FAT SIGNALS - Lipases and Lipolysis

Cell Metabolism
Review
FAT SIGNALS - Lipases and Lipolysis

in Lipid Metabolism and Signaling
Rudolf Zechner,1,* Robert Zimmermann,1 Thomas O. Eichmann,1 Sepp D. Kohlwein,1 Guenter Haemmerle,1 Achim Lass,1
and Frank Madeo1
1Institute of Molecular Biosciences, University of Graz, Austria
*Correspondence: [email protected]
DOI 10.1016/j.cmet.2011.12.018
Open access under CC BY-NC-ND license.
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.
From Fat Ferments to Lipases: A Short Historical present in excess. FAs are essential as substrates for energy
Overview production and the synthesis of most lipids, including membrane
Lipolysis describes the hydrolysis of triacylglycerols (TGs), lipids and lipids involved in cellular signaling. Accordingly, all uni-
commonly referred to as fat. In the mid-19th century the great and multicellular organisms are able to synthesize FAs de novo
French physiologist Claude Bernard (Bernard, 1856) noted that (endogenous FAs) from carbohydrate and/or protein metabo-
the pancreatic juice of mammals was able to efficiently degrade lites. Despite their fundamental physiological importance, an
fat in the form of butter and oil. His observation led to the partial oversupply of FAs is highly detrimental. Increased concentra-
characterization of a pancreatic fat-splitting ferment by Balser tions of nonesterified FAs disrupt the integrity of biological
(Balser, 1882), Langerhans (Langerhans, 1890), and Flexner membranes, alter cellular acid-base homeostasis, and elicit the
(Flexner, 1897). The importance of lipolysis to general metabo- generation of harmful bioactive lipids. These effects, in turn,
lism became apparent when Whitehead (Whitehead, 1909) impair membrane function and induce endoplasmic reticulum
discovered that fat (TGs) could not enter cells in its unhydrolyzed (ER) stress, mitochondrial dysfunction, inflammation, and cell
form. The absolute requirement for TG hydrolysis for the cellular death. Collectively, these deleterious effects are subsumed
uptake or release of fatty acids (FAs) and glycerol defines three under the term lipotoxicity (Unger et al., 2010). As a countermea-
processes in vertebrate physiology where lipolysis is essential: sure, essentially all cells are able to detoxify nonesterified FAs by
gastrointestinal lipolysis mediates the catabolism of dietary fat; esterification with glycerol to yield inert TGs. Additionally, higher
vascular lipolysis is responsible for the hydrolysis of lipopro- organisms store FAs in a specialized organ (i.e., adipose tissue),
tein-associated TGs in the blood; and intracellular lipolysis cata- which supplies FAs to other high-demand tissues, such as
lyzes the breakdown of TGs stored in intracellular lipid droplets liver and muscle (exogenous FAs). The carefully regulated
(LDs) for subsequent export of FAs (from adipose tissue) or their balance of FA esterification and TG hydrolysis creates an effi-
metabolism (in nonadipose tissues). cient buffer system, allowing sufficient FA flux without nonphy-
Although fundamental aspects of lipolysis were understood siological increases in cellular nonesterified FA concentrations.
early on, it took more than a century to identify, isolate, and char- Moreover, FA cycling creates metabolic intermediates that can
acterize the main fat-splitting ferments, which have been called be utilized in anabolic processes or as extra- or intracellular
lipases since 1900. The chief lipolytic enzymes of the gastroin- signaling molecules.
testinal tract are lingual lipase, gastric lipase, pancreatic lipase, This review focuses on the catabolic branch of the FA cycle.
and pancreatic lipase-related proteins 1, 2, and 3. Vascular TG We summarize recent advances in understanding the enzymatic
hydrolysis depends on lipoprotein lipase (LPL) and hepatic TG mechanisms of the lipolytic process and the (patho)physiological
lipase. Pancreatic and vascular lipases are structurally related impact of lipolysis on energy homeostasis and cellular signaling.
and prototypic for the pancreatic lipase family. Intracellular
lipolysis of TGs involves neutral (pH-optimum around pH 7) Neutral Lipolysis: Three Steps, Three Enzymes
and acid lipases present in lysosomes (pH optimum between Neutral hydrolysis of TGs to FAs and glycerol requires three
pH 4–5). Well-characterized neutral TG hydrolases include consecutive steps that involve at least three different enzymes:
adipose triglyceride lipase (ATGL) and hormone-sensitive lipase ATGL catalyzes the initial step of lipolysis, converting TGs to
(HSL), whereas lysosomal acid lipase (LAL) is the most important diacylglycerols (DGs); HSL is mainly responsible for the hydro-
lipase in lysosomes. Besides an active serine site, these lysis of DGs to monoacylglycerols (MGs) and MG lipase (MGL)
enzymes share no obvious structural homologies and are unre- hydrolyzes MGs. In adipose tissue, ATGL and HSL are respon-
lated to the pancreatic lipase family. sible for more than 90% of TG hydrolysis (Schweiger et al.,
Lipolysis is the catabolic branch of the FA cycle that provides 2006). Although most nonadipose tissues also express ATGL
FAs in times of metabolic need and removes them when they are and HSL, expression levels are low in some tissues, raising the
Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 279

