Dissecting Adipose Tissue Lipolysis

with particular focus on the molecular regulation of the two main lipases, ATGL and HSL, and
the intracellular and extracellular signals affecting their activity.

Journal of Molecular Endocrinology
(2014) 52, R199R222
T S NIELSEN
and others
Dissecting adipose tissue

lipolysis
Review
52 :3
R199R222
Dissecting adipose tissue lipolysis:

molecular regulation and
implications for metabolic disease
Thomas Svava Nielsen
1,2
, Niels Jessen
Niels Mller and Sten Lund
2,3
, Jens Otto L Jrgensen ,
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b
8000 Aarhus C, Denmark
3
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupga rdsvej 100, 8200 Aarhus N, Denmark
Abstract
Lipolysis is the process by which triglycerides (TGs) are hydrolyzed to free fatty acids (FFAs)
and glycerol. In adipocytes, this is achieved by sequential action of adipose TG lipase
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Key Words
(ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase. The activity in the
"
lipolysis
lipolytic pathway is tightly regulated by hormonal and nutritional factors. Under conditions
"
adipose tissue
of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a
"
ATGL
to provide the organism with a sufficient supply of substrate for oxidative metabolism.
"
HSL
However, failure to efficiently suppress lipolysis when FFA demands are low can have
"
free fatty acids
"
type 2 diabetes
profound increase in FFA release from adipose tissue (AT). This response is crucial in order
serious metabolic consequences and is believed to be a key mechanism in the

development of type 2 diabetes in obesity. As the discovery of ATGL in 2004, substantial
progress has been made in the delineation of the remarkable complexity of the
regulatory network controlling adipocyte lipolysis. Notably, regulatory mechanisms have
been identified on multiple levels of the lipolytic pathway, including gene transcription
and translation, post-translational modifications, intracellular localization, proteinprotein
interactions, and protein stability/ degradation. Here, we provide an overview of the
recent advances in the field of AT lipolysis
Introduction
The major energy reserve in mammals consists of fat
stored in adipose tissue (AT). In periods of excess energy
intake, dietary lipids are taken up by fat cells
(adipocytes) in AT and esterified into triglycerides (TGs),
which are stored in cytosolic lipid droplets (LDs). In
conditions like fasting and exercise, when mobilization
of endogenous energy stores is required, TG is
hydrolyzed through the process of lipolysis and released
to the circulation as free fatty acids
http://jme.endocrinology-journals.org
DOI: 10.1530/JME-13-0277
2014 Society for

Endocrinology
Printed in Great
(FFAs). These are delivered to peripheral tissues where

they can serve as substrate for b-oxidation and ATP
production. Only adipocytes have the ability to secrete
FFAs into the circulation (Kolditz & Langin 2010).
Hence, in the postabsorptive state and during
physical exercise, the vast majority of the systemic FFA
originates from AT (Jensen 2003). The unique ability of
AT to balance storage and release of lipids in response
to altered nutrient demands
Published by Bioscientifica Ltd.
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provides the organism with an FFA-buffering system of

essentially unlimited capacity (Frayn 2002). However, the
metabolic consequences of an excessive expansion of AT
are considerable. In humans, obesity is closely associated
with numerous risk factors that constitute the so-called
metabolic syndrome. This includes abdominal obesity,
hypertension, dyslipidemia, and glucose intolerance,
which are key elements in the pathogenesis of cardiovascular disease and type 2 diabetes (Alberti et al. 2009). The
physiological link between obesity and metabolic disease
in humans is currently not completely understood, and
one of the great enigmas is the remarkable individual
differences in the predisposition to obesity-induced
metabolic disease. This has led to the proposal of the
AT expandability hypothesis (Virtue & Vidal-Puig 2010,
Hardy et al. 2012), which states that the capacity of AT to
expand appropriately when lipid storage is needed is
limited for a given individual. Hence, when the limit is
exceeded, lipids begin to accumulate in ectopic tissues
causing metabolic dysfunction and insulin resistance due
to lipotoxic effects. An emerging view is that this
lipotoxicity is likely not caused by excess TG in itself,
but rather by an excess of lipid intermediates and
metabolites released from hypertrophic adipocytes.
Several recent reviews have addressed these mechanisms
in detail (Boura-Halfon & Zick 2009, Virtue & Vidal-Puig
2010, Copps & White 2012, Hardy et al. 2012, Zechner
et al. 2012, Czech et al. 2013). Notably, it is now clear that
besides serving as energy-dense metabolic substrates,
most, if not all, lipolytic products and intermediates like
diacylglycerol (DG), monoacylglycerol (MG), and FFA
(and metabolites derived from these) play essential roles
in multiple signaling pathways, both at the systemic and
at the intracellular level (Zechner et al. 2012). When
present in excess, several of these lipid intermediates
have been suggested to induce insulin resistance in
ectopic tissues by interfering with insulin signaling at the
level of the insulin receptor substrate (IRS) proteins
(Boura-Halfon
& Zick 2009, Copps & White 2012).
Being the major lipid species released from AT, FFA
is likely one of the key elements in ectopic lipid
accumulation and lipotoxicity. Thus, experimental
elevation of plasma FFA levels in human subjects
acutely and dose dependently counteracts peripheral
insulin-stimulated glucose uptake and oxidation (Belfort
et al. 2005, Gormsen et al. 2007, Hoeg et al. 2011).
Furthermore, high FFA levels attenuate the insulinmediated suppression of hepatic glucose production
contributing to the impairment of whole-body glucose

