FAT SIGNALS–lipases and lipolysis in lipid metabolism and signaling

Abstract

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.

Full text

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

question of whether other lipases are additionally required for
efficient lipolysis.
ATGL: the Initial Step of Lipolysis
ATGL is the newest member of the lipolytic enzyme trio. The
enzyme, first described in 2004 (Jenkins et al., 2004; Villena
et al., 2004; Zimmermann et al., 2004), belongs to the family
patatin domain-containing proteins including nine human and
eight murine members. The patatin domain was originally
discovered in lipid hydrolases of the potato and other plants
and named after the most abundant protein of the potato tuber,
patatin. Because some members of the family act as phospholi-
pases, the proteins were officially named patatin-like phospholi-
pase domain-containing protein A1 to A9 (PNPLA1–9) (Wilson
et al., 2006). Unfortunately, this name is misleading because it
implies that all members of this family are phospholipases.
However, several PNPLA proteins have only minor or no phos-
pholipase activity. A more appropriate designation for the family
should be considered.
ATGL (officially annotated as PNPLA2) preferentially hydro-
lyzes TGs. Orthologous enzymes are found in essentially all
eukaryotic species, including vertebrates, invertebrates, plants,
and fungi. The human protein comprises 504 amino acids (AA).
In analogy with patatin, the active site of the enzyme contains
an unusual catalytic dyad (S47 and D166) within the patatin
domain (Rydel et al., 2003). This domain comprises 180 AA
and is embedded within a 250 AA abasandwich structure
at the protein’s NH
2
-terminal half. The COOH-terminal half has
a predominantly regulatory function and contains a predicted
hydrophobic region for LD binding (Duncan et al., 2010;
Schweiger et al., 2008). Loss of this region increases the specific
in vitro activity of ATGL against artificial TG substrates but blunts
the intracellular activity due to the inability of the truncated
enzyme to bind to cellular LDs.
Regulation of ATGL
Regulation of ATGL expression and enzyme activity is complex
(Lass et al., 2011). ATGL mRNA expression is elevated by perox-
isome proliferator-activated receptor (PPAR) agonists, glucocor-
ticoids, and fasting, whereas insulin and food intake decrease
expression. More recently, it was shown that mTOR complex
1-dependent signaling reduces ATGL mRNA levels (Chakrabarti
et al., 2010). Conversely, activation of FoxO1 by SIRT1-mediated
deacetylation activates lipolysis by increasing ATGL mRNA
levels. SIRT1 silencing has the opposite effect (Chakrabarti
et al., 2011). The abundance of ATGL (and HSL) mRNA does
not always correlate with cellular lipase activity. For example,
isoproterenol and tumor necrosis factor-areduce ATGL (and
HSL) mRNA levels in adipocytes (Kralisch et al., 2005) but,
conversely, stimulate lipase activities and FA and glycerol
release. The discrepancy between enzyme mRNA levels and
activities is explained by the extensive posttranslational regula-
tion of ATGL and HSL (discussed below). Thus, cellular lipase
mRNA levels are inadequate as indicators of enzyme activities.
At least two serine residues in ATGL can be phosphorylated
(S406 and S430 in the murine enzyme) (Bartz et al., 2007). In
contrast to HSL (see below), ATGL modification is not protein
kinase A (PKA)-dependent (Zimmermann et al., 2004). Instead,
the laboratory of H.-S. Sul recently showed that AMP-activated
kinase (AMPK) phosphorylates S406, leading to increased
hydrolytic activity of murine ATGL (Ahmadian et al., 2011). The
role of AMPK in the regulation of lipolysis has been controversial,
with data showing that AMPK induces (Gaidhu et al., 2009; Yin
et al., 2003), inhibits (Daval et al., 2005; Gauthier et al., 2008),
or has no effect (Chakrabarti et al., 2011) on lipolysis. Interest-
ingly, in the nematode Caenorhabiditis (C.) elegans, AMPK-
mediated phosphorylation of ATGL-1 (the worm ortholog of
mammalian ATGL) at different phosphorylation sites inhibits TG
hydrolysis (Narbonne and Roy, 2009), delays the consumption
of TG stores, and prolongs life span during the stress-induced
dauer larval stage. The functional role of the second phosphory-
lation site (S430) is not known.
ATGL requires a coactivator protein, comparative gene
identification-58 (CGI-58), for full hydrolase activity (Lass et al.,
2006). CGI-58 was originally discovered in a screen comparing
the proteomes of humans and C. elegans. The gene is now
officially named a/bhydrolase domain-containing protein-5
(ABHD5), owing to the presence of an a/bhydrolase domain
commonly found in esterases, thioesterases, and lipases. How-
ever, CGI-58 is unlikely to exhibit hydrolase activity due to the
fact that asparagine-153 (N153) in CGI-58 replaces a nucleophilic
serine residue that is required in the active site of enzymatically
functional members of the esterase/thioesterase/lipase family.
Interestingly, substitution of N153 by serine does not convert
CGI-58 into a lipid hydrolase for TGs, DGs, MGs, or short
FA-glycerol esters (A. Lass et al., unpublished). In the epidermis
of the skin, CGI-58 may also stimulate another, currently
unknown, TG hydrolase distinct from ATGL (Radner et al.,
2010). Importantly, two laboratories showed that CGI-58, at least
in vitro, exhibits enzymatic activity as an acylCoA-dependent
acylglycerol-3-phosphate acyltransferase (AGPAT) (Ghosh
et al., 2008; Montero-Moran et al., 2010). The physiological role
of this activity requires clarification. It may affect phosphatidic
acid or lysophosphatidic acid signaling (Brown et al., 2010).
Recently, Yang et al. (Yang et al., 2010b) discovered a specific
peptide inhibitor for ATGL. The protein was originally identified in
blood mononuclear cells to act at the G0 to G1 transition of the
cell cycle. Consistent with this function, it was named G0G1
switch protein 2 (G0S2). Human and murine G0S2 have a pre-
dicted primary structure of 103 AA. The protein is found in
many tissues, with highest concentrations in adipose tissue
and liver. Consistent with lipase activities, G0S2 expression is
very low in adipose tissue during fasting but increases after
feeding (Yang et al., 2010b). Conversely, fasting or PPARa-agon-
ists increase hepatic G0S2 expression (Zandbergen et al.,
2005). The protein localizes to multiple cellular compartments,
including LDs, cytoplasm, ER, and mitochondria. The different
localizations may reflect multiple functions for G0S2 in regulating
lipolysis, the cell cycle, and, possibly, apoptosis via its ability
to interact with the mitochondrial antiapoptotic factor Bcl2
(Welch et al., 2009). In vitro, LD binding and inhibition of ATGL
depend on a physical interaction between the NH
2
-terminal
region of G0S2 (involving AA 27–42) and the patatin domain of
ATGL (Lu et al., 2010). Elucidation of whether G0S2 also regu-
lates tissue-specific lipolysis in vivo will require the characteriza-
tion of G0S2 transgenic and knockout mouse models.