Cell Metabolism
Review
question of whether other lipases are additionally required for role of AMPK in the regulation of lipolysis has been controversial,
efficient lipolysis. with data showing that AMPK induces (Gaidhu et al., 2009; Yin
ATGL: the Initial Step of Lipolysis et al., 2003), inhibits (Daval et al., 2005; Gauthier et al., 2008),
ATGL is the newest member of the lipolytic enzyme trio. The or has no effect (Chakrabarti et al., 2011) on lipolysis. Interest-
enzyme, first described in 2004 (Jenkins et al., 2004; Villena ingly, in the nematode Caenorhabiditis (C.) elegans, AMPK-
et al., 2004; Zimmermann et al., 2004), belongs to the family mediated phosphorylation of ATGL-1 (the worm ortholog of
patatin domain-containing proteins including nine human and mammalian ATGL) at different phosphorylation sites inhibits TG
eight murine members. The patatin domain was originally hydrolysis (Narbonne and Roy, 2009), delays the consumption
discovered in lipid hydrolases of the potato and other plants of TG stores, and prolongs life span during the stress-induced
and named after the most abundant protein of the potato tuber, dauer larval stage. The functional role of the second phosphory-
patatin. Because some members of the family act as phospholi- lation site (S430) is not known.
pases, the proteins were officially named patatin-like phospholi- ATGL requires a coactivator protein, comparative gene
pase domain-containing protein A1 to A9 (PNPLA1–9) (Wilson identification-58 (CGI-58), for full hydrolase activity (Lass et al.,
et al., 2006). Unfortunately, this name is misleading because it 2006). CGI-58 was originally discovered in a screen comparing
implies that all members of this family are phospholipases. the proteomes of humans and C. elegans. The gene is now
However, several PNPLA proteins have only minor or no phos- officially named a/b hydrolase domain-containing protein-5
pholipase activity. A more appropriate designation for the family (ABHD5), owing to the presence of an a/b hydrolase domain
should be considered. commonly found in esterases, thioesterases, and lipases. How-
ATGL (officially annotated as PNPLA2) preferentially hydro- ever, CGI-58 is unlikely to exhibit hydrolase activity due to the
lyzes TGs. Orthologous enzymes are found in essentially all fact that asparagine-153 (N153) in CGI-58 replaces a nucleophilic
eukaryotic species, including vertebrates, invertebrates, plants, serine residue that is required in the active site of enzymatically
and fungi. The human protein comprises 504 amino acids (AA). functional members of the esterase/thioesterase/lipase family.
In analogy with patatin, the active site of the enzyme contains Interestingly, substitution of N153 by serine does not convert
an unusual catalytic dyad (S47 and D166) within the patatin CGI-58 into a lipid hydrolase for TGs, DGs, MGs, or short
domain (Rydel et al., 2003). This domain comprises 180 AA FA-glycerol esters (A. Lass et al., unpublished). In the epidermis
and is embedded within a 250 AA a b a sandwich structure of the skin, CGI-58 may also stimulate another, currently
at the protein’s NH2-terminal half. The COOH-terminal half has unknown, TG hydrolase distinct from ATGL (Radner et al.,
a predominantly regulatory function and contains a predicted 2010). Importantly, two laboratories showed that CGI-58, at least
hydrophobic region for LD binding (Duncan et al., 2010; in vitro, exhibits enzymatic activity as an acylCoA-dependent
Schweiger et al., 2008). Loss of this region increases the specific acylglycerol-3-phosphate acyltransferase (AGPAT) (Ghosh
in vitro activity of ATGL against artificial TG substrates but blunts et al., 2008; Montero-Moran et al., 2010). The physiological role
the intracellular activity due to the inability of the truncated of this activity requires clarification. It may affect phosphatidic
enzyme to bind to cellular LDs. acid or lysophosphatidic acid signaling (Brown et al., 2010).
Regulation of ATGL Recently, Yang et al. (Yang et al., 2010b) discovered a specific
Regulation of ATGL expression and enzyme activity is complex peptide inhibitor for ATGL. The protein was originally identified in
(Lass et al., 2011). ATGL mRNA expression is elevated by perox- blood mononuclear cells to act at the G0 to G1 transition of the
isome proliferator-activated receptor (PPAR) agonists, glucocor- cell cycle. Consistent with this function, it was named G0G1
ticoids, and fasting, whereas insulin and food intake decrease switch protein 2 (G0S2). Human and murine G0S2 have a pre-
expression. More recently, it was shown that mTOR complex dicted primary structure of 103 AA. The protein is found in
1-dependent signaling reduces ATGL mRNA levels (Chakrabarti many tissues, with highest concentrations in adipose tissue
et al., 2010). Conversely, activation of FoxO1 by SIRT1-mediated and liver. Consistent with lipase activities, G0S2 expression is
deacetylation activates lipolysis by increasing ATGL mRNA very low in adipose tissue during fasting but increases after
levels. SIRT1 silencing has the opposite effect (Chakrabarti feeding (Yang et al., 2010b). Conversely, fasting or PPARa-agon-
et al., 2011). The abundance of ATGL (and HSL) mRNA does ists increase hepatic G0S2 expression (Zandbergen et al.,
not always correlate with cellular lipase activity. For example, 2005). The protein localizes to multiple cellular compartments,
isoproterenol and tumor necrosis factor-a reduce ATGL (and including LDs, cytoplasm, ER, and mitochondria. The different
HSL) mRNA levels in adipocytes (Kralisch et al., 2005) but, localizations may reflect multiple functions for G0S2 in regulating
conversely, stimulate lipase activities and FA and glycerol lipolysis, the cell cycle, and, possibly, apoptosis via its ability
release. The discrepancy between enzyme mRNA levels and to interact with the mitochondrial antiapoptotic factor Bcl2
activities is explained by the extensive posttranslational regula- (Welch et al., 2009). In vitro, LD binding and inhibition of ATGL
tion of ATGL and HSL (discussed below). Thus, cellular lipase depend on a physical interaction between the NH2-terminal
mRNA levels are inadequate as indicators of enzyme activities. region of G0S2 (involving AA 27–42) and the patatin domain of
At least two serine residues in ATGL can be phosphorylated ATGL (Lu et al., 2010). Elucidation of whether G0S2 also regu-
(S406 and S430 in the murine enzyme) (Bartz et al., 2007). In lates tissue-specific lipolysis in vivo will require the characteriza-
contrast to HSL (see below), ATGL modification is not protein tion of G0S2 transgenic and knockout mouse models.
kinase A (PKA)-dependent (Zimmermann et al., 2004). Instead, LD-associated proteins participate in the CGI-58-mediated
the laboratory of H.-S. Sul recently showed that AMP-activated regulation of ATGL (Figure 1, left). In hormonally nonstimulated
kinase (AMPK) phosphorylates S406, leading to increased white and brown adipocytes, perilipin-1 interacts with CGI-58,
hydrolytic activity of murine ATGL (Ahmadian et al., 2011). The preventing its binding to and, thus, induction of ATGL. Upon
280 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

Cell Metabolism
Review
2008). PEDF is a widely expressed 50 kD protein of the noninhi-

