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

The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis. The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis. Fatty acids deposited as triacylglycerol (TG) 3The abbreviations used are: TG, triacylglycerol; ATGL, adipose triglyceride lipase; ATGL-ko mice, ATGL-deficient knock-out mice; CDS, Chanarin-Dorfman syndrome; CGI-58, comparative gene identification protein 58; HSL, hormone-sensitive lipase; HSL-ko mice, HSL-deficient knock-out mice; DG, diacylglycerol; FFA, free fatty acid(s); GST, glutathione S-transferase; MG, monoacylglycerol; PKA, protein kinase A; PL, phospholipid; TGH, triacylglycerol hydrolase; WAT, white adipose tissue; WT, wild type. 3The abbreviations used are: TG, triacylglycerol; ATGL, adipose triglyceride lipase; ATGL-ko mice, ATGL-deficient knock-out mice; CDS, Chanarin-Dorfman syndrome; CGI-58, comparative gene identification protein 58; HSL, hormone-sensitive lipase; HSL-ko mice, HSL-deficient knock-out mice; DG, diacylglycerol; FFA, free fatty acid(s); GST, glutathione S-transferase; MG, monoacylglycerol; PKA, protein kinase A; PL, phospholipid; TGH, triacylglycerol hydrolase; WAT, white adipose tissue; WT, wild type. in white adipose tissue (WAT) represent the primary energy store in animals. In periods of increased energy demand, TG is hydrolyzed, and free fatty acids (FFA) are released into the circulation. The hydrolysis of TG is catalyzed by adipose tissue lipases in sequential steps leading to the formation of FFA and glycerol. The first step within the hydrolysis cascade generating FFA and diacylglycerol (DG) is rate-limiting for subsequent reactions. Hormone-sensitive lipase (HSL) has long been considered as catalyzing this initial step. However, in recent years it became evident that at least one additional lipase must exist capable of hydrolyzing TG. Observations that HSL-deficient (HSL-ko) mice are not obese (1Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (494) Google Scholar, 2Wang S.P. Laurin N. Himms-Hagen J. Rudnicki M.A. Levy E. Robert M.F. Pan L. Oligny L. Mitchell G.A. Obes. Res. 2001; 9: 119-128Crossref PubMed Scopus (189) Google Scholar, 3Harada K. Shen W.J. Patel S. Natu V. Wang J. Osuga J. Ishibashi S. Kraemer F.B. Am. J. Physiol. 2003; 285: E1182-E1195Crossref PubMed Scopus (138) Google Scholar) but accumulate DG in adipose tissue and muscle (4Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar) suggest that HSL may be rate-limiting for DG hydrolysis rather than for the first and rate-limiting step within the TG lipolysis cascade. In addition to HSL, three other lipases have been reported to be involved in adipose TG hydrolysis. Triacylglycerol hydrolase (TGH) is highly expressed in liver and adipose tissue and has been suggested to represent a major adipocyte lipase (5Soni K.G. Lehner R. Metalnikov P. O'Donnell P. Semache M. Gao W. Ashman K. Pshezhetsky A.V. Mitchell G.A. J. Biol. Chem. 2004; 279: 40683-40689Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The recently identified TGH-2 exhibits high homology to TGH and a similar tissue distribution pattern (6Okazaki H. Igarashi M. Nishi M. Tajima M. Sekiya M. Okazaki S. Yahagi N. Ohashi K. Tsukamoto K. Amemiya-Kudo M. Matsuzaka T. Shimano H. Yamada N. Aoki J. Morikawa R. Takanezawa Y. Arai H. Nagai R. Kadowaki T. Osuga J. Ishibashi S. Diabetes. 2006; 55: 2091-2097Crossref PubMed Scopus (61) Google Scholar). Both TGH and TGH-2 are capable of hydrolyzing TG. However, they are much more efficient in hydrolyzing substrates esterified with short-chain fatty acids compared with TG esterified with long-chain fatty acids (6Okazaki H. Igarashi M. Nishi M. Tajima M. Sekiya M. Okazaki S. Yahagi N. Ohashi K. Tsukamoto K. Amemiya-Kudo M. Matsuzaka T. Shimano H. Yamada N. Aoki J. Morikawa R. Takanezawa Y. Arai H. Nagai R. Kadowaki T. Osuga J. Ishibashi S. Diabetes. 2006; 55: 2091-2097Crossref PubMed Scopus (61) Google Scholar, 7Lehner R. Verger R. Biochemistry. 