LD-associated proteins participate in the CGI-58-mediated
regulation of ATGL (Figure 1, left). In hormonally nonstimulated
white and brown adipocytes, perilipin-1 interacts with CGI-58,
preventing its binding to and, thus, induction of ATGL. Upon
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b-adrenergic stimulation, protein kinase A (PKA) phosphorylates
perilipin-1 at multiple sites, including the critical serine-517
residue, causing the release of CGI-58. The effector then binds
and stimulates ATGL (Granneman et al., 2009; Miyoshi et al.,
2007). Thus, b-adrenergic stimulation of PKA induces ATGL
activity by phosphorylation of perilipin-1 and not by direct
enzyme phosphorylation. Consistent with this model, frameshift
mutants of perilipin-1 in humans (L404fs and V398fs) fail to bind
CGI-58, leading to unrestrained lipolysis, partial lipodystrophy,
hypertriglyceridemia, and insulin resistance (Gandotra et al.,
2011). ATGL-mediated TG hydrolysis in nonadipose tissues
with high FA oxidation rates, such as muscle and liver, follows
another mechanism. In these tissues, perilipin-1 is replaced by
perilipin-5 (Figure 1, right). During fasting, perilipin-5 recruits
both ATGL and CGI-58 to LDs by direct binding of the enzyme
and its coactivator. Formation of the ternary complex involves
the COOH-terminal region of perilipin-5 (AA 200–463) (Granne-
man et al., 2011). The role of perilipin-5 within this complex is still
a matter of discussion. Recent data suggest that it is involved in
the interaction of LDs with mitochondria and inhibits ATGL-
mediated TG hydrolysis (Wang et al., 2011). Whether perilipins-2,
-3, and -4 also interact with either ATGL or CGI-58 is disputed.
Overexpression of perilipin-2 in hepatocyte cell lines inhibits
ATGL activity by restricting its physical access to LDs. Direct
protein-protein interaction is probably not required (Bell et al.,
2008; Listenberger et al., 2007).
Recently, several groups reported that pigment epithelium-
derived factor (PEDF) induces TG hydrolysis in adipose tissue,
muscle, and liver, via ATGL (Borg et al., 2011; Chung et al.,
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
(GBF1), or deficiency of the coatamer protein coat-complex I
and II, ATGL translocation to LDs is blocked and the enzyme
remains associated with the ER (Soni et al., 2009). The process
requires physical binding of ATGL to GBF1 (Ellong et al., 2011).
HSL: the Main DG Lipase
In the early 1960s, it was noted that a lipolytic activity present in
adipose tissue was induced by hormonal stimulation. A land-
mark paper published by D. Steinberg’s group (Vaughan et al.,
1964) described the isolation and characterization of both HSL
and MGL. Although this classic work originally noted that HSL
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
many nonadipose tissues. This view required revision when
HSL-deficient mice efficiently hydrolyzed TGs (Osuga et al.,
2000). HSL-deficient mice showed no signs of TG accumulation
in either adipose or nonadipose tissues; instead, they accumu-
alted large amounts of DGs in many tissues, suggesting that
in vivo the enzyme was more important as a DG- than a TG-
hydrolase (Haemmerle et al., 2002). Although originally some-
what controversial (Ryde
´n et al., 2007), it is now accepted that
ATGL is responsible for the initial step of lipolysis in human
adipocytes, and that HSL is rate-limiting for the catabolism of
DGs (Bezaire et al., 2009). In addition to DGs, HSL also hydro-
lyzes ester bonds of many other lipids (e.g., TGs, MGs, choles-
teryl esters, and retinyl esters) and short-chain carbonic acid
esters (Fredrikson et al., 1986).
The HSL expression profile essentially mirrors that of ATGL.
Highest mRNA and protein concentrations are found in white
adipose tissue (WAT) and brown adipose tissue (BAT); low
expression is detected in many other tissues, including muscle,
testis, steroidogenic tissues, and pancreatic islets (Holm et al.,
2000). Alternative exon usage leads to tissue-specific differ-
ences in mRNA and protein size (Holst et al., 1996). In adipose
tissue, the HSL protein comprises 768 AA. Unlike ATGL, with
orthologous enzymes found across all eukarya, HSL is less ubiq-
uitous phylogenetically. For example, no HSL ortholog is known
in birds, C. elegans,D. melanogaster, and Saccharomyces (S.)
cerevisiae. Interestingly, the closest structural relatives to HSL
are found in prokaryotes (e.g., lipase 2 in Moraxella TA144)
(Langin et al., 1993). Functional studies have delineated in HSL
an NH
2
-terminal lipid-binding region, the a/bhydrolase fold
Figure 1. Lipolysis in Adipose and Oxidative Tissues during Fasting
In adipose tissues, beta-adrenergic stimulation of lipolysis leads to the
consecutive hydrolysis of TG and the formation of FAs and glycerol. The
process requires three enzymes: ATGL cleaves the first esterbond in TGs, HSL
hydrolyzes DGs, and MGL MGs. For full hydrolytic activity, ATGL interacts with
its coactivator protein CGI-58, whereas HSL is phosphorylated, translocates
to the LD, and interacts with phosphorylated PLIN-1. Expression of the ATGL
inhibitor G0S2 during fasting is low in adipose and high in oxidative tissues
(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-
tion of these proteins. ATGL, adipose triglyceride lipase; CGI-58, comparative
gene identification-58; DG, diacylglycerol; FA, fatty acid; G, glycerol; G0S2,
G0/G1 switch gene 2; HSL, hormone-sensitive lipase; MG, monoacylglycerol;
MGL, monoglyceride lipase; PLIN-1, perilipin-1; PLIN-5, perilipin-5; TG, tri-
acylglycerol.
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domain including the catalytic triad, and the regulatory module
containing all known phosphorylation sites important for regula-
tion of enzyme activity (Holm et al., 2000).