bitory serpin family of serine protease inhibitors (Filleur et al.,
2009). It exhibits a large spectrum of bioactivities, including anti-
angiogenic, antitumorigenic, neuroprotective, antioxidative, and
antiinflammatory effects. PEDF binds to ATGL and activates its
enzymatic activity (Borg et al., 2011; Notari et al., 2006). Although
the mechanism remains to be clarified, ATGL activation by PEDF
may be involved in the pathogenesis of insulin resistance and the
development of hepatosteatosis.
Another important aspect of ATGL regulation was identified by
genetic analyses of LD formation in Drosophila (D.) melanogaster
L2 cells (Beller et al., 2008; Guo et al., 2008). Compelling results
showed that ATGL delivery to LDs requires functional vesicular
transport. In the absence of essential protein components of
the transport machinery, such as ADP-ribosylation factor 1
(ARF1), small GTP-binding protein 1 (SAR1), the guanine-nucle-
otide exchange factor Golgi-Brefeldin A resistance factor
Figure 1. Lipolysis in Adipose and Oxidative Tissues during Fasting
In adipose tissues, beta-adrenergic stimulation of lipolysis leads to the (GBF1), or deficiency of the coatamer protein coat-complex I
consecutive hydrolysis of TG and the formation of FAs and glycerol. The and II, ATGL translocation to LDs is blocked and the enzyme
process requires three enzymes: ATGL cleaves the first esterbond in TGs, HSL remains associated with the ER (Soni et al., 2009). The process
hydrolyzes DGs, and MGL MGs. For full hydrolytic activity, ATGL interacts with
its coactivator protein CGI-58, whereas HSL is phosphorylated, translocates requires physical binding of ATGL to GBF1 (Ellong et al., 2011).
to the LD, and interacts with phosphorylated PLIN-1. Expression of the ATGL HSL: the Main DG Lipase
inhibitor G0S2 during fasting is low in adipose and high in oxidative tissues In the early 1960s, it was noted that a lipolytic activity present in
(e.g., liver). In oxidative tissues PLIN-1 is not present on LDs. Instead, PLIN-5 is
expressed and interacts with both ATGL and CGI-58, facilitating LD localiza-
adipose tissue was induced by hormonal stimulation. A land-
tion of these proteins. ATGL, adipose triglyceride lipase; CGI-58, comparative mark paper published by D. Steinberg’s group (Vaughan et al.,
gene identification-58; DG, diacylglycerol; FA, fatty acid; G, glycerol; G0S2, 1964) described the isolation and characterization of both HSL
G0/G1 switch gene 2; HSL, hormone-sensitive lipase; MG, monoacylglycerol; and MGL. Although this classic work originally noted that HSL
MGL, monoglyceride lipase; PLIN-1, perilipin-1; PLIN-5, perilipin-5; TG, tri-
acylglycerol. is a much better DG hydrolase than TG hydrolase, standard
textbook knowledge perpetuated the conclusion that HSL was
rate-limiting for the catabolism of fat stores in adipose and
b-adrenergic stimulation, protein kinase A (PKA) phosphorylates many nonadipose tissues. This view required revision when
perilipin-1 at multiple sites, including the critical serine-517 HSL-deficient mice efficiently hydrolyzed TGs (Osuga et al.,
residue, causing the release of CGI-58. The effector then binds 2000). HSL-deficient mice showed no signs of TG accumulation
and stimulates ATGL (Granneman et al., 2009; Miyoshi et al., in either adipose or nonadipose tissues; instead, they accumu-
2007). Thus, b-adrenergic stimulation of PKA induces ATGL alted large amounts of DGs in many tissues, suggesting that
activity by phosphorylation of perilipin-1 and not by direct in vivo the enzyme was more important as a DG- than a TG-
enzyme phosphorylation. Consistent with this model, frameshift hydrolase (Haemmerle et al., 2002). Although originally some-
mutants of perilipin-1 in humans (L404fs and V398fs) fail to bind what controversial (Rydén et al., 2007), it is now accepted that
CGI-58, leading to unrestrained lipolysis, partial lipodystrophy, ATGL is responsible for the initial step of lipolysis in human
hypertriglyceridemia, and insulin resistance (Gandotra et al., adipocytes, and that HSL is rate-limiting for the catabolism of
2011). ATGL-mediated TG hydrolysis in nonadipose tissues DGs (Bezaire et al., 2009). In addition to DGs, HSL also hydro-
with high FA oxidation rates, such as muscle and liver, follows lyzes ester bonds of many other lipids (e.g., TGs, MGs, choles-
another mechanism. In these tissues, perilipin-1 is replaced by teryl esters, and retinyl esters) and short-chain carbonic acid
perilipin-5 (Figure 1, right). During fasting, perilipin-5 recruits esters (Fredrikson et al., 1986).
both ATGL and CGI-58 to LDs by direct binding of the enzyme The HSL expression profile essentially mirrors that of ATGL.
and its coactivator. Formation of the ternary complex involves Highest mRNA and protein concentrations are found in white
the COOH-terminal region of perilipin-5 (AA 200–463) (Granne- adipose tissue (WAT) and brown adipose tissue (BAT); low
man et al., 2011). The role of perilipin-5 within this complex is still expression is detected in many other tissues, including muscle,
a matter of discussion. Recent data suggest that it is involved in testis, steroidogenic tissues, and pancreatic islets (Holm et al.,
the interaction of LDs with mitochondria and inhibits ATGL- 2000). Alternative exon usage leads to tissue-specific differ-
mediated TG hydrolysis (Wang et al., 2011). Whether perilipins-2, ences in mRNA and protein size (Holst et al., 1996). In adipose
-3, and -4 also interact with either ATGL or CGI-58 is disputed. tissue, the HSL protein comprises 768 AA. Unlike ATGL, with
Overexpression of perilipin-2 in hepatocyte cell lines inhibits orthologous enzymes found across all eukarya, HSL is less ubiq-
ATGL activity by restricting its physical access to LDs. Direct uitous phylogenetically. For example, no HSL ortholog is known
protein-protein interaction is probably not required (Bell et al., in birds, C. elegans, D. melanogaster, and Saccharomyces (S.)
2008; Listenberger et al., 2007). cerevisiae. Interestingly, the closest structural relatives to HSL
Recently, several groups reported that pigment epithelium- are found in prokaryotes (e.g., lipase 2 in Moraxella TA144)
derived factor (PEDF) induces TG hydrolysis in adipose tissue, (Langin et al., 1993). Functional studies have delineated in HSL
muscle, and liver, via ATGL (Borg et al., 2011; Chung et al., an NH2-terminal lipid-binding region, the a/b hydrolase fold

Cell Metabolism
Review
domain including the catalytic triad, and the regulatory module (unpublished data). MGL received significant attention following
containing all known phosphorylation sites important for regula- the realization that glycerophospholipid-derived MG 2-arachido-
tion of enzyme activity (Holm et al., 2000). nylglycerol (2-AG) is a major agonist for endocannabinoid
Regulation of HSL signaling and is inactivated by the hydrolytic activity of MGL
Since ATGL and HSL hydrolyze TGs in a coordinated manner, it is (see MG-signaling, below). The enzyme is ubiquitously ex-
not unexpected that they share many regulatory similarities. In pressed with highest expression levels in adipose tissue. The
adipose tissue, HSL enzyme activity is strongly induced by importance of MGL for efficient degradation of MGs was recently
b-adrenergic stimulation, whereas insulin has a strong inhibitory confirmed in mutant mouse models (Chanda et al., 2010; Schlos-
effect. The mechanisms of enzyme regulation, however, differ burg et al., 2010; Taschler et al., 2011). Lack of MGL impairs
markedly between the two lipases. While b-adrenergic stimula- lipolysis and is associated with increased MG levels in adipose
tion regulates ATGL primarily via recruitment of the coactivator and nonadipose tissues alike.
CGI-58 (see above), HSL is a major target for PKA-catalyzed MGL shares homology with esterases, lysophospholipases,
phosphorylation (Strålfors and Belfrage, 1983). Other kinases, and haloperoxidases, and contains a consensus GXSXG motif
including AMPK, extracellular signal-regulated kinase, glycogen within a catalytic triad (S122, A239, and H269 for mouse MGL)
synthase kinase-4, and Ca2+/calmodulin-dependent kinase, that is typical of lipases and esterases. Very recently, the crystal
also phosphorylate HSL to modulate its enzyme activity (Lass structure of MGL was solved (Bertrand et al., 2010; Labar et al.,
et al., 2011). The enzyme has at least five potential phosphoryla- 2010). The enzyme exhibits the classic fold of the a/b hydrolases,
tion sites, of which S660 and S663 appear to be particularly crystallizes as a dimer, and exhibits a wide, hydrophobic access
important for hydrolytic activity (Anthonsen et al., 1998). Enzyme to the catalytic site. An apolar helix-domain lid covers the active
phosphorylation affects enzyme activity moderately (an approxi- site and mediates the interaction of MGL with membrane struc-
mate 2-fold induction). For full activation, HSL must gain access tures and the recruitment of substrate.
to LDs, which, in adipose tissue, is mediated by perilipin-1. Simul- Other Lipases Implicated in TG Catabolism
taneously with HSL, PKA also phosphorylates perilipin-1 on six Experiments with ATGL-deficient mice and small-molecule HSL
consensus serine residues. As a result, HSL binds to the NH2- inhibitors revealed that ATGL and HSL are responsible for more
terminal region of perilipin-1, thereby gaining access to LDs than 90% of the lipolytic activity in WAT and cultured adipocytes
(Miyoshi et al., 2007; Shen et al., 2009; Wang et al., 2009). (Schweiger et al., 2006). In nonadipose tissues, the contribution
Together, HSL-phosphorylation and enzyme translocation to of other neutral lipases to the catabolism of stored TGs may be
LDs coupled with ATGL activation by CGI-58 result in a more more prominent. For example, in the liver of fasted mice, ATGL
than 100-fold increase in TG hydrolysis in adipocytes (Figure 1). accounts for less than 50% of neutral TG hydrolase activity
This activation process is modulated by other factors. For (Reid et al., 2008). This activity is physiologically important
example, receptor-interacting protein 140 (RIP-140) was shown because ATGL-deficient mice develop hepatosteatosis (Haem-
to induce lipolysis by binding to perilipin-1, increasing HSL merle et al., 2006; Wu et al., 2011). However, the pronounced
translocation to LDs, and activating ATGL via CGI-58 dissociation remaining activity of hepatic TG hydrolase(s) in ATGL-deficient
from perilipin-1 (Ho et al., 2011). In nonadipose tissues, such as mice indicates that other lipases contribute to the highly dynamic
skeletal muscle, HSL is activated by phosphorylation in response turnover of TGs. This view is supported by the observation that
to adrenaline and muscle contraction (Watt et al., 2006). These mice lacking ATGL in the liver have no apparent defect in VLDL
tissues lack perilipin-1, and it remains to be determined which biogenesis (Wu et al., 2011), although assembly and secretion
alternative mechanisms regulate HSL access to LDs. of hepatic VLDL particles require substantial mobilization of
Insulin-mediated deactivation of lipolysis is associated with hepatic TG stores. Because HSL is also poorly expressed in
transcriptional downregulation of ATGL and HSL expression hepatocytes, the existence of alternative hepatic DG hydrolases
(Kershaw et al., 2006; Kralisch et al., 2005). Additionally, insulin seems likely.
signaling results in phosphorylation and activation of various Several members of the carboxylesterase/lipase family and
phosphodiesterase (PDE) isoforms by PKB/AKT (Enoksson the PNPLA family have been suggested as potential TG hydro-
et al., 1998), PDE-catalyzed hydrolysis of cAMP, and inhibition lases. One of them, carboxyl esterase-3/triglyceride hydrolase-1
of PKA. These actions halt lipolysis by preventing phosphoryla- (Ces-3/Tgh-1, ortholog of human Ces-1), has gained major
tion of both HSL and perilipin-1, activation and translocation interest because the recent characterization of Ces-3/Tgh-1-
of HSL, and activation of ATGL by CGI-58. In addition to its deficient mice provided compelling evidence that the enzyme
peripheral action, insulin also acts centrally via the sympathetic participates in the assembly and secretion of hepatic VLDL
nervous system to inhibit lipolysis in WAT. Elegant studies by (Wei et al., 2010). How this biological function conforms to
Scherer and coworkers (Scherer et al., 2011) showed that the strict luminal localization of Tgh-1 in the ER remains to be
increased insulin levels in the brain inhibit HSL and perilipin elucidated.
phosphorylation, leading to reduced HSL and ATGL activities. Structural relatives of ATGL within the PNPLA family were also
MGL: the Final Step in Lipolysis considered as potential TG hydrolases. For example, PNPLA4
MGL is considered to be the rate-limiting enzyme for the break- and -5 exhibit TG-hydrolase, DG transacylase, and retinylester
down of MGs derived from extracellular TG hydrolysis (by LPL), hydrolase activity in vitro (Kienesberger et al., 2009b). Whether
intracellular TG hydrolysis (by ATGL and HSL), and intracellular these activities are also relevant in vivo remains to be deter-
phospholipid hydrolysis (by phospholipase C and membrane- mined. The member with highest homology to ATGL is adiponu-
associated DG lipase a and b). The enzyme localizes to cell trin (PNPLA3), with over 50% AA identity within the patatin
membranes, cytoplasma (Sakurada and Noma, 1981), and LDs domain. Adiponutrin was originally discovered as a nutritionally