1997; 36: 1861-1868Crossref PubMed Scopus (98) Google Scholar), and in vivo evidence for a role of these enzymes in lipolysis is lacking. Adipose triglyceride lipase (ATGL; official name, PNPLA 2 (patatin-like phospholipase domain containing protein-2); alternative names are desnutrin (8Villena J.A. Roy S. Sarkadi-Nagy E. Kim K.H. Sul H.S. J. Biol. Chem. 2004; 279: 47066-47075Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar), phospholipase A2ζ (9Jenkins C.M. Mancuso D.J. Yan W. Sims H.F. Gibson B. Gross R.W. J. Biol. Chem. 2004; 279: 48968-48975Abstract Full Text Full Text PDF PubMed Scopus (664) Google Scholar), and transport-secretion protein) is highly expressed in adipose tissue and specifically removes the first fatty acid from the TG molecule generating FFA and DG (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar). The drastic impairment of adipocyte lipolysis in ATGL inhibition studies in vitro indicates that the enzyme is responsible for most of the HSL-independent lipolytic activity (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar, 11Kershaw E.E. Hamm J.K. Verhagen L.A. Peroni O. Katic M. Flier J.S. Diabetes. 2006; 55: 148-157Crossref PubMed Scopus (286) Google Scholar). An essential role of ATGL in lipolysis became evident from studies in ATGL-deficient (ATGL-ko) mice (12Haemmerle G. Lass A. Zimmermann R. Gorkiewicz G. Meyer C. Rozman J. Heldmaier G. Maier R. Theussl C. Eder S. Kratky D. Wagner E.F. Klingenspor M. Hoefler G. Zechner R. Science. 2006; 312: 734-737Crossref PubMed Scopus (978) Google Scholar). ATGL-ko mice exhibited enlarged fat deposits and TG accumulation in multiple tissues. FFA release in response to isoproterenol is drastically reduced in ATGL-ko WAT, suggesting a key role of the enzyme in hormone-stimulated lipolysis. The most important activators of lipolysis are catecholamines, which increase cellular cAMP levels followed by the activation of protein kinase A (PKA) (13Holm C. Biochem. Soc. Trans. 2003; 31: 1120-1124Crossref PubMed Scopus (0) Google Scholar). PKA phosphorylates cytosolic HSL and the lipid droplet-associated protein, perilipin A. This process leads to the translocation of HSL to the lipid droplet where the enzyme gains access to TG stores (14Clifford G.M. Londos C. Kraemer F.B. Vernon R.G. Yeaman S.J. J. Biol. Chem. 2000; 275: 5011-5015Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Phosphorylation of both proteins is necessary for the initiation of HSL-mediated lipolysis (15Su C.L. Sztalryd C. Contreras J.A. Holm C. Kimmel A.R. Londos C. J. Biol. Chem. 2003; 278: 43615-43619Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). The regulation of ATGL activity appears to be quite different compared with that described for HSL. ATGL is not a target for PKA-mediated phosphorylation and is localized on the lipid droplet in the basal and hormone-stimulated state of the cell (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar). These observations suggest that ATGL is not activated by translocation to the lipid substrate as demonstrated for HSL. Instead, ATGL activity is regulated by an activator protein annotated as α/β-fold domain-containing protein 5 (ABHD5) (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar), also known as gene identification of or protein have been identified as for Chanarin-Dorfman C. F. F. B. A. R. H. A. J. M. M. J. Am. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). accumulate TG in multiple leading to the alternative lipid Patel A. G. T.M. G. J. PubMed Scopus Google Scholar, C. S. F. PubMed Scopus Google Scholar). of with to ATGL (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar) and of from the lipid droplet to the T. N. S. T. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). These that TG accumulation in is by ATGL activation (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). the TG accumulation in ATGL-ko mice (12Haemmerle G. Lass A. Zimmermann R. Gorkiewicz G. Meyer C. Rozman J. Heldmaier G. Maier R. Theussl C. Eder S. Kratky D. Wagner E.F. Klingenspor M. Hoefler G. Zechner R. Science. 