lipolysis
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tolerance (Roden et al. 2000). Consist- ently, improvements

in whole-body insulin sensitivity
and oral glucose tolerance can be obtained by

pharmacological reductions of chronically elevated
plasma FFA levels both in type 2 diabetic patients,
obese nondiabetic subjects, and nondiabetic subjects
genetically predisposed to
type
2
diabetes
(Santomauro et al. 1999, Cusi et al. 2007).
Accordingly, excessive FFA mobilization from AT is
widely conceived as playing a pivotal role in insulin
resistance and type 2 diabetes, suggesting that
dysregula- tion of AT lipolysis in the obese state is a
contributing factor to the development of metabolic
disease.
Major signaling pathways in AT lipolysis

Lipolysis is the sequential hydrolysis of one TG
molecule into three FFAs and one glycerol by a class of
hydrolytic enzymes commonly known as lipases. In
mammalian lipolysis, three lipases act in sequence with
the concomitant release of one FFA in each step (Fig.
1); adipose TG lipase (ATGL) converts TG to DG and is
the rate-limiting enzyme in the lipolytic pathway
(Zimmermann et al. 2004). DG is hydrolyzed to MG by
hormone-sensitive lipase (HSL; Haemmerle et al. 2002),
and monoglyceride lipase (MGL) cleaves MG into
glycerol and FFA (Fredrikson et al. 1986). The major
positive
regulators
of
human
lipolysis
are
catecholamines and natriuretic peptides (NPs), while

antilipolysis primarily is mediated by insulin and
catecholamines.
Catecholamines
The catecholamines, and specifically the stress hormones
adrenaline and noradrenaline, are the primary mediators
of adrenergic signaling in AT. The manner by which
catecholamines regulate lipolysis is unusual as these
hormones are able to both stimulate and inhibit lipolysis
depending on their relative affinity for different
adrenergic receptors (ARs). Thus, stimulation of lipolysis
requires the activation of b-ARs on the surface of the
adipocyte, while antilipolytic signals are transmitted
by the a2-AR
ATGL
TG
HSL
DG
FFA
MGL
MG
FFA
Glycerol
FFA
Figure 1
Schematic illustration of the lipolytic pathway. To fully hydrolyze TGs,
ATGL, HSL, and MGL act in sequence, with the release of one FFA in
each step. This successively converts TG to DG, then to MG, and finally
to glycerol and a total of tree FFA. TG, triglyceride; ATGL, adipose TG
lipase; DG, diacylglycerol; FFA, free fatty acid; HSL, hormone-sensitive
lipase; MG,
monoacylglycerol; MGL, monoglyceride lipase.
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(Robidoux et al. 2004; Fig. 2). Three different b-AR