Cell Metabolism
Review
regulated adipose-specific transcript of unknown function portions of cytoplasmic LDs (autolipophagosomes). The autoli-
(Baulande et al., 2001). Interest in adiponutrin increased tremen- pophagosomes ultimately fuse with lysosomes, where their lipid
dously when H. Hobbs and colleagues found a strong genetic content is degraded by LAL. Consistent with a role for lipo-
association between a nonsynonymous AA change (I148M) in autophagy during starvation, Singh et al. found that deletion of
adiponutrin and susceptibility to develop nonalcoholic fatty liver Atg7 causes lipid accumulation in the liver. Chronic fat feeding
disease (NAFLD) (Romeo et al., 2008). Several other groups impairs the autophagic removal of lipid stores in the liver,
confirmed and extended this important finding by showing prompting excessive hepatic lipid deposition. Hotamisligil and
robust associations of I148M with alcoholic- and nonalcoholic colleagues (Yang et al., 2010a) strengthened these findings by
liver disease, hepatic fibrosis, and liver cirrhosis (Krawczyk showing that hepatic Atg7 expression is severely impaired in
et al., 2011; Tian et al., 2010; Yuan et al., 2008). The close simi- ob/ob mice, contributing to the hepatosteatosis in these animals.
larity to ATGL as well as the presence of conserved structural Liver fat accumulation was reduced by liver-specific restoration
motifs typical for lipases/esterases (a b a sandwich structure of Atg7 expression.
and the GXSXG motif within a catalytic dyad) suggest a lipase While the effects of autophagy in genetically obese mice and in
function for adiponutrin. In accordance with this assumption, mice fed high-fat diets seem consistent, a role for autophagy in
several groups reported that adiponutrin acts as a TG hydrolase lipid metabolism of normal mice remains controversial. First,
and additionally exhibits DG transacylase activity (He et al., autophagy appears to be predominantly relevant in the liver after
2010; Huang et al., 2011; Jenkins et al., 2004; Lake et al., abnormally long fasting periods. Normally, during shorter fasting
2005). However, the expression profile generated in response periods the hepatic fat content increases due to the induction of
to fasting/feeding and the induction of adiponutrin gene expres- adipose tissue lipolysis and increased FA supply to the liver. It is
sion by SREBP1a/c and CHREBP argued against an in vivo role unlikely that autophagy would be induced under this condition.
of adiponutrin in lipolysis (Dubuquoy et al., 2011; He et al., 2010; Consistent with this prediction, Hotamisligil and colleagues did
Kershaw et al., 2006; Lake et al., 2005). Pinpointing the functional not observe hepatic steatosis or changes in serum TG or FA
role of adiponutrin was also confounded when PNPLA3-deficient levels in lean mice following siRNA-mediated suppression of
mice exhibited no detectable phenotype in lipid, lipoprotein, or Atg7, arguing that lipoautophagy is not involved (Yang et al.,
energy metabolism (Basantani et al., 2011; Chen et al., 2010). 2010a). Second, hepatosteatosis as a result of Atg7 deficiency
Overexpression of the I148M variant of adiponutrin caused TG was observed in some but not all studies. Although Atg7 defi-
accumulation (He et al., 2010), whereas overexpression of ciency leads to severe liver enlargement, it is controversial
wild-type adiponutrin in the liver created no obvious phenotype whether TGs accumulate. In fact, Uchiyama and colleagues
(He et al., 2010). Overall, the biochemical and (patho)physiolog- reported that hepatic Atg7 deletion upon starvation inhibits LD
ical function of adiponutrin remains unclear. formation both in vivo and in vitro, which leads to a lower hepatic
TG content (Shibata et al., 2009, 2010). Consistent with a role
Autophagy and Acid Lipolysis for LC3 in LD formation, RNAi-mediated suppression of LC3-
In addition to classical lipolysis by extralysosomal neutral expression prevented LD formation in a panel of different
lipases, TGs and cholesteryl esters can also be hydrolyzed by (hepatic and nonhepatic) cell lines. Interestingly, LC3 localized
LAL. LAL is thought to catabolize primarily lipoprotein-associ- to the surface of LDs, and the authors argued that lipidation of
ated lipids subsequent to their receptor-mediated endocytosis LC3 by phosphatidylethanolamine (formation of LC3-II), which
and fusion with lysosomes. Accordingly, the contribution of is the initial step in autophagosome formation during autophagy,
LAL activity to lipolysis of intracellular LDs was not considered is also required for LD formation. A potential role of autophagy in
relevant. Given the lysosomal localization of LAL, it was not intu- lipogenesis but not in lipolysis is consistent with the finding that
itively obvious how lipids from LDs would enter lysosomes. external administration of FAs induces, rather than inhibits, auto-
Addressing this, Singh and colleagues reported compelling phagy when LDs are formed in the fasting liver (Tang et al., 2011).
evidence linking lipolysis to macroautophagy (Singh et al., A role for autophagy in lipogenesis also became evident from
2009a). Macroautophagy is a lysosomal pathway that degrades analysis of adipose tissue in Atg7-deficient mice. Assuming
superfluous or damaged organelles as well as cytoplasmic inclu- a lipolytic defect, we speculated that ablation of autophagy in
sions, such as misfolded protein aggregates (Levine and adipocytes would result in an obese phenotype (Zechner and
Kroemer, 2008). These cytoplasmic cargos are trapped inside Madeo, 2009). In contrast, however, adipose-specific knockout
double-membrane vesicles (autophagosomes) that ultimately of Atg7 resulted in lean mice with reduced adipose mass,
fuse with lysosomes, where their contents are degraded. enhanced insulin sensitivity, and an elevated rate of b-oxidation
Subsequently, lipids and AA are released into the cytosol and (Singh et al., 2009b). The adipocytes contained smaller, multiloc-
contribute to energy and AA supply in times of starvation. ular LDs and exhibited normal basal lipolysis. In line with this,
Thus, along with lipolysis, macroautophagy is one of two inhibition of autophagy in cultured adipocytes using Atg7 siRNA
conserved responses to organismal and cellular fasting. blocked TG accumulation (Singh et al., 2009b). Taken together,
Singh and coworkers (Singh et al., 2009a) found that, in addi- these data argue for a currently poorly understood role of auto-
tion to conventional neutral lipases, autophagy of LDs is required phagy in the biogenesis of LDs. Interestingly, while adipose-
for fasting-induced lipolysis in murine liver and cultured hepato- specific Atg7-deficient mice display reduced WAT mass, BAT
cytes. They showed that recruitment of microtubule-associated mass increases (Baerga et al., 2009; Singh et al., 2009b). Singh
protein 1 light chain 3 (LC-3) and formation of a regional et al. argued that inhibition of white adipocyte differentiation
membrane through conjugation of autophagy-related protein 7 may lead to a defect in lipogenesis or that blocked autophagy
(Atg7) gives rise to double-membrane vesicles that engulf may promote WAT to BAT transdifferentiation.