2006; 312: 734-737Crossref PubMed Scopus (978) Google Scholar) and in a similar of and ATGL in and To the contribution of ATGL and HSL to murine adipose we additional lipases are involved in the hydrolysis of TG and is capable of lipolysis in the of demonstrate that TG hydrolysis is abolished both ATGL and HSL are to lipolysis in ATGL-deficient WAT, suggesting that ATGL the sole lipase activated by were on a and on a HSL-deficient and ATGL-deficient mice were by as described (4Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, G. Lass A. Zimmermann R. Gorkiewicz G. Meyer C. Rozman J. Heldmaier G. Maier R. Theussl C. Eder S. Kratky D. Wagner E.F. Klingenspor M. Hoefler G. Zechner R. Science. 2006; 312: 734-737Crossref PubMed Scopus (978) Google Scholar). used for were to of were by between and of murine expressed in and as described (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). of WAT of wild-type and HSL-ko mice and in containing on in A 2 an The WAT for at at The and used for TG hydrolase In of fat were and with were in containing fatty in the or of the HSL inhibitor 76-0079 at for this the fat were into and for a at of the were and for FFA and protein fat were with and in were the for TG and of substrate for the of TG hydrolase activity containing and as with a The substrate of of The cytosolic with different of with a inhibitor of HSL were with of the substrate in a at for The by of and of at for the in of the by the of lipolytic the by of containing and for and and The and The quantitatively and The lipid in and to with acid as were with and the to and and FFA were The by (4Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). by were considered for and ATGL and HSL the in WAT the of the HSL inhibitor we TG hydrolase activities in cytosolic preparations of WAT of ATGL-ko and HSL-ko mice in the and of in 76-0079 reduced the TG hydrolase activity in WAT of ATGL-ko mice in a inhibition at a of In contrast, 76-0079 had no effect on activity in HSL-ko that the inhibitor not ATGL or other lipases. HSL is to represent the rate-limiting DG hydrolase in WAT (4Haemmerle G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar). To determine 76-0079 DG accumulation in WAT, the lipolytic were to and the present in DG, MG, and FFA in inhibition of FFA release with increased DG The increased from to in the and of reduced DG not of reduced DG hydrolysis and of the high lipase activity present in WAT. the TG hydrolase activities in cytosolic preparations of WT, and HSL-ko WAT. with WT, HSL-ko and ATGL-ko WAT exhibited TG hydrolase activities and In the of the activities in and ATGL-ko WAT were reduced by and The activity in HSL-ko WAT not In with where both ATGL and HSL are inhibition of both enzymes in more than 95% of TG hydrolase TG hydrolase activities in cytosolic preparations of murine adipose tissue are of ATGL and HSL to lipolysis in the of ATGL activity is by the of (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). in the addition of to increased TG hydrolase activity in a to that in the cytosolic is not to ATGL To determine the effect of on TG hydrolase activity in WT, and ATGL-ko mice, cytosolic were with the TG substrate in the and of increased TG hydrolase activity in and HSL-ko preparations by and but not capable of the activity in ATGL-ko WAT. were in the of TG hydrolase activity in of and HSL-ko WAT by and and had no effect in ATGL-ko WAT. These demonstrate that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. In contrast, of ATGL-deficient with TG hydrolase activity by suggesting a effect of on HSL activity in in vitro FFA in WAT in the of ATGL and HSL of lipolytic activity in tissue preparations in vitro not the in we the of ATGL and HSL in lipolysis in organ cultures of WAT. To determine the effect of 76-0079 on fat from mice were with of the inhibitor in the or of in 76-0079 reduced the release in WAT