Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic × receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.

We developed decision rule sets for Lipid Data Analyzer (LDA; http://genome.tugraz.at/lda2), enabling automated and reliable annotation of lipid species and their molecular structures in high-throughput data from chromatography-coupled tandem mass spectrometry. Platform independence was proven in various mass spectrometric experiments, comprising low- and high-resolution instruments and several collision energies. We propose that this independence and the capability to identify novel lipid molecular species render current state-of-the-art lipid libraries now obsolete.

The ability to deposit triacylglycerol (TG) within specifi c cellular organelles is an evolutionary conserved process present in virtually every mammalian cell and in most microorganisms ( 1-3 ). TG storage within lipid droplets (LDs) not only represents an energy reservoir, but is also an important source for the generation of membrane and signaling lipids ( 4 ). However, excessive accumulation of lipids is a hallmark of many metabolic disorders including obesity, hepatic steatosis, and cardiac steatosis ( 5-7 ). Apart from that, fatty acid (FA) esterifi cation and deposition within neutral lipids protect cells from the harmful excess of nonesterifi ed FAs also referred to as lipotoxicity ( 8,9 ). The LD surface is characterized by the presence of various hydrophobic proteins including members of the so-called PAT family ( 1, 10 ) (designation derived from perilipin, adipophilin, and tail-interacting protein of 47 kDa ) and neutral lipid hydrolases, which are involved in TG breakdown and the release of FAs and glycerol.

This article is available online at http://www.jlr.orgCarbohydrates and FAs are the major energy substrates in the working muscle. The use of FAs for energy conversion depends, among other things, on exercise intensity and duration. During prolonged exercise, when carbohydrate reserves get depleted, oxidation of FAs becomes increasingly important ( 1, 2 ). Under these conditions, FAs are imported from plasma sources or mobilized from intramyocellular stores. Most of the body's energy reserves are stored in white adipose tissue (WAT) implicating that the supply of the muscle with energy during prolonged exercise is largely dependent on adipose lipolysis. The mobilization of FAs in adipose tissue is tightly controlled by hormones. Catecholamines and other effectors activate lip ases resulting in increased FA release into the circulation ( 3, 4 ). Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major triglyceride (TG) lipases in this process. HSL most effi ciently hydrolyses diglycerides (DGs), but is also capable of degrading several other lipid substrates including TGs, monoglycerides, cholesteryl ester, and retinyl ester ( 5 ). In HSL-deficient WAT, TG hydrolysis results in the accumulation of DG, suggesting that HSL is a major DG hydrolase in vivo ( 6 ). ATGL specifi cally performs the fi rst step in lipolysis, generating DGs and FAs ( 7 ). ATGL-defi ciency in mice results in obesity caused by severely reduced TG hydrolysis in adipose tissue. Increased deposition of TG is also observed in many other tissues ( 8 ). In the absence of both enzymes, hormone-induced FA release in WAT is decreased by more than 95% ( 9 ). Together, these observations suggest that effi cient lipolysis is dependent on the coordinate action of Abstract FAs are mobilized from triglyceride (TG) stores during exercise to supply the working muscle with energy. Mice defi cient for adipose triglyceride lipase (ATGL-ko) exhi bit defective lipolysis and accumulate TG in adipose tissue and muscle, suggesting that ATGL defi ciency affects energy availability and substrate utilization in working muscle. In this study, we investigated the effect of moderate treadmill exercise on blood energy metabolites and liver glycogen stores in mice lacking ATGL. Because ATGL-ko mice exhibit massive accumulation of TG in the heart and cardiomyopathy, we also investigated a mouse model lacking ATGL in all tissues except cardiac muscle (ATGL-ko/CM). In contrast to ATGL-ko mice, these mice did not accumulate TG in the heart and had normal life expectancy. Exercise experiments revealed that ATGL-ko and ATGL-ko/CM mice are unable to increase circulating FA levels during exercise. The reduced availability of FA for energy conversion led to rapid depletion of liver glycogen stores and hypoglycemia. Together, our studies suggest that ATGL-ko mice cannot adjust circulating FA levels to the increased energy requirements of the working muscle, resulting in an increased use of carbohydrates for energy conversion. Thus, ATGL activity is required...

Background:The role of CGI-58 in muscle triacylglycerol catabolism is unknown. The presence of CGI-58 increases the lipolytic activity of adipose triglyceride lipase (ATGL). Results: Muscle-specific CGI-58 deficiency causes muscle steatosis and cardiac dysfunction despite elevated ATGL protein expression. Conclusion: Muscle lipolysis critically depends on both CGI-58 and ATGL. Significance: Muscle CGI-58 deficiency provokes severe cardiac steatosis and dysfunction.