)

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