of mice to basal levels at the inhibitor used inhibition of FFA release at 76-0079 the FFA release with fat of WT, and ATGL-ko The of fat with increased basal FFA release in with WT, FFA release in HSL-ko and ATGL-ko WAT reduced by and The addition of 76-0079 had no effect on FFA release in HSL-ko WAT, that the inhibitor is for HSL. In fat of and ATGL-ko mice, 76-0079 FFA release by and The FFA mobilization from ATGL-ko fat of the release in WAT WAT stores and FFA to the of the An of TG and hydrolysis may in as 2 and The of FFA is by the hydrolysis of TG stores in WAT. In FFA levels are and a between FFA levels and the of G. J. 2002; PubMed Scopus Google Scholar). studies in mice with of ATGL suggest that a of adipose lipolysis may in and (12Haemmerle G. Lass A. Zimmermann R. Gorkiewicz G. Meyer C. Rozman J. Heldmaier G. Maier R. Theussl C. Eder S. Kratky D. Wagner E.F. Klingenspor M. Hoefler G. Zechner R. Science. 2006; 312: 734-737Crossref PubMed Scopus (978) Google Scholar). lipolysis is to the of in and and adipose tissue lipases represent for the of ATGL-ko and HSL-ko mice a to FFA from adipose that both enzymes to the hydrolysis of TG (1Osuga J. Ishibashi S. Oka T. Yagyu H. Tozawa R. Fujimoto A. Shionoiri F. Yahagi N. Kraemer F.B. Tsutsumi O. Yamada N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 787-792Crossref PubMed Scopus (494) Google Scholar, G. Zimmermann R. Hayn M. Theussl C. Waeg G. Wagner E. Sattler W. Magin T.M. Wagner E.F. Zechner R. J. Biol. Chem. 2002; 277: 4806-4815Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, G. Lass A. Zimmermann R. Gorkiewicz G. Meyer C. Rozman J. Heldmaier G. Maier R. Theussl C. Eder S. Kratky D. Wagner E.F. Klingenspor M. Hoefler G. Zechner R. Science. 2006; 312: 734-737Crossref PubMed Scopus (978) Google Scholar, G. Zimmermann R. Strauss J.G. Kratky D. Riederer M. G. Zechner R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). However, it additional lipases that were capable of hydrolyzing TG. The present that ATGL and HSL are the rate-limiting enzymes in FFA The drastically reduced TG hydrolase activity in vitro and the FFA release from organ cultures of WAT in the of both ATGL and HSL activity demonstrate that other enzymes for these lipases. to ATGL and HSL in hydrolyzing TG ATGL the initial hydrolysis and DG for subsequent reactions. HSL DG into and FFA (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar). demonstrated in this study, FFA mobilization is present in organ cultures of ATGL-ko and HSL-ko WAT, that both enzymes are capable of TG and that both enzymes are to FFA mobilization in ATGL-ko WAT is suggesting that HSL is efficient in TG hydrolysis compared with ATGL or other enzymes are not capable of for HSL-mediated DG hydrolysis. efficient lipolysis in murine WAT is on the of DG by ATGL and subsequent hydrolysis of DG by HSL. The inhibition of lipolysis in WAT of mice an HSL-specific inhibitor in reduced DG catabolism and DG accumulation similar to that in HSL-ko FFA release from WAT cultures reduced by This be DG hydrolysis is fatty acids within the DG were in a a HSL inhibitor in mouse D. A. G. J. A. M. E. A. C.M. N. V. Gross R.W. Holm C. P. Diabetes. PubMed Scopus Google Scholar). In the FFA release from HSL-ko WAT This is with a in TG in HSL-ko WAT. This in efficient of FFA and be responsible for the in FFA release in HSL-ko adipose tissue R. Haemmerle G. Wagner Strauss J.G. Kratky D. Zechner R. J. Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and ATGL are essential of the lipolytic the leading to ATGL activation to be demonstrate that is not capable of TG hydrolase activity in ATGL-deficient WAT, suggesting that ATGL is the major target for CGI-58-mediated activation of lipolysis. in is by that PKA (13Holm C. Biochem. Soc. Trans. 