Cell Metabolism
Review
In summary, autophagy may have pleiotropic roles in lipid

metabolism depending on the cell- or tissue-type. In the liver,
autophagy may contribute to lipolysis under a high-fat diet or pro-
longed fasting. Alternatively, autophagy may promote lipid accu-
mulation under normal fasting conditions. In WAT, autophagy
appears to be involved in adipocyte differentiation and lipogen-
esis but not in lipolysis. The role of autophagy in the breakdown
of fat in other lipolytically active tissues, such as muscle, macro-
phages, and steroidogenic cells remains to be determined.
Lipolysis: A Role in Lipid-Mediated Signaling?

Textbook knowledge tells us that TGs are the most efficient way
to store large amounts of FAs as an energy reserve. Consistent
with this view, cellular LDs were long seen as a relatively inert
storage depot for fat in adipose tissue that is mobilized at times Figure 2. ATGL-Mediated Lipolysis Is Required for PPAR Signaling
and OXPHOS
of increased energy demand. This view changed when it was
Fatty acids from exogenous or endogenous sources are activated to acyl-
realized that 1) LDs are present in essentially all cell types, CoAs, which are subject to mitochondrial oxidation or TG formation. ATGL-
including those for which mere energy storage does not seem mediated lipolysis of TG generates lipolytic products (FA and DG), which may
to be the main purpose; 2) LDs, particularly in nonadipose act directly (e.g., FA) or after conversion (e.g., DG to phospholipids) as ligands
for nuclear receptors (for details see text). Activation of nuclear receptor
tissues, undergo very dynamic changes of formation and degra- PPARa via lipolytic cleavage of TGs is required for normal mitochondrial
dation; and 3) LDs represent a reservoir of bioactive lipids and function and OXPHOS. In ATGL-deficient mice, defective PPARa activation
lipid-derived hormones in adipose and nonadipose tissues. and OXPHOS can be restored by treatment with PPARa agonists. ATGL,
adipose triglyceride lipase; CD36, cluster of differentiation 36; DG, diac-
A role for neutral lipid metabolism in signaling gained substan- ylglycerol; FA, fatty acid; FATP, fatty acid transport protein; LPL, lipoprotein
tial interest when it was noted that increased cellular TG concen- lipase; OXPHOS, oxidative phosphorylation; PPARa/d, peroxisome pro-
trations are strongly associated with insulin resistance in skeletal liferator-activated receptor alpha/delta; RA, retinoic acid; RXR, retinoid X
receptor; TG, triacylglycerol.
muscle and liver (Cohen et al., 2011; Kelley et al., 2002). The rela-
tively inert nature of TGs makes it unlikely that they interfere
directly with insulin signaling. The concept that TGs themselves and -2, and PPARd (also designated PPARb). PPARa and
are not the culprit was also supported by the so-called athletes’ PPARd are highly expressed in oxidative tissues and regulate
paradox. Endurance athletes accumulate more TGs in LDs of genes involved in substrate delivery, substrate oxidation, and
skeletal myocytes than do untrained individuals, yet their muscle oxidative phosphorylation (OXPHOS). In contrast, PPARg is
is highly insulin-sensitive. Similarly, mice that lack ATGL accu- more important in lipogenesis and lipid synthesis, with highest
mulate large amounts of fat in numerous tissues (including skel- expression levels in WAT. The full transcriptional activity of
etal muscle, cardiac muscle, liver, kidneys, and macrophages) PPARs requires the binding of cognate lipid ligands, heterodime-
but exhibit increased insulin sensitivity (Haemmerle et al., rization with another nuclear receptor (retinoid-X receptor, RXR),
2006; Kienesberger et al., 2009a). Increased insulin sensitivity and interaction with a number of transcriptional coactivators,
is observed despite the fact that ATGL-deficiency leads to an including PPARg coactivator-1 (PGC-1). In addition to FAs, other
insulin-secretion defect in pancreatic islets (Peyot et al., 2009). lipid ligands also have been described to activate PPARs, such
In humans, ATGL-deficiency leads to neutral lipid storage as acyl-CoAs, glycerol-phospholipids, and eicosanoids.
disease with myopathy (NLSDM), with a similar lipid phenotype FAs involved in signaling originate from import of exogenous
as observed in ATGL-deficient mice (Fischer et al., 2007). FAs (from circulating FA-albumin complexes or from LPL-medi-
Patients lacking the ATGL coactivator CGI-58 not only develop ated hydrolysis of plasma VLDL and chylomicrons) or from
neutral lipid storage disease but also exhibit a severe skin defect endogenous de novo synthesis. Recently it was shown that
(neutral lipid storage disease with ichthyosis, NLSDI) (Lefèvre neither source of FA can generate PPAR ligands directly; rather,
et al., 2001). To date, defective pancreatic insulin production a cycle of FA esterification and rehydrolysis is required (Haem-
and alterations in insulin sensitivity have not been reported in merle et al., 2011) (Figure 2). As a consequence, lipolysis-
patients with NLSDM or NLSDI. In conclusion, cellular TG impaired ATGL-deficient mice exhibit a severe defect in PPARa
content can be a marker of insulin resistance under certain phys- signaling in oxidative tissues such as liver (Ong et al., 2011),
iological conditions but is not a regulator of insulin signaling. macrophages (Chandak et al., 2010), and BAT (Ahmadian
et al., 2011). The most dramatic phenotype is observed in
Lipolysis-Derived FAs and PPAR Signaling cardiac muscle (Haemmerle et al., 2011). The reduced expres-
Besides their powerful role as energy substrates and precursors sion of PPARa target genes in ATGL knockout animals causes
of other lipids, FAs are directly involved in cellular signaling path- severe mitochondrial dysfunction, decreased rates of substrate
ways and regulation of gene transcription. FAs or FA derivatives oxidation and OXPHOS, massive cardiac lipid accumulation,
can bind to and activate members of the nuclear receptor family and lethal cardiomyopathy within a few months after birth. HSL
of transcription factors that control the expression of genes deficiency is also associated with moderately decreased PPARa
involved in lipid and energy homeostasis and inflammation. target-gene expression but does not generate a comparable
The best-studied FA-activated nuclear receptors are the PPARs. cardiac phenotype, indicating the specific importance of ATGL
The PPAR family consists of four members: PPARa, PPARg-1 activity in the generation of PPARa ligands or ligand precursors.