Regulation of HSL
Since ATGL and HSL hydrolyze TGs in a coordinated manner, it is
not unexpected that they share many regulatory similarities. In
adipose tissue, HSL enzyme activity is strongly induced by
b-adrenergic stimulation, whereas insulin has a strong inhibitory
effect. The mechanisms of enzyme regulation, however, differ
markedly between the two lipases. While b-adrenergic stimula-
tion regulates ATGL primarily via recruitment of the coactivator
CGI-58 (see above), HSL is a major target for PKA-catalyzed
phosphorylation (Stra
˚lfors and Belfrage, 1983). Other kinases,
including AMPK, extracellular signal-regulated kinase, glycogen
synthase kinase-4, and Ca
2+
/calmodulin-dependent kinase,
also phosphorylate HSL to modulate its enzyme activity (Lass
et al., 2011). The enzyme has at least five potential phosphoryla-
tion sites, of which S660 and S663 appear to be particularly
important for hydrolytic activity (Anthonsen et al., 1998). Enzyme
phosphorylation affects enzyme activity moderately (an approxi-
mate 2-fold induction). For full activation, HSL must gain access
to LDs, which, in adipose tissue, is mediated by perilipin-1. Simul-
taneously with HSL, PKA also phosphorylates perilipin-1 on six
consensus serine residues. As a result, HSL binds to the NH
2
-
terminal region of perilipin-1, thereby gaining access to LDs
(Miyoshi et al., 2007; Shen et al., 2009; Wang et al., 2009).
Together, HSL-phosphorylation and enzyme translocation to
LDs coupled with ATGL activation by CGI-58 result in a more
than 100-fold increase in TG hydrolysis in adipocytes (Figure 1).
This activation process is modulated by other factors. For
example, receptor-interacting protein 140 (RIP-140) was shown
to induce lipolysis by binding to perilipin-1, increasing HSL
translocation to LDs, and activating ATGL via CGI-58 dissociation
from perilipin-1 (Ho et al., 2011). In nonadipose tissues, such as
skeletal muscle, HSL is activated by phosphorylation in response
to adrenaline and muscle contraction (Watt et al., 2006). These
tissues lack perilipin-1, and it remains to be determined which
alternative mechanisms regulate HSL access to LDs.
Insulin-mediated deactivation of lipolysis is associated with
transcriptional downregulation of ATGL and HSL expression
(Kershaw et al., 2006; Kralisch et al., 2005). Additionally, insulin
signaling results in phosphorylation and activation of various
phosphodiesterase (PDE) isoforms by PKB/AKT (Enoksson
et al., 1998), PDE-catalyzed hydrolysis of cAMP, and inhibition
of PKA. These actions halt lipolysis by preventing phosphoryla-
tion of both HSL and perilipin-1, activation and translocation
of HSL, and activation of ATGL by CGI-58. In addition to its
peripheral action, insulin also acts centrally via the sympathetic
nervous system to inhibit lipolysis in WAT. Elegant studies by
Scherer and coworkers (Scherer et al., 2011) showed that
increased insulin levels in the brain inhibit HSL and perilipin
phosphorylation, leading to reduced HSL and ATGL activities.
MGL: the Final Step in Lipolysis
MGL is considered to be the rate-limiting enzyme for the break-
down of MGs derived from extracellular TG hydrolysis (by LPL),
intracellular TG hydrolysis (by ATGL and HSL), and intracellular
phospholipid hydrolysis (by phospholipase C and membrane-
associated DG lipase aand b). The enzyme localizes to cell
membranes, cytoplasma (Sakurada and Noma, 1981), and LDs
(unpublished data). MGL received significant attention following
the realization that glycerophospholipid-derived MG 2-arachido-
nylglycerol (2-AG) is a major agonist for endocannabinoid
signaling and is inactivated by the hydrolytic activity of MGL
(see MG-signaling, below). The enzyme is ubiquitously ex-
pressed with highest expression levels in adipose tissue. The
importance of MGL for efficient degradation of MGs was recently
confirmed in mutant mouse models (Chanda et al., 2010; Schlos-
burg et al., 2010; Taschler et al., 2011). Lack of MGL impairs
lipolysis and is associated with increased MG levels in adipose
and nonadipose tissues alike.
MGL shares homology with esterases, lysophospholipases,
and haloperoxidases, and contains a consensus GXSXG motif
within a catalytic triad (S122, A239, and H269 for mouse MGL)
that is typical of lipases and esterases. Very recently, the crystal
structure of MGL was solved (Bertrand et al., 2010; Labar et al.,
2010). The enzyme exhibits the classic fold of the a/bhydrolases,
crystallizes as a dimer, and exhibits a wide, hydrophobic access
to the catalytic site. An apolar helix-domain lid covers the active
site and mediates the interaction of MGL with membrane struc-
tures and the recruitment of substrate.
Other Lipases Implicated in TG Catabolism
Experiments with ATGL-deficient mice and small-molecule HSL
inhibitors revealed that ATGL and HSL are responsible for more
than 90% of the lipolytic activity in WAT and cultured adipocytes
(Schweiger et al., 2006). In nonadipose tissues, the contribution
of other neutral lipases to the catabolism of stored TGs may be
more prominent. For example, in the liver of fasted mice, ATGL
accounts for less than 50% of neutral TG hydrolase activity
(Reid et al., 2008). This activity is physiologically important
because ATGL-deficient mice develop hepatosteatosis (Haem-
merle et al., 2006; Wu et al., 2011). However, the pronounced
remaining activity of hepatic TG hydrolase(s) in ATGL-deficient
mice indicates that other lipases contribute to the highly dynamic
turnover of TGs. This view is supported by the observation that
mice lacking ATGL in the liver have no apparent defect in VLDL
biogenesis (Wu et al., 2011), although assembly and secretion
of hepatic VLDL particles require substantial mobilization of
hepatic TG stores. Because HSL is also poorly expressed in
hepatocytes, the existence of alternative hepatic DG hydrolases
seems likely.
Several members of the carboxylesterase/lipase family and
the PNPLA family have been suggested as potential TG hydro-
lases. One of them, carboxyl esterase-3/triglyceride hydrolase-1
(Ces-3/Tgh-1, ortholog of human Ces-1), has gained major
interest because the recent characterization of Ces-3/Tgh-1-
deficient mice provided compelling evidence that the enzyme
participates in the assembly and secretion of hepatic VLDL
(Wei et al., 2010). How this biological function conforms to
the strict luminal localization of Tgh-1 in the ER remains to be
elucidated.
