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.

Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormonesensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR. Monoacylglycerols (MG)3 are short lived intermediates of lipid catabolism derived from extracellular or intracellular sources. Pancreatic lipase and lipoprotein lipase generate MG by the hydrolysis of dietary triacylglycerols (TG) and circulating lipoproteins, respectively (1, 2). The lipolytic products, MG and free fatty acids (FFA), are subsequently taken up by cells, and MG are hydrolyzed into FFA and glycerol or re-esterified by the monoacylglycerol acyltransferase reaction (3). Within cells, MG are derived from the hydrolysis of glycerophospholipids or TG. Glycerophospholipids may be degraded by phospholipase C generating sn-1,2-diacylglycerols (DG), which are further hydrolyzed by sn-1-specific DG lipase resulting in the formation of 2-MG (4). The breakdown of TG is initiated by adipose triglyceride lipase (ATGL), and the produced DG is hydrolyzed by hormone-sensitive lipase (HSL) (5). The stereospecificity of ATGL has not been studied so far. Yet, similar to DG lipase, HSL hydrolyzes DG preferentially in sn-1(3) position generating 2-MG (6). Monoglyceride lipase (MGL) degrades sn-1(3) and 2-MG at identical specific rates (7). The enzyme is expressed in most cell types and is considered the rate-limiting enzyme in the degradation of MG (8, 9).In ad...

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.

Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFDinduced obesity and insulin resistance.E ssentially all organisms face the problem of continuous energy demand in an environment of irregular food supply. To overcome this dilemma, metazoan organisms developed special storage depots for substrates that are used for energy production. In vertebrates, by far the most efficient energy reservoir is adipose tissue (1). This highly expandable organ is able to store all major nutritional components (fat, carbohydrates, and proteins) as triglycerides (TGs). Adipose tissue mass and TG content depend on the balance of anabolic and catabolic pathways. Lipid storage in response to nutrient supply involves the generation of adipocytes (adipogenesis), the induction of fatty acid (FA) synthesis from glucose and amino acids (de novo lipogenesis), and the synthesis of TGs (lipid synthesis). These processes are activated by a complex transcriptional network involving CCAAT/ enhancer-binding proteins (C/EBPs), sterol regulatory enhancer binding proteins (SREBPs), and the heterodimer of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and retinoid-X receptor (RXR) (2, 3).The opposing metabolic pathway of TG catabolism (lipolysis) requires activation of enzymes called lipases. Adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) hydrolyze all three ester bonds of TGs in a stepwise manner to yield FAs and glycerol (4). Lipolysis is an exquisitely regulated proce...

Background: Perilipin 5 (Plin5) protects cardiac lipid droplets from uncontrolled lipolysis. Results: Plin5-mediated inhibition of lipid droplet triglyceride breakdown is reversed by the action of protein kinase A (PKA) depending on serine 155 of Plin5. Conclusion:The lipolytic barrier function of Plin5 is under regulation of PKA. Significance: Regulation of Plin5 is implicated in the development of lipolysis-related cardiac disease.