subtypes exist (b1, b2, and b3), but in humans, only
the b1 and b2 isoforms are involved in lipolysis (Mauriege
et al. 1988, Barbe et al. 1996, Tavernier et al. 1996). Both
a2-AR and b-AR belong to the G-protein-coupled
receptor (GPCR) family: the G-protein associated with
a2-AR contain the inhibitory Gi subunit, while b-ARassociated
G-proteins
contain
the
stimulating
Gs
subunit (Lafontan
& Berlan 1993). The activation of the receptors causes the
G-proteins to interact with adenylyl cyclase (AC), which
is inhibited by interaction with Gi and activated by
interaction with Gs (Lafontan & Berlan 1993). Upon
activation, AC converts ATP to cAMP, resulting in an
increase in intracellular cAMP levels, which activates
protein kinase A (PKA, also known as cAMP-dependent
protein kinase; Langin 2006). Activated PKA phosphorylates the LD-associated protein PLIN1 (Greenberg
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Garton et al. 1988, Anthonsen et al. 1998). Phosphorylation of PLIN1 promotes the release of comparative gene
identification-58 (CGI-58), which is a potent co-activator
of ATGL (Lass et al. 2006, Granneman et al. 2009). This
facilitates the activation of ATGL, thus initiating the
stimulated lipolytic cascade. Furthermore, PKA-mediated
phosphorylation of HSL causes a rapid activation and
translocation of the lipase from the cytosol to the surface
of the LDs (Egan et al. 1992). Here, it docks on the
phosphorylated PLIN1 and thereby gains access to its DG
substrate, which is being generated by ATGL (Shen et al.
2009, Wang et al. 2009).
Natriuretic peptides
In addition to catecholamines, the cardiac hormones
atrial NP (ANP) and B-type NP (BNP) are important
positive regulators of AT lipolysis in humans. NPs, which
NPR-A
1/2-AR
AC
Gi
GC
Cytosol
Gs
ATP
PKB/Akt
GTP
cAMP
PIP3
PI3K
cGMP
PDE3B
PDE5
PKA
IR
PKG
5-AMP
PIP2
R201
et al. 1991) and cytoplasmic HSL (Stralfors et al. 1984,
2-AR
PDK
52 :3

lipolysis
5-GMP
IRS1/2
HSL
P
P
P P
HSL
Three FFA
+ glycerol
P
Figure 2
Primary signaling pathways in human lipolysis. Black and red lines
indicate pro-lipolytic and anti-lipolytic signaling events, respectively.
Arrows
indicate stimulation and/or translocation and blunt lines indicate inhibition. Stimulation of lipolysis is dependent on PKA- or PKG-mediated
phosphorylation of HSL and PLIN1. PKG is activated by cGMP, which
is
increased in response to activation of the GC-coupled NPR-A. Similarly,
stimulation of the Gs-protein-coupled b1/2-ARs activates AC, which
generates cAMP and activates PKA. Conversely, activation of Gi-protein-
MGL
MG
DG
TG
P
P
Lipid droplet
coupled a2-ARs inhibits AC and thereby reduces cAMP-dependent
signaling to lipolysis. Stimulation of the insulin signaling pathway through
the IR
increases the activity of PDE3B, which converts cAMP to 50 -AMP, thus
decreasing PKA activity and suppressing lipolysis. PKG activity is reduced by
PDE5-mediated conversion of cGMP to 5 0 -GMP, although the upstream

signals regulating this process are currently unknown. The dashed line
indicates a putative Akt-independent insulin pathway acting
selectively on PLIN1. a2-ARs, a2-adrenergic receptors; AC, adenylyl
cyclase; TG, triglyceride; ATGL, adipose TG lipase; b1/2-ARs, b1- and
b2-adrenergic
receptors; CGI-58, comparative gene identification-58; DG,
diacylglycerol; FFA, free fatty acid; GC, guanylyl cyclase; HSL, hormonesensitive lipase; IR, insulin receptor; IRS1/2, IR substrates 1 and 2; MG,
monoacylglycerol; MGL, monoglyceride lipase; NPR-A, type-A natriuretic
peptide receptor; PDE3B, phosphodiesterase 3B; PDK, phosphoinositidedependent kinase; PI3K,
phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB/Akt, protein
kinase B; PLIN1, perilipin 1.
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are released from the atrial and ventricular walls of the