Structural relatives of ATGL within the PNPLA family were also
considered as potential TG hydrolases. For example, PNPLA4
and -5 exhibit TG-hydrolase, DG transacylase, and retinylester
hydrolase activity in vitro (Kienesberger et al., 2009b). Whether
these activities are also relevant in vivo remains to be deter-
mined. The member with highest homology to ATGL is adiponu-
trin (PNPLA3), with over 50% AA identity within the patatin
domain. Adiponutrin was originally discovered as a nutritionally
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regulated adipose-specific transcript of unknown function
(Baulande et al., 2001). Interest in adiponutrin increased tremen-
dously when H. Hobbs and colleagues found a strong genetic
association between a nonsynonymous AA change (I148M) in
adiponutrin and susceptibility to develop nonalcoholic fatty liver
disease (NAFLD) (Romeo et al., 2008). Several other groups
confirmed and extended this important finding by showing
robust associations of I148M with alcoholic- and nonalcoholic
liver disease, hepatic fibrosis, and liver cirrhosis (Krawczyk
et al., 2011; Tian et al., 2010; Yuan et al., 2008). The close simi-
larity to ATGL as well as the presence of conserved structural
motifs typical for lipases/esterases (abasandwich structure
and the GXSXG motif within a catalytic dyad) suggest a lipase
function for adiponutrin. In accordance with this assumption,
several groups reported that adiponutrin acts as a TG hydrolase
and additionally exhibits DG transacylase activity (He et al.,
2010; Huang et al., 2011; Jenkins et al., 2004; Lake et al.,
2005). However, the expression profile generated in response
to fasting/feeding and the induction of adiponutrin gene expres-
sion by SREBP1a/c and CHREBP argued against an in vivo role
of adiponutrin in lipolysis (Dubuquoy et al., 2011; He et al., 2010;
Kershaw et al., 2006; Lake et al., 2005). Pinpointing the functional
role of adiponutrin was also confounded when PNPLA3-deficient
mice exhibited no detectable phenotype in lipid, lipoprotein, or
energy metabolism (Basantani et al., 2011; Chen et al., 2010).
Overexpression of the I148M variant of adiponutrin caused TG
accumulation (He et al., 2010), whereas overexpression of
wild-type adiponutrin in the liver created no obvious phenotype
(He et al., 2010). Overall, the biochemical and (patho)physiolog-
ical function of adiponutrin remains unclear.
Autophagy and Acid Lipolysis
In addition to classical lipolysis by extralysosomal neutral
lipases, TGs and cholesteryl esters can also be hydrolyzed by
LAL. LAL is thought to catabolize primarily lipoprotein-associ-
ated lipids subsequent to their receptor-mediated endocytosis
and fusion with lysosomes. Accordingly, the contribution of
LAL activity to lipolysis of intracellular LDs was not considered
relevant. Given the lysosomal localization of LAL, it was not intu-
itively obvious how lipids from LDs would enter lysosomes.
Addressing this, Singh and colleagues reported compelling
evidence linking lipolysis to macroautophagy (Singh et al.,
2009a). Macroautophagy is a lysosomal pathway that degrades
superfluous or damaged organelles as well as cytoplasmic inclu-
sions, such as misfolded protein aggregates (Levine and
Kroemer, 2008). These cytoplasmic cargos are trapped inside
double-membrane vesicles (autophagosomes) that ultimately
fuse with lysosomes, where their contents are degraded.
Subsequently, lipids and AA are released into the cytosol and
contribute to energy and AA supply in times of starvation.
Thus, along with lipolysis, macroautophagy is one of two
conserved responses to organismal and cellular fasting.
Singh and coworkers (Singh et al., 2009a) found that, in addi-
tion to conventional neutral lipases, autophagy of LDs is required
for fasting-induced lipolysis in murine liver and cultured hepato-
cytes. They showed that recruitment of microtubule-associated
protein 1 light chain 3 (LC-3) and formation of a regional
membrane through conjugation of autophagy-related protein 7
(Atg7) gives rise to double-membrane vesicles that engulf
portions of cytoplasmic LDs (autolipophagosomes). The autoli-
pophagosomes ultimately fuse with lysosomes, where their lipid
content is degraded by LAL. Consistent with a role for lipo-
autophagy during starvation, Singh et al. found that deletion of
Atg7 causes lipid accumulation in the liver. Chronic fat feeding
impairs the autophagic removal of lipid stores in the liver,
prompting excessive hepatic lipid deposition. Hotamisligil and
colleagues (Yang et al., 2010a) strengthened these findings by
showing that hepatic Atg7 expression is severely impaired in
ob/ob mice, contributing to the hepatosteatosis in these animals.
Liver fat accumulation was reduced by liver-specific restoration
of Atg7 expression.
While the effects of autophagy in genetically obese mice and in
mice fed high-fat diets seem consistent, a role for autophagy in
lipid metabolism of normal mice remains controversial. First,
autophagy appears to be predominantly relevant in the liver after
abnormally long fasting periods. Normally, during shorter fasting
periods the hepatic fat content increases due to the induction of
adipose tissue lipolysis and increased FA supply to the liver. It is
unlikely that autophagy would be induced under this condition.
Consistent with this prediction, Hotamisligil and colleagues did
not observe hepatic steatosis or changes in serum TG or FA
levels in lean mice following siRNA-mediated suppression of
Atg7, arguing that lipoautophagy is not involved (Yang et al.,
2010a). Second, hepatosteatosis as a result of Atg7 deficiency
was observed in some but not all studies. Although Atg7 defi-
ciency leads to severe liver enlargement, it is controversial
whether TGs accumulate. In fact, Uchiyama and colleagues
reported that hepatic Atg7 deletion upon starvation inhibits LD
formation both in vivo and in vitro, which leads to a lower hepatic
TG content (Shibata et al., 2009, 2010). Consistent with a role
for LC3 in LD formation, RNAi-mediated suppression of LC3-
expression prevented LD formation in a panel of different
(hepatic and nonhepatic) cell lines. Interestingly, LC3 localized
to the surface of LDs, and the authors argued that lipidation of
LC3 by phosphatidylethanolamine (formation of LC3-II), which
is the initial step in autophagosome formation during autophagy,
is also required for LD formation. A potential role of autophagy in
lipogenesis but not in lipolysis is consistent with the finding that
external administration of FAs induces, rather than inhibits, auto-
phagy when LDs are formed in the fasting liver (Tang et al., 2011).