Cell Metabolism
Review
NLSDM or NLSDI in humans due to the deficiency of ATGL or

CGI-58, respectively, may also lead to reduced PPARa signaling
and defective OXPHOS. Although not proven experimentally,
this assumption stems from the finding that NLSDM patients
also develop systemic TG accumulation and cardiomyopathy.
In many patients, this condition is lethal if they do not undergo
heart transplantation (Hirano et al., 2008). Importantly, at least
in mice, the mitochondrial defect can be prevented by applica-
tion of PPARa activators, such as Wy16453 or fenofibrate
(Haemmerle et al., 2011). Treatment of ATGL-deficient mice
leads to increased PPARa signaling, disappearance of cardiac
steatosis, and improved mitochondrial function and OXPHOS,
as well as prolonged survival. Whether pharmacological PPARa
activation will also be beneficial for patients with NLSDM is
currently not known but remains a promising possibility.
In addition to the instrumental role of ATGL in PPARa signaling,
the enzyme may also affect PPARg function. Festuccia et al.
(Festuccia et al., 2006) showed that rosiglitazone-mediated
PPARg activation and lipid accumulation are associated with
increased lipolysis in WAT of rats and that increased lipolysis
was due to induction of ATGL and MGL. Although it seems
counterintuitive that lipolysis is induced during increased TG
Figure 3. Lipolysis and Lipid Signaling
synthesis, it is conceivable that this step is required to promote
Lipid intermediates involved in cellular signaling are generated by anabolic and
PPARg-activated expression of lipogenic genes. Moreover, the catabolic reactions in distinct cellular compartments. 1,2-DGs, the ligands of
fact that HSL-deficiency also leads to downregulation of PPARg conventional and novel PKCs, are formed at the plasma membrane by
target-gene expression in WAT (Shen et al., 2011; Zimmermann PLC-mediated degradation of PIP2. This reaction also generates IP3,
a signaling molecule, which leads to Ca2+ efflux from the ER. De novo
et al., 2003) suggests that lipolysis is involved in PPARg signaling. synthesis of 1,2-DGs at the ER may also contribute to PKC activation. FAs
are ligands for nuclear receptors. They are generated by de novo synthesis or
Lipolysis-Derived FAs and Insulin Signaling hydrolysis of neutral lipids or phospholipids. 2-AG is an important MG involved
in endocannabinoid signaling. It originates from membrane-associated
It is well established that both plasma and cellular FA concen- phospholipid hydolysis by PLCs and the subsequent hydrolysis of DGs by
trations correlate positively with increased insulin resistance DAGLs. The contribution of TG hydrolysis by ATGL and HSL to cellular 2-AG
(Boden and Shulman, 2002). Several mechanisms are discussed. concentrations is not known. The 2-AG signal is inactivated by MGL. AGPAT,
acyl-CoA acylglycerol-3-phosphate acyltransferase; 2-AG, 2-arachidonoyl-
Increased cellular concentrations of nonesterified FAs, particularly
glycerol; ATGL, adipose triglyceride lipase; DAGL, diacylglycerol lipase; DG,
palmitate, can drive the synthesis of lipotoxic lipids such as ceram- diacylglycerol; 11, 2-DG, diacyl-sn1,2-glycerol, DGAT, acyl-CoA: diac-
ides, which interfere with functional insulin signaling (Summers, ylglycerol acyltransferase; FA, fatty acid; G, glycerol; G3P, glycerol-3-phos-
2010). Additionally, FAs can directly or indirectly—via increased phate; GPAT, glycerol-3-phosphate acyltransferase; HSL, hormone-sensitive
lipase; IP3, inositol-1,4,5-trisphosphate; LPA, lysophosphatidic acid; MG,
production of reactive oxygen species—activate redox-sensitive monoacylglycerol; MGL, monoglyceride lipase; PA, phosphatidic acid;
serine kinases, which, in turn, inactivate the insulin response PAPase, PA phosphohydrolase; PIP2, phosphatidylinositol 4,5-bisphosphate;
(Vallerie and Hotamisligil, 2010). Yet, not all FA species seem to PKC, protein kinase C; PLC, phospholipase C; TG, triacylglycerol.
have the same inhibitory effect on insulin signaling. Whereas
palmitate consistently decreases the insulin response, palmito-
leate actually enhances the insulin signal in liver and muscle DGs affect many metabolic and mitogenic activities via activa-
(Cao et al., 2008). Palmitoleate is mostly generated by de novo tion of protein kinase-C (PKC). Metabolic regulation involves
synthesis in adipose tissue. Its effects on insulin signaling in liver suppression of insulin signaling via phosphorylation of insulin
and muscle suggest that this FA is a lipokine with endocrine func- receptor substrate-1, leading to insulin resistance in muscle
tion. Additionally, it is conceivable that hepatic palmitoleate also and liver (Samuel et al., 2010). Only one DG stereoisomer,
contributes to insulin sensitization in a paracrine fashion. Whether 1,2-diacyl-sn-glycerols (1,2-DGs), is able to activate PKCs,
lipolysis contributes to the generation of palmitoleate or other FAs whereas the others, 1,3-diacyl-sn-glycerols (1,3-DGs) and
with a downstream effect on insulin signaling requires additional 2,3-diacyl-sn-glycerols (2,3-DGs), lack this bioactivity (Boni
studies. ATGL-deficient mice have low plasma FA concentrations and Rando, 1985). 1,2-DGs activate conventional and novel
and are highly insulin-sensitive, arguing for a protective role of PKC isoforms after recruitment of the enzymes to the plasma
reduced lipolysis and low FA levels. Whether low plasma FAs in membrane by receptor of activated C kinase (RACK) proteins
HSL-deficient mice also affect insulin sensitivity is controversial (Turban and Hajduch, 2011). Accordingly, both stereo-specific
(Mulder et al., 2003; Park et al., 2005; Voshol et al., 2003). and location-specific preconditions are required for DGs to acti-
vate PKCs. Three potential sources exist for the generation of
Lipolysis-Derived DGs Are Unlikely to Affect 1,2-DGs (Figure 3). Classical signaling 1,2-DGs derive from
PKC Signaling phospholipase C (PLC)-mediated hydrolysis of phosphatidylino-
The potential of DGs to act as second messengers was discov- sitol-4,5-phosphate in the plasma membrane. Vertebrates have
ered approximately 50 years ago when researchers realized that 13 isoforms of PLC grouped within 6 isotypes. Both products of

