Adipose Triglyceride Lipase and Hormone-sensitive Lipase Are the Major Enzymes in Adipose Tissue Triacylglycerol Catabolism

Schweiger, Martina; Schreiber, Renate; Haemmerle, Guenter; Lass, Achim; Fledelius, Christian; Jacobsen, Poul; Törnqvist, Hans; Zechner, Rudolf; Zimmermann, R.

doi:10.1074/jbc.m608048200

Cited by 602 publications

(504 citation statements)

References 32 publications

(49 reference statements)

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“…1a). Furthermore, adipocytes from aged fasted mice failed to induce Hsl and Atgl expression (Extended Data 1h, i), which together control 90% of TG hydrolysis in adipose tissue 8 . Interestingly, stimulation of VAT from young and aged mice with NE caused similar induction of Hsl, Atgl and lipolysis (Extended data 1j and Fig.…”

Section: Main Textmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

353

352

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Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

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Section: Main Textmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

353

352

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“…The accumulation of diglycerides (DG) in the adipose tissue of HSL knockout mice suggests that HSL is the rate limiting enzyme for the hydrolysis of DG and not TG (Haemmerle et al, 2002). Adipose TG lipase (ATGL) has been suggested to be the key enzyme involved in TG hydrolysis in the adipose tissue (Schweiger et al, 2006;Haemmerle et al, 2006;Zimmermann et al, 2004). TG lipolysis was shown to be severely impaired in ATGL-deficient mice accumulating large amount of fat in major organs and leading to premature death .…”

Section: Introductionmentioning

confidence: 99%

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

Kim

Saidel

Kalhan

2008

Journal of Theoretical Biology

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Regulation of lipolysis in adipose tissue is critical to whole body fuel homeostasis and to the development of insulin resistance. Due to the challenging nature of laboratory investigations of regulatory mechanisms in adipose tissue, mathematical models could provide a valuable adjunct to such experimental work. We have developed a computational model to analyze key components of adipose tissue metabolism in vivo in human in the fasting state. The various key components included triglyceride-fatty acid cycling, regulation of lipolytic reactions, and glyceroneogenesis. The model, consisting of spatially lumped blood and cellular compartments, included essential transport processes and biochemical reactions. Concentration dynamics for major substrates were described by mass balance equations. Model equations were solved numerically to simulate dynamic responses to intravenous epinephrine infusion. Model simulations were compared with the corresponding experimental measurements of the arteriovenous difference across the abdominal subcutaneous fat bed in humans. The model can simulate physiological responses arising from the different expression levels of lipases. Key findings of this study are as follows: (1) Distinguishing the active metabolic subdomain (~3% of total tissue volume) is critical for simulating data. (2) During epinephrine infusion, lipases are differentially activated such that diglyceride breakdown is ~4 times faster than triglyceride breakdown. (3) Glyceroneogenesis contributes more to glycerol-3-phosphate synthesis during epinephrine infusion when pyruvate oxidation is inhibited by a high acetyl-CoA/free-CoA ratio.

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“…Adipose triglyceride lipase (ATGL; PNPLA2; desnutrin; calcium-PLA [128,129]) is rate-limiting for the mobilisation of mTAG foroxidation. ATGL expression is increased by FAs, exercise, high fat feeding [130], starvation [131] and STZ-diabetes [132] suggesting that plasma-derived FAs activate lipolysis.…”

Section: Myocardial Triacylglycerol Lipolysismentioning

confidence: 99%

The role of triacylglycerol in cardiac energy provision

Evans

Hui‐Kang

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity.Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through bloodborne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FA) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives.Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3Key words:heart; triacylglycerol; very-low-density lipoprotein; VLDL; chylomicron; lipid droplet Highlights: Triacylglycerols are supplied to the myocardium within chylomicrons and VLDL  Heart assimilates triacylglycerol-rich lipoproteins by LPL and receptor-mediated routes  Exogenous triacylglycerol-derived fatty acids enter an intracellular lipid pool  Intracardiac triacylglycerol is an important source of fatty acids for oxidation  Dysregulation of triacylglycerol metabolism is associated with cardiac dysfunction

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Adipose Triglyceride Lipase and Hormone-sensitive Lipase Are the Major Enzymes in Adipose Tissue Triacylglycerol Catabolism

Cited by 602 publications

References 32 publications

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

A computational model of adipose tissue metabolism: Evidence for intracellular compartmentation and differential activation of lipases

The role of triacylglycerol in cardiac energy provision

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