A role for autophagy in lipogenesis also became evident from
analysis of adipose tissue in Atg7-deficient mice. Assuming
a lipolytic defect, we speculated that ablation of autophagy in
adipocytes would result in an obese phenotype (Zechner and
Madeo, 2009). In contrast, however, adipose-specific knockout
of Atg7 resulted in lean mice with reduced adipose mass,
enhanced insulin sensitivity, and an elevated rate of b-oxidation
(Singh et al., 2009b). The adipocytes contained smaller, multiloc-
ular LDs and exhibited normal basal lipolysis. In line with this,
inhibition of autophagy in cultured adipocytes using Atg7 siRNA
blocked TG accumulation (Singh et al., 2009b). Taken together,
these data argue for a currently poorly understood role of auto-
phagy in the biogenesis of LDs. Interestingly, while adipose-
specific Atg7-deficient mice display reduced WAT mass, BAT
mass increases (Baerga et al., 2009; Singh et al., 2009b). Singh
et al. argued that inhibition of white adipocyte differentiation
may lead to a defect in lipogenesis or that blocked autophagy
may promote WAT to BAT transdifferentiation.
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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
of increased energy demand. This view changed when it was
realized that 1) LDs are present in essentially all cell types,
including those for which mere energy storage does not seem
to be the main purpose; 2) LDs, particularly in nonadipose
tissues, undergo very dynamic changes of formation and degra-
dation; and 3) LDs represent a reservoir of bioactive lipids and
lipid-derived hormones in adipose and nonadipose tissues.
A role for neutral lipid metabolism in signaling gained substan-
tial interest when it was noted that increased cellular TG concen-
trations are strongly associated with insulin resistance in skeletal
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
are not the culprit was also supported by the so-called athletes’
paradox. Endurance athletes accumulate more TGs in LDs of
skeletal myocytes than do untrained individuals, yet their muscle
is highly insulin-sensitive. Similarly, mice that lack ATGL accu-
mulate large amounts of fat in numerous tissues (including skel-
etal muscle, cardiac muscle, liver, kidneys, and macrophages)
but exhibit increased insulin sensitivity (Haemmerle et al.,
2006; Kienesberger et al., 2009a). Increased insulin sensitivity
is observed despite the fact that ATGL-deficiency leads to an
insulin-secretion defect in pancreatic islets (Peyot et al., 2009).
In humans, ATGL-deficiency leads to neutral lipid storage
disease with myopathy (NLSDM), with a similar lipid phenotype
as observed in ATGL-deficient mice (Fischer et al., 2007).
Patients lacking the ATGL coactivator CGI-58 not only develop
neutral lipid storage disease but also exhibit a severe skin defect
(neutral lipid storage disease with ichthyosis, NLSDI) (Lefe
`vre
et al., 2001). To date, defective pancreatic insulin production
and alterations in insulin sensitivity have not been reported in
patients with NLSDM or NLSDI. In conclusion, cellular TG
content can be a marker of insulin resistance under certain phys-
iological conditions but is not a regulator of insulin signaling.
Lipolysis-Derived FAs and PPAR Signaling
Besides their powerful role as energy substrates and precursors
of other lipids, FAs are directly involved in cellular signaling path-
ways and regulation of gene transcription. FAs or FA derivatives
can bind to and activate members of the nuclear receptor family
of transcription factors that control the expression of genes
involved in lipid and energy homeostasis and inflammation.
The best-studied FA-activated nuclear receptors are the PPARs.
The PPAR family consists of four members: PPARa, PPARg-1
and -2, and PPARd(also designated PPARb). PPARaand
PPARdare highly expressed in oxidative tissues and regulate
genes involved in substrate delivery, substrate oxidation, and
oxidative phosphorylation (OXPHOS). In contrast, PPARgis
more important in lipogenesis and lipid synthesis, with highest
expression levels in WAT. The full transcriptional activity of
PPARs requires the binding of cognate lipid ligands, heterodime-
rization with another nuclear receptor (retinoid-X receptor, RXR),
and interaction with a number of transcriptional coactivators,
including PPARgcoactivator-1 (PGC-1). In addition to FAs, other
lipid ligands also have been described to activate PPARs, such
as acyl-CoAs, glycerol-phospholipids, and eicosanoids.
FAs involved in signaling originate from import of exogenous
FAs (from circulating FA-albumin complexes or from LPL-medi-
ated hydrolysis of plasma VLDL and chylomicrons) or from
endogenous de novo synthesis. Recently it was shown that
neither source of FA can generate PPAR ligands directly; rather,
a cycle of FA esterification and rehydrolysis is required (Haem-
merle et al., 2011)(Figure 2). As a consequence, lipolysis-
impaired ATGL-deficient mice exhibit a severe defect in PPARa
signaling in oxidative tissues such as liver (Ong et al., 2011),
macrophages (Chandak et al., 2010), and BAT (Ahmadian
et al., 2011). The most dramatic phenotype is observed in
cardiac muscle (Haemmerle et al., 2011). The reduced expres-
sion of PPARatarget genes in ATGL knockout animals causes
severe mitochondrial dysfunction, decreased rates of substrate
oxidation and OXPHOS, massive cardiac lipid accumulation,
and lethal cardiomyopathy within a few months after birth. HSL
deficiency is also associated with moderately decreased PPARa
target-gene expression but does not generate a comparable
cardiac phenotype, indicating the specific importance of ATGL
activity in the generation of PPARaligands or ligand precursors.
Figure 2. ATGL-Mediated Lipolysis Is Required for PPAR Signaling
and OXPHOS
Fatty acids from exogenous or endogenous sources are activated to acyl-
CoAs, which are subject to mitochondrial oxidation or TG formation. ATGL-
mediated lipolysis of TG generates lipolytic products (FA and DG), which may
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
PPARavia lipolytic cleavage of TGs is required for normal mitochondrial
function and OXPHOS. In ATGL-deficient mice, defective PPARaactivation
and OXPHOS can be restored by treatment with PPARaagonists. ATGL,
adipose triglyceride lipase; CD36, cluster of differentiation 36; DG, diac-
ylglycerol; FA, fatty acid; FATP, fatty acid transport protein; LPL, lipoprotein
lipase; OXPHOS, oxidative phosphorylation; PPARa/d, peroxisome pro-
liferator-activated receptor alpha/delta; RA, retinoic acid; RXR, retinoid X
receptor; TG, triacylglycerol.
284 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.
Cell Metabolism
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NLSDM or NLSDI in humans due to the deficiency of ATGL or
CGI-58, respectively, may also lead to reduced PPARasignaling
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 PPARaactivators, such as Wy16453 or fenofibrate
(Haemmerle et al., 2011). Treatment of ATGL-deficient mice
leads to increased PPARasignaling, 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 PPARasignaling,
the enzyme may also affect PPARgfunction. Festuccia et al.