heart in response to myotube distension (Clerico et al.
2011), stimulate the guanylyl cyclase (GC)-linked type-A
NP receptor on the adipocytes (Sengenes et al. 2000)
(Fig. 2). Accordingly, upon stimulation of the receptor,
GC converts intracellular GTP into cGMP resulting in the
activation of PKG (also known as the cGMP-dependent
protein kinase), and, just like PKA, this kinase activates
the lipolytic cascade by phosphorylation of PLIN1 and
HSL (Sengenes et al. 2003). However, despite the
similarities between PKA- and PKG-mediated lipolysis,
they are distinct pathways and, unlike the cAMPdependent
pathway,
NP-mediated
lipolysis
is
unresponsive
to
the
antilipolytic
effects
of
phosphodiesterase 3B (PDE3B; Sengenes et al. 2000,
Moro et al. 2004a). Instead, counter-regulation of the
NP pathway is believed to occur by hydrolysis of
cGMP by other members of the PDE family of PDEs
(Armani et al. 2011). Indeed, PDE5 expression and
activity has been found in isolated human adipocytes
from both subcutaneous AT (Moro et al. 2007a) and
visceral AT (Aversa et al. 2011); however, this enzyme
appears to be insufcient to control ANP-mediated
lipolysis (Moro et al. 2007a). Hence, at present, the details
of the regulatory pathways counteracting the lipolytic
action of NPs in vivo remains poorly understood (Armani
et al. 2011).
Insulin
Lipolysis is exceptionally sensitive to the action of insulin
(Jensen & Nielsen 2007), which constitutes the major
antilipolytic pathway in human lipolysis (Fig. 2). The IR
possesses intrinsic tyrosine kinase activity. Thus, binding
of insulin induces IR autophosphorylation and subsequent phosphorylation of the IRS1/2 (White 1998).
This promotes the activation of phosphatidylinositol 3kinase (PI3K), which converts phosphatidylinositol- 4,5bisphosphate (PIP2) into phosphatidylinositol-3,4,5triphosphate (PIP3) (Whitman et al. 1988, Carpenter et al.
1990). Generation of PIP3 activates the phosphoinositidedependent kinase causing phosphorylation and
activation of Akt (also known as PKB; Alessi et al. 1997,
Stokoe et al. 1997). Finally, PKB/Akt activates PDE3B,
which degrades cAMP to 50 -AMP (Choi et al. 2006). This
inactivates PKA leading to reduced phosphorylation of
HSL and PLIN1 and suppression of lipolysis.
Interestingly, in a study predating the elucidation of
the canonical insulin signaling pathway, it was demon-

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strated that besides the inhibitory effect on PKA-mediated

signaling, insulin also acts to reduce lipolysis in primary
rat adipocytes by a cAMP-independent mechanism

(Londos et al. 1985). By carefully measuring PKA
activity ratios in response to increasing concentrations
of isoprenaline (a b-AR agonist), the authors found
that when insulin was added to the cells at
submaximal
lipolytic stimulation, the insulinmediated reduction in PKA activity was not sufficient
to explain the resulting drop in lipolysis. Conversely,
under conditions of maximal lipolysis, insulin-mediated
changes in PKA activity could fully account for the
resulting change in lipolytic rates. A recent study in
3T3-L1 adipocytes has partially delineated this
bimodal insulin effect by showing that insulinmediated antilipolysis at submaximal b-AR stimulation (but not at maximal stimulation) can proceed
through an alternative PI3K-dependent pathway that
is independent of Akt (Choi et al. 2010). Acting
through as yet unidentified downstream effectors, the
pathway was shown to inhibit lipolysis by selectively
reducing PLIN1 phosphorylation without affecting the
phosphorylation status of HSL (Fig. 2). Considering the
key role of PLIN1 in the regulation of ATGL- and HSLmediated lipolysis such a pathway would indeed be
expected to have a substantial impact on overall
lipolytic rates.
Besides the inhibitory effects on the lipolytic
pathway, insulin also promotes lipid storage by
activating a range of pathways involved in the uptake,

synthesis, and storage of TG in adipocytes. A
comprehensive review of these lipogenic effects of
insulin has been published recently (Czech et al. 2013).
Alternative regulatory pathways

Although catecholamines, insulin, and NPs represent the
major regulators of human lipolysis, several other factors
can modulate lipolysis in AT, either directly by receptormediated signaling or indirectly by remodeling of the
lipolytic cascade. Figure 3 shows an overview of the
different alternative pathways described below.
Agents acting through cAMP-dependent signaling
GPCR pathways affecting the activity of AC are particularly numerous, emphasizing the central role of the
cAMP- dependent pathway in the regulation of TG
hydrolysis.
Thyroid-stimulating hormone (TSH) and the melanocortins (MCs) adrenocorticotrophic hormone (