2003; 31: 1120-1124Crossref PubMed Scopus (0) Google Scholar). In to HSL, ATGL is not a target for PKA-mediated and on lipid in the basal and the activated state an activation with the translocation of HSL (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar). However, the of is by In the basal is present on adipose lipid stores and with perilipin A V. A. C. A. S. L. G. Wang R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). A is present on lipid and TG stores from hydrolysis. it has been suggested that this is from HSL-mediated studies that perilipin A has a effect of the of HSL C. G. H. Contreras J.A. Kimmel A.R. Londos C. J. Cell Biol. 2003; PubMed Scopus Google Scholar, L. P. Wang Kraemer F.B. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. A.R. Londos C. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In response to PKA perilipin A is and is released from the lipid droplet V. A. C. A. S. L. G. Wang R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). This of to perilipin A represent an ATGL is in the basal is to perilipin in or activation of lipolytic is released from perilipin A and for ATGL in increased TG hydrolysis. However, additional are to the ATGL activity and the role of perilipin in this is capable of TG hydrolase activity not in WAT but also in adipose and liver (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). appears to be expressed and the tissue distribution pattern of from that of ATGL (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar, V. A. C. A. S. L. G. Wang R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). These observations the that an additional in lipid or other lipases than ATGL in tissues. in mouse adipose tissue may not the in adipose to ATGL, of the has been reported to TG and hydrolase activity as as activity J. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar). The mouse of is unknown R. Strauss J.G. Haemmerle G. Lass A. Zimmermann R. PubMed Scopus Google Scholar) the that additional lipases to adipose lipolysis. D. A. G. J. A. M. E. A. C.M. N. V. Gross R.W. Holm C. P. Diabetes. PubMed Scopus Google Scholar) in a HSL inhibitor to that HSL is the major lipase for hormone-stimulated ATGL in basal lipolysis. However, ATGL is highly expressed in (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar, D. A. G. J. A. M. E. A. C.M. N. V. Gross R.W. Holm C. P. Diabetes. PubMed Scopus Google Scholar) and as as the activity as demonstrated for mouse TG and is by (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). of present in from to ATGL, and a TG accumulation is in as as in ATGL-ko mice (12Haemmerle G. Lass A. Zimmermann R. Gorkiewicz G. Meyer C. Rozman J. Heldmaier G. Maier R. Theussl C. Eder S. Kratky D. Wagner E.F. Klingenspor M. Hoefler G. Zechner R. Science. 2006; 312: 734-737Crossref PubMed Scopus (978) Google Scholar, A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar). Together, these observations suggest that and ATGL similar in lipolysis in and studies suggested that TG accumulation in of in and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Res. Full Text Full Text PDF PubMed Google Scholar) reported from TG stores to as as increased in from a These in may be by the activities of ATGL and HSL. ATGL DG from TG, which be for In contrast, HSL-mediated lipolysis of TG not in DG accumulation of the high activity of HSL DG (10Zimmermann R. Strauss J.G. Haemmerle G. Schoiswohl G. Birner-Gruenberger R. Riederer M. Lass A. Neuberger G. Eisenhaber F. Hermetter A. Zechner R. Science. 2004; 306: 1383-1386Crossref PubMed Scopus (1451) Google Scholar). ATGL activation as in (16Lass A. Zimmermann R. Haemmerle G. Riederer M. Schoiswohl G. Schweiger M. Kienesberger P. Strauss J.G. Gorkiewicz G. Zechner R. Cell Metab. 2006; 3: 309-319Abstract Full Text Full Text PDF PubMed Scopus (653) Google Scholar) the of DG for in as a in increased In demonstrate that ATGL and HSL are quantitatively the most important lipases in murine adipose Additional known or unknown lipases appear to play only a minor role in TG hydrolysis. The of CGI-58-mediated of TG hydrolysis in ATGL-deficient WAT that ATGL the only adipose lipase activated by We E. Zechner for the