(Festuccia et al., 2006) showed that rosiglitazone-mediated
PPARgactivation 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
synthesis, it is conceivable that this step is required to promote
PPARg-activated expression of lipogenic genes. Moreover, the
fact that HSL-deficiency also leads to downregulation of PPARg
target-gene expression in WAT (Shen et al., 2011; Zimmermann
et al., 2003) suggests that lipolysis is involved in PPARgsignaling.
Lipolysis-Derived FAs and Insulin Signaling
It is well established that both plasma and cellular FA concen-
trations correlate positively with increased insulin resistance
(Boden and Shulman, 2002). Several mechanisms are discussed.
Increased cellular concentrations of nonesterifiedFAs, particularly
palmitate,can drive the synthesisof lipotoxic lipids suchas ceram-
ides, which interfere with functional insulin signaling (Summers,
2010). Additionally, FAs can directly or indirectly—via increased
production of reactive oxygen species—activate redox-sensitive
serine kinases, which, in turn, inactivate the insulin response
(Vallerie and Hotamisligil, 2010). Yet, not all FA species seem to
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
(Cao et al., 2008). Palmitoleate is mostly generated by de novo
synthesis in adipose tissue. Its effects on insulin signaling in liver
and muscle suggest that this FA is a lipokine with endocrine func-
tion. Additionally, it is conceivable that hepatic palmitoleate also
contributes to insulin sensitization in a paracrine fashion. Whether
lipolysis contributes to the generation of palmitoleate or other FAs
with a downstream effect on insulin signaling requires additional
studies. ATGL-deficient mice have low plasma FA concentrations
and are highly insulin-sensitive, arguing for a protective role of
reduced lipolysis and low FA levels. Whether low plasma FAs in
HSL-deficient mice also affect insulin sensitivity is controversial
(Mulder et al., 2003; Park et al., 2005; Voshol et al., 2003).
Lipolysis-Derived DGs Are Unlikely to Affect
PKC Signaling
The potential of DGs to act as second messengers was discov-
ered approximately 50 years ago when researchers realized that
DGs affect many metabolic and mitogenic activities via activa-
tion of protein kinase-C (PKC). Metabolic regulation involves
suppression of insulin signaling via phosphorylation of insulin
receptor substrate-1, leading to insulin resistance in muscle
and liver (Samuel et al., 2010). Only one DG stereoisomer,
1,2-diacyl-sn-glycerols (1,2-DGs), is able to activate PKCs,
whereas the others, 1,3-diacyl-sn-glycerols (1,3-DGs) and
2,3-diacyl-sn-glycerols (2,3-DGs), lack this bioactivity (Boni
and Rando, 1985). 1,2-DGs activate conventional and novel
PKC isoforms after recruitment of the enzymes to the plasma
membrane by receptor of activated C kinase (RACK) proteins
(Turban and Hajduch, 2011). Accordingly, both stereo-specific
and location-specific preconditions are required for DGs to acti-
vate PKCs. Three potential sources exist for the generation of
1,2-DGs (Figure 3). Classical signaling 1,2-DGs derive from
phospholipase C (PLC)-mediated hydrolysis of phosphatidylino-
sitol-4,5-phosphate in the plasma membrane. Vertebrates have
13 isoforms of PLC grouped within 6 isotypes. Both products of
Figure 3. Lipolysis and Lipid Signaling
Lipid intermediates involved in cellular signaling are generated by anabolic and
catabolic reactions in distinct cellular compartments. 1,2-DGs, the ligands of
conventional and novel PKCs, are formed at the plasma membrane by
PLC-mediated degradation of PIP2. This reaction also generates IP3,
a signaling molecule, which leads to Ca
2+
efflux from the ER. De novo
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
hydrolysis of neutral lipids or phospholipids. 2-AG is an important MG involved
in endocannabinoid signaling. It originates from membrane-associated
phospholipid hydolysis by PLCs and the subsequent hydrolysis of DGs by
DAGLs. The contribution of TG hydrolysis by ATGL and HSL to cellular 2-AG
concentrations is not known. The 2-AG signal is inactivated by MGL. AGPAT,
acyl-CoA acylglycerol-3-phosphate acyltransferase; 2-AG, 2-arachidonoyl-
glycerol; ATGL, adipose triglyceride lipase; DAGL, diacylglycerol lipase; DG,
diacylglycerol; 11, 2-DG, diacyl-sn1,2-glycerol, DGAT, acyl-CoA: diac-
ylglycerol acyltransferase; FA, fatty acid; G, glycerol; G3P, glycerol-3-phos-
phate; GPAT, glycerol-3-phosphate acyltransferase; HSL, hormone-sensitive
lipase; IP3, inositol-1,4,5-trisphosphate; LPA, lysophosphatidic acid; MG,
monoacylglycerol; MGL, monoglyceride lipase; PA, phosphatidic acid;
PAPase, PA phosphohydrolase; PIP2, phosphatidylinositol 4,5-bisphosphate;
PKC, protein kinase C; PLC, phospholipase C; TG, triacylglycerol.
Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 285
Cell Metabolism
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the enzymatic reaction, 1,2-DGs and inositol-1,4,5-phosphate
(IP
3
), are potent second messengers. Whereas 1,2-DGs remain
plasma membrane-associated, IP
3
dissociates and induces
Ca
2+
release from the ER, which is required in addition to
1,2-DGs for activation of conventional PKCs.
Although PLCs generate the ‘‘correct’’ stereoisomer (1,2-DGs)
in the ‘‘correct’’ cellular location for PKC activation, it remains
controversial whether other cellular sources also contribute
to the production of signaling 1,2-DGs. De novo synthesis via
dual acylation of sn-glycerol-3-phosphate by acyl-CoA glyc-
erol-3-phosphate acyltransferases (GPATs) and acyl-CoA acyl-
glycerol-3-phosphate acyltransferases (AGPATs), and subse-
quent dephosphorylation of phosphatidic acid by phosphatidic
acid phosphohydrolases (PAPases) also leads to the formation
of 1,2-DGs (Figure 3). However, this pathway of DG synthesis
is restricted to ER membranes. Accordingly, a model proposing
activation of PKC by ER-associated 1,2-DGs needs to include
PKC localization to the ER or contact sites between the plasma
membrane and the ER membrane.