Cell Metabolism
Review
the enzymatic reaction, 1,2-DGs and inositol-1,4,5-phosphate predictor for lipid-induced, PKC-mediated insulin resistance
(IP3), are potent second messengers. Whereas 1,2-DGs remain than total cellular DG concentrations.
plasma membrane-associated, IP3 dissociates and induces
Ca2+ release from the ER, which is required in addition to Monoacylglycerol Signaling and Lipolysis
1,2-DGs for activation of conventional PKCs. The signaling potential of MGs was recognized when it
Although PLCs generate the ‘‘correct’’ stereoisomer (1,2-DGs) was found that the phospholipid-derived MG 2-AG activates
in the ‘‘correct’’ cellular location for PKC activation, it remains cannabinoid receptors (CBR), thereby regulating food intake,
controversial whether other cellular sources also contribute lipid metabolism, and energy homeostasis. The endocannabi-
to the production of signaling 1,2-DGs. De novo synthesis via noid system (ECS) refers to a group of neuromodulatory lipids
dual acylation of sn-glycerol-3-phosphate by acyl-CoA glyc- (endocannabinoids, ECs), two G protein-coupled receptors
erol-3-phosphate acyltransferases (GPATs) and acyl-CoA acyl- (CBR1 and CBR2), and enzymes involved in the synthesis and
glycerol-3-phosphate acyltransferases (AGPATs), and subse- degradation of ECs (Di Marzo, 2009). The best-characterized
quent dephosphorylation of phosphatidic acid by phosphatidic ECs are N-arachidonoyl ethanolamine (AEA, anandamide) and
acid phosphohydrolases (PAPases) also leads to the formation 2-AG. Their biological effect is mimicked by D9-tetrahydrocan-
of 1,2-DGs (Figure 3). However, this pathway of DG synthesis nabinol (THC), the major psychoactive component of marijuana.
is restricted to ER membranes. Accordingly, a model proposing The ECS regulates a diverse spectrum of physiological pro-
activation of PKC by ER-associated 1,2-DGs needs to include cesses, including motor function, pain, appetite, cognition,
PKC localization to the ER or contact sites between the plasma emotional behavior, and immunity. In the nervous system,
membrane and the ER membrane. 2-AG acts as a retrograde messenger, inhibiting presynaptic
The third potential source of DGs derives from the lipolysis of neurotransmitter release (Alger and Kim, 2011). It is produced
LD-associated TGs by ATGL (Figure 3). The stereospecificity of postsynaptically and traverses the synaptic cleft to stimulate
ATGL has not been reported. However, our unpublished obser- presynaptic CBR1. Subsequently, 2-AG is internalized into the
vations showed that the enzyme preferentially hydrolyzes sn-1 presynaptic terminal and inactivated by the MGL reaction,
and sn-2 ester bonds but not sn-3 esters. This indicates that forming glycerol and arachidonic acid. The ECS is active in
ATGL generates 1,3-DGs and 2,3-DGs but not 1,2-DGs. In neurons and nonneuronal cells such as immune cells, hepato-
accordance with the subsequent hydrolysis of 1,3-DGs and cytes, and adipocytes. Treatment of obese patients with the
2,3-DGs by HSL, this enzyme has a stereo-preference for the CBR1-antagonist rimonabant (Christopoulou and Kiortsis,
hydrolysis of FAs in the sn-3 position of DGs (Rodriguez et al., 2011) and studies with animal models lacking CBR1 revealed
2010). In TGs, HSL preferably hydrolyses sn-1(3) ester bonds that blockade of the ECS reduces food intake, decreases lipo-
(Fredrikson and Belfrage, 1983). Therefore, neither the ATGL genesis, and increases energy consumption. Conversely, an
nor the HSL reaction generate 1,2-DGs on LDs. Additionally, it overactive ECS has a central orexigenic effect and reduces
is questionable whether LD-associated DGs would dissociate energy expenditure, promoting lipid deposition in peripheral
from LDs to participate in the recruitment and activation of tissues like the liver and WAT (Cota, 2008). Because of these
PKC at the plasma membrane. From all this, it seems unlikely biological effects, the ECS has been linked to the pathogenesis
that lipolytically generated DGs act as signaling mediators. of metabolic diseases. Obese patients may have an overactive
In a recent review, Shulman and colleagues (Samuel et al., ECS, which stimulates appetite and promotes lipid deposition
2010) summarized numerous animal and human studies pro- (Perkins and Davis, 2008).
viding evidence that cellular DG concentrations account for the It is generally assumed that signaling 2-AG originates from
development of lipid-induced insulin resistance in type 2 dia- the degradation of glycerophospholipids containing arachidonic
betes, lipodystrophy, and other conditions. Consistent with this acid in the sn-2 position (Figure 3). Various isoforms of PLC
hypothesis, mice lacking DG-kinase-d, the major enzyme that generate 1,2-DGs (see above), which are subsequently hydro-
inactivates the DG signal, have increased DG levels and lyzed by DG lipase (DAGL) to 2-AG. Whether HSL also partici-
increased insulin resistance (Chibalin et al., 2008). However, pates in the hydrolysis of plasma membrane-associated
considering the structural complexity of DG species and their 1,2-DGs to generate 2-AG is not known. Current evidence
localization in different cellular compartments, a general correla- suggests that at least two isoforms of DAGL (DAGLa and DAGLb)
tion between total cellular DG concentrations and insulin re- exist in the brain and liver (Bisogno et al., 2003). Mice lacking
sistance seems unlikely. This is supported by studies where DAGLa exhibit a substantial decrease in brain and spinal cord
increased total cellular DG concentrations in mutant mouse 2-AG levels, whereas DAGLb appears to be more important in
models were not associated with insulin resistance. For ex- peripheral tissues, such as the liver (Gao et al., 2010). Whether
ample, HSL-deficient mice accumulate large amounts of DGs the catabolism of arachidonic acid-containing TGs in LDs by
in adipose and many nonadipose tissues due to defective DG ATGL and HSL also contributes to the cellular 2-AG and arach-
catabolism. Yet, most studies agree that this does not lead to idonic acid pool is not known.
PKC hyperactivation or a severely defective insulin response Recent studies using an MGL-specific small-molecule inhib-
(Mulder et al., 2003; Park et al., 2005; Voshol et al., 2003). itor (JZL184) and MGL knockout mice provided compelling
Similarly, CGI-58 silencing in the liver leads to increased DG evidence that MGL is the major enzyme in the degradation of
levels, but normal (chow diet) or increased (high-fat diet) glucose 2-AG and other MGs esterified with long-chain FAs (Chanda
tolerance and insulin sensitivity (Brown et al., 2010). et al., 2010; Schlosburg et al., 2010; Taschler et al., 2011).
Taken together, determination of the specific 1,2-DG concen- Animals lacking MGL or mice treated with JZL184 show abnor-
trations in the plasma membrane may provide a more reliable mally high amounts of various MG species in the brain and