The third potential source of DGs derives from the lipolysis of
LD-associated TGs by ATGL (Figure 3). The stereospecificity of
ATGL has not been reported. However, our unpublished obser-
vations showed that the enzyme preferentially hydrolyzes sn-1
and sn-2 ester bonds but not sn-3 esters. This indicates that
ATGL generates 1,3-DGs and 2,3-DGs but not 1,2-DGs. In
accordance with the subsequent hydrolysis of 1,3-DGs and
2,3-DGs by HSL, this enzyme has a stereo-preference for the
hydrolysis of FAs in the sn-3 position of DGs (Rodriguez et al.,
2010). In TGs, HSL preferably hydrolyses sn-1(3) ester bonds
(Fredrikson and Belfrage, 1983). Therefore, neither the ATGL
nor the HSL reaction generate 1,2-DGs on LDs. Additionally, it
is questionable whether LD-associated DGs would dissociate
from LDs to participate in the recruitment and activation of
PKC at the plasma membrane. From all this, it seems unlikely
that lipolytically generated DGs act as signaling mediators.
In a recent review, Shulman and colleagues (Samuel et al.,
2010) summarized numerous animal and human studies pro-
viding evidence that cellular DG concentrations account for the
development of lipid-induced insulin resistance in type 2 dia-
betes, lipodystrophy, and other conditions. Consistent with this
hypothesis, mice lacking DG-kinase-d, the major enzyme that
inactivates the DG signal, have increased DG levels and
increased insulin resistance (Chibalin et al., 2008). However,
considering the structural complexity of DG species and their
localization in different cellular compartments, a general correla-
tion between total cellular DG concentrations and insulin re-
sistance seems unlikely. This is supported by studies where
increased total cellular DG concentrations in mutant mouse
models were not associated with insulin resistance. For ex-
ample, HSL-deficient mice accumulate large amounts of DGs
in adipose and many nonadipose tissues due to defective DG
catabolism. Yet, most studies agree that this does not lead to
PKC hyperactivation or a severely defective insulin response
(Mulder et al., 2003; Park et al., 2005; Voshol et al., 2003).
Similarly, CGI-58 silencing in the liver leads to increased DG
levels, but normal (chow diet) or increased (high-fat diet) glucose
tolerance and insulin sensitivity (Brown et al., 2010).
Taken together, determination of the specific 1,2-DG concen-
trations in the plasma membrane may provide a more reliable
predictor for lipid-induced, PKC-mediated insulin resistance
than total cellular DG concentrations.
Monoacylglycerol Signaling and Lipolysis
The signaling potential of MGs was recognized when it
was found that the phospholipid-derived MG 2-AG activates
cannabinoid receptors (CBR), thereby regulating food intake,
lipid metabolism, and energy homeostasis. The endocannabi-
noid system (ECS) refers to a group of neuromodulatory lipids
(endocannabinoids, ECs), two G protein-coupled receptors
(CBR1 and CBR2), and enzymes involved in the synthesis and
degradation of ECs (Di Marzo, 2009). The best-characterized
ECs are N-arachidonoyl ethanolamine (AEA, anandamide) and
2-AG. Their biological effect is mimicked by D
9
-tetrahydrocan-
nabinol (THC), the major psychoactive component of marijuana.
The ECS regulates a diverse spectrum of physiological pro-
cesses, including motor function, pain, appetite, cognition,
emotional behavior, and immunity. In the nervous system,
2-AG acts as a retrograde messenger, inhibiting presynaptic
neurotransmitter release (Alger and Kim, 2011). It is produced
postsynaptically and traverses the synaptic cleft to stimulate
presynaptic CBR1. Subsequently, 2-AG is internalized into the
presynaptic terminal and inactivated by the MGL reaction,
forming glycerol and arachidonic acid. The ECS is active in
neurons and nonneuronal cells such as immune cells, hepato-
cytes, and adipocytes. Treatment of obese patients with the
CBR1-antagonist rimonabant (Christopoulou and Kiortsis,
2011) and studies with animal models lacking CBR1 revealed
that blockade of the ECS reduces food intake, decreases lipo-
genesis, and increases energy consumption. Conversely, an
overactive ECS has a central orexigenic effect and reduces
energy expenditure, promoting lipid deposition in peripheral
tissues like the liver and WAT (Cota, 2008). Because of these
biological effects, the ECS has been linked to the pathogenesis
of metabolic diseases. Obese patients may have an overactive
ECS, which stimulates appetite and promotes lipid deposition
(Perkins and Davis, 2008).
It is generally assumed that signaling 2-AG originates from
the degradation of glycerophospholipids containing arachidonic
acid in the sn-2 position (Figure 3). Various isoforms of PLC
generate 1,2-DGs (see above), which are subsequently hydro-
lyzed by DG lipase (DAGL) to 2-AG. Whether HSL also partici-
pates in the hydrolysis of plasma membrane-associated
1,2-DGs to generate 2-AG is not known. Current evidence
suggests that at least two isoforms of DAGL (DAGLaand DAGLb)
exist in the brain and liver (Bisogno et al., 2003). Mice lacking
DAGLaexhibit a substantial decrease in brain and spinal cord
2-AG levels, whereas DAGLbappears to be more important in
peripheral tissues, such as the liver (Gao et al., 2010). Whether
the catabolism of arachidonic acid-containing TGs in LDs by
ATGL and HSL also contributes to the cellular 2-AG and arach-
idonic acid pool is not known.
Recent studies using an MGL-specific small-molecule inhib-
itor (JZL184) and MGL knockout mice provided compelling
evidence that MGL is the major enzyme in the degradation of
2-AG and other MGs esterified with long-chain FAs (Chanda
et al., 2010; Schlosburg et al., 2010; Taschler et al., 2011).
Animals lacking MGL or mice treated with JZL184 show abnor-
mally high amounts of various MG species in the brain and
286 Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc.
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peripheral tissues. In the brain, lack of MGL activity leads to
a more than 20-fold increase in 2-AG, suggesting that MGL-defi-
ciency could lead to hyperactivation of the ECS. Indeed, JZL184
treatment of mice provoked cannabimimetic effects in mice,
including analgesia, hypothermia, and hypomotility (Long et al.,
2009). However, genetic ablation of MGL in mice did not result
in a hyperactive ECS or any obvious phenotype. This surprising
observation was explained by desensitization of brain CBR1
leading to functional antagonism, and highlights the important
role of 2-AG as a retrograde neurotransmitter (Chanda et al.,
2010; Schlosburg et al., 2010). Obviously, increased brain
2-AG concentrations provoke counter-regulatory mechanisms
similar to those observed when animals are chronically fed
CBR agonists (Lichtman and Martin, 2005).
Although MGL-deficiency in mice does not produce cannabi-
mimetic effects, the lack of MGL activity substantially affects
lipolysis and metabolism in adipose tissue and nonadipose
tissues (Taschler et al., 2011). MGL deficiency results in the
accumulation of MGs and a reduction of circulating TG and glyc-
erol levels in fasted animals. Unexpectedly, and in contrast to the
proposed role of the ECS in obesity-related metabolic diseases,
MGL knockout mice exhibit improved insulin sensitivity and
glucose tolerance when fed a high-fat diet. The cause for this
finding may be complex, considering that MGL-deficiency is
associated with desensitized CBRs. Investigation of mice lack-
ing MGL, specifically in the brain or peripheral tissues, should
help to unravel the question of whether central or peripheral
effects cause attenuation of insulin resistance.
Lipolysis in the Cell Cycle, Cancer, and Cachexia:
A Question of Lipid Signaling?
The first observation to indicate that lipolysis is linked to efficient
cell-cycle progression was reported in the yeast S. cerevisiae.
Yeast expresses three TG lipases of the patatin domain-contain-
ing family termed Tgl3 to 5 (Czabany et al., 2007). Tgl4 is a func-
tional ortholog of mammalian ATGL (Kurat et al., 2006). Deletion
of Tgl3 and Tgl4 abolishes virtually all cellular TG lipase activity
and causes a marked delay of entry into the cell division cycle
of starved cells upon refeeding (Kurat et al., 2009). Tgl4 is
activated via phosphorylation by the cyclin-dependent kinase
Cdk1/Cdc28 (ortholog of mammalian Cdc2). Concomitantly,
Cdk1/Cdc28 inhibits lipogenesis by phosphorylation of phos-
phatidic acid phosphohydrolase (Pah1). This suggests that TG
levels oscillate during the cell-division cycle to either deposit
de novo synthesized FAs in TGs or, conversely, to provide FAs
during phases of increased demand. Tgl4 phosphorylation and
activation occur at the G1/S transition of the cell-division cycle,
which coincides with bud emergence and requires increased
amounts of membrane lipids. Pah1 phosphorylation and inacti-
vation occur at the G2/M transition of the cell cycle, indicating
that a window exists during the cell cycle in which both the initial
step of lipogenesis and lipolysis may operate in parallel. This is
feasible because both activities are confined to different organ-
elles, namely the ER and LDs, respectively. The specific check-
point proteins that regulate cell-cycle progression in response
to lipolysis are currently unknown. Recent evidence shows that
the synthesis of phosphatidylinositol (PI), a precursor for signal-
ing molecules in cell-cycle regulation in yeast (e.g., IP
3
and
inositol-containing ceramides), strongly depends on intact lipol-
ysis (Gaspar et al., 2011). Thus, cell cycle-regulated TG lipolysis
may provide critical precursors for signaling molecules for cell
division.
A highly interesting study recently demonstrated that MGL
promotes the oncogenic properties of mammalian cancer cells
(Nomura et al., 2010). The authors demonstrated that overex-
pression or disruption of MGL activity increased or decreased,
respectively, the proliferation of cancer cells, and that MGL is
highly expressed in aggressive tumor cell lines or primary
tumors. The study also provided evidence that MGL influences
tumor proliferation by metabolic effects rather than by CBR-
dependent mechanisms. The lack of MGL reduced cellular
nonesterified FA concentrations. Growth of tumor cells in
response to MGL-knockdown was not impaired after addition
of exogenous nonesterified FAs or in mice fed a high-fat diet.
This led to the conclusion that MGL affects the concentration
of FA-derived tumorigenic lipid metabolites, such as LPA and
PGE
2
. Although the involved lipid signal(s) requires identification,
these studies clearly designate MGL as an interesting target for
cancer therapy.
Lipolytic signaling may also be causally involved in the patho-
genesis of cancer-associated cachexia (CAC). In a recent study,
Das et al. (Das et al., 2011) demonstrated that ATGL-deficient
mice are protected against tumor-induced loss of adipose tissue
and skeletal muscle. HSL-deficient mice were also protected,
although to a lesser degree. ATGL-deficient mice maintained
body weight and composition despite increased circulating
factors that induce lipolysis, muscle proteolysis, and apoptosis
(e.g., TNFa, interleukin-6, and zinc-a-glycoprotein 1). This sug-
gests that lipolysis is integrated in a signal transduction network
that eventually leads to the loss of adipose tissue and muscle.
This view is also consistent with the observation that the activity
of lipolytic enzymes and release of FAs and glycerol are
increased in adipose tissue of cancer patients with cachexia
(Agustsson et al., 2007; Das et al., 2011; Ryde
´n et al., 2008).
The nature of the lipolytic signal involved is currently unknown.
It is also unclear whether the signal originates from lipolysis in
one tissue (such as adipose tissue) and promotes wasting in
an endocrine manner or whether wasting requires autonomous
lipolysis in all tissues that are affected by wasting. Although the
underlying mechanism is not yet defined, this study suggests
that inhibition of lipolysis may help to prevent cachexia in
patients with cancer or other chronic diseases.
Conclusion
Recent discoveries of enzymes and regulatory factors have led
to a revision of our perception of lipolysis. The complexity of
the process and its regulation are still only partially understood.
Additionally, we have just begun to address the role of lipolytic
products and intermediates in cellular signaling. Important
topics for future investigations include: 1) better understanding
of the biochemical factors and processes that coordinately
regulate the lipolytic machinery in response to hormonal activa-
tors and inhibitors, 2) the physiological function of lipolysis in
numerous nonadipose tissues and the tissue-specific differ-
ences in lipolytic mechanisms, and 3) the characterization
of lipolytic signals and the molecular mechanisms of their
effects on gene transcription, the cell cycle, and cell growth.
The recent examples of lipases affecting tumor proliferation or
Cell Metabolism 15, March 7, 2012 ª2012 Elsevier Inc. 287
Cell Metabolism
Review

cancer-associated cachexia emphasize the potential impor-
tance of lipolysis in human disease.
ACKNOWLEDGMENTS
This work was supported by the grants P20602, P18434, P21296, F30 SFB
LIPOTOX, the Doktoratskollegs W901 and W1226, and the Wittgenstein Award
Z136, which are funded by the Austrian Science Foundation. Funding was also
provided by the grant ‘‘GOLD: Genomics Of Lipid-associated Disorders,’’
which is part of the Austrian Genome Project ‘‘GEN-AU: Genome Research
in Austria’’ funded by the Austrian Ministry of Science and Research and the
FFG. Additional support was obtained from the European commission grant
agreements no. 202272 (LipidomicNet), the City of Graz and the Province of
Styria. We thank Dr. Ellen Zechner, Mag. Caroline Schober-Trummler, and
Mag. Dr. Tarek Mustafa for careful and critical reading of the manuscript.
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