Cell Metabolism
Review
peripheral tissues. In the brain, lack of MGL activity leads to ysis (Gaspar et al., 2011). Thus, cell cycle-regulated TG lipolysis
a more than 20-fold increase in 2-AG, suggesting that MGL-defi- may provide critical precursors for signaling molecules for cell
ciency could lead to hyperactivation of the ECS. Indeed, JZL184 division.
treatment of mice provoked cannabimimetic effects in mice, A highly interesting study recently demonstrated that MGL
including analgesia, hypothermia, and hypomotility (Long et al., promotes the oncogenic properties of mammalian cancer cells
2009). However, genetic ablation of MGL in mice did not result (Nomura et al., 2010). The authors demonstrated that overex-
in a hyperactive ECS or any obvious phenotype. This surprising pression or disruption of MGL activity increased or decreased,
observation was explained by desensitization of brain CBR1 respectively, the proliferation of cancer cells, and that MGL is
leading to functional antagonism, and highlights the important highly expressed in aggressive tumor cell lines or primary
role of 2-AG as a retrograde neurotransmitter (Chanda et al., tumors. The study also provided evidence that MGL influences
2010; Schlosburg et al., 2010). Obviously, increased brain tumor proliferation by metabolic effects rather than by CBR-
2-AG concentrations provoke counter-regulatory mechanisms dependent mechanisms. The lack of MGL reduced cellular
similar to those observed when animals are chronically fed nonesterified FA concentrations. Growth of tumor cells in
CBR agonists (Lichtman and Martin, 2005). response to MGL-knockdown was not impaired after addition
Although MGL-deficiency in mice does not produce cannabi- of exogenous nonesterified FAs or in mice fed a high-fat diet.
mimetic effects, the lack of MGL activity substantially affects This led to the conclusion that MGL affects the concentration
lipolysis and metabolism in adipose tissue and nonadipose of FA-derived tumorigenic lipid metabolites, such as LPA and
tissues (Taschler et al., 2011). MGL deficiency results in the PGE2. Although the involved lipid signal(s) requires identification,
accumulation of MGs and a reduction of circulating TG and glyc- these studies clearly designate MGL as an interesting target for
erol levels in fasted animals. Unexpectedly, and in contrast to the cancer therapy.
proposed role of the ECS in obesity-related metabolic diseases, Lipolytic signaling may also be causally involved in the patho-
MGL knockout mice exhibit improved insulin sensitivity and genesis of cancer-associated cachexia (CAC). In a recent study,
glucose tolerance when fed a high-fat diet. The cause for this Das et al. (Das et al., 2011) demonstrated that ATGL-deficient
finding may be complex, considering that MGL-deficiency is mice are protected against tumor-induced loss of adipose tissue
associated with desensitized CBRs. Investigation of mice lack- and skeletal muscle. HSL-deficient mice were also protected,
ing MGL, specifically in the brain or peripheral tissues, should although to a lesser degree. ATGL-deficient mice maintained
help to unravel the question of whether central or peripheral body weight and composition despite increased circulating
effects cause attenuation of insulin resistance. factors that induce lipolysis, muscle proteolysis, and apoptosis
(e.g., TNFa, interleukin-6, and zinc-a-glycoprotein 1). This sug-
Lipolysis in the Cell Cycle, Cancer, and Cachexia: gests that lipolysis is integrated in a signal transduction network
A Question of Lipid Signaling? that eventually leads to the loss of adipose tissue and muscle.
The first observation to indicate that lipolysis is linked to efficient This view is also consistent with the observation that the activity
cell-cycle progression was reported in the yeast S. cerevisiae. of lipolytic enzymes and release of FAs and glycerol are
Yeast expresses three TG lipases of the patatin domain-contain- increased in adipose tissue of cancer patients with cachexia
ing family termed Tgl3 to 5 (Czabany et al., 2007). Tgl4 is a func- (Agustsson et al., 2007; Das et al., 2011; Rydén et al., 2008).
tional ortholog of mammalian ATGL (Kurat et al., 2006). Deletion The nature of the lipolytic signal involved is currently unknown.
of Tgl3 and Tgl4 abolishes virtually all cellular TG lipase activity It is also unclear whether the signal originates from lipolysis in
and causes a marked delay of entry into the cell division cycle one tissue (such as adipose tissue) and promotes wasting in
of starved cells upon refeeding (Kurat et al., 2009). Tgl4 is an endocrine manner or whether wasting requires autonomous
activated via phosphorylation by the cyclin-dependent kinase lipolysis in all tissues that are affected by wasting. Although the
Cdk1/Cdc28 (ortholog of mammalian Cdc2). Concomitantly, underlying mechanism is not yet defined, this study suggests
Cdk1/Cdc28 inhibits lipogenesis by phosphorylation of phos- that inhibition of lipolysis may help to prevent cachexia in
phatidic acid phosphohydrolase (Pah1). This suggests that TG patients with cancer or other chronic diseases.
levels oscillate during the cell-division cycle to either deposit
de novo synthesized FAs in TGs or, conversely, to provide FAs Conclusion
during phases of increased demand. Tgl4 phosphorylation and Recent discoveries of enzymes and regulatory factors have led
activation occur at the G1/S transition of the cell-division cycle, to a revision of our perception of lipolysis. The complexity of
which coincides with bud emergence and requires increased the process and its regulation are still only partially understood.
amounts of membrane lipids. Pah1 phosphorylation and inacti- Additionally, we have just begun to address the role of lipolytic
vation occur at the G2/M transition of the cell cycle, indicating products and intermediates in cellular signaling. Important
that a window exists during the cell cycle in which both the initial topics for future investigations include: 1) better understanding
step of lipogenesis and lipolysis may operate in parallel. This is of the biochemical factors and processes that coordinately
feasible because both activities are confined to different organ- regulate the lipolytic machinery in response to hormonal activa-
elles, namely the ER and LDs, respectively. The specific check- tors and inhibitors, 2) the physiological function of lipolysis in
point proteins that regulate cell-cycle progression in response numerous nonadipose tissues and the tissue-specific differ-
to lipolysis are currently unknown. Recent evidence shows that ences in lipolytic mechanisms, and 3) the characterization
the synthesis of phosphatidylinositol (PI), a precursor for signal- of lipolytic signals and the molecular mechanisms of their
ing molecules in cell-cycle regulation in yeast (e.g., IP3 and effects on gene transcription, the cell cycle, and cell growth.
inositol-containing ceramides), strongly depends on intact lipol- The recent examples of lipases affecting tumor proliferation or

Cell Metabolism
Review
cancer-associated cachexia emphasize the potential impor- of the first sn1-DAG lipases points to the spatial and temporal regulation of
endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468.
tance of lipolysis in human disease.
Boden, G., and Shulman, G.I. (2002). Free fatty acids in obesity and type 2 dia-
ACKNOWLEDGMENTS betes: defining their role in the development of insulin resistance and beta-cell
dysfunction. Eur. J. Clin. Invest. 32 (Suppl 3 ), 14–23.
This work was supported by the grants P20602, P18434, P21296, F30 SFB Boni, L.T., and Rando, R.R. (1985). The nature of protein kinase C activation by
LIPOTOX, the Doktoratskollegs W901 and W1226, and the Wittgenstein Award physically defined phospholipid vesicles and diacylglycerols. J. Biol. Chem.
Z136, which are funded by the Austrian Science Foundation. Funding was also 260, 10819–10825.
provided by the grant ‘‘GOLD: Genomics Of Lipid-associated Disorders,’’
which is part of the Austrian Genome Project ‘‘GEN-AU: Genome Research Borg, M.L., Andrews, Z.B., Duh, E.J., Zechner, R., Meikle, P.J., and Watt, M.J.
in Austria’’ funded by the Austrian Ministry of Science and Research and the (2011). Pigment epithelium-derived factor regulates lipid metabolism via
FFG. Additional support was obtained from the European commission grant adipose triglyceride lipase. Diabetes 60, 1458–1466.
agreements no. 202272 (LipidomicNet), the City of Graz and the Province of
Styria. We thank Dr. Ellen Zechner, Mag. Caroline Schober-Trummler, and Brown, J.M., Betters, J.L., Lord, C., Ma, Y., Han, X., Yang, K., Alger, H.M.,
Melchior, J., Sawyer, J., Shah, R., et al. (2010). CGI-58 knockdown in mice
Mag. Dr. Tarek Mustafa for careful and critical reading of the manuscript.
causes hepatic steatosis but prevents diet-induced obesity and glucose
intolerance. J. Lipid Res. 51, 3306–3315.
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Cell Metabolism

FAT SIGNALS - Lipases and Lipolysis

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 279

280 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

2008). PEDF is a widely expressed 50 kD protein of the noninhi-

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 281

282 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 283

In summary, autophagy may have pleiotropic roles in lipid

Lipolysis: A Role in Lipid-Mediated Signaling?

284 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

NLSDM or NLSDI in humans due to the deficiency of ATGL or

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 285

286 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 287

288 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 289

290 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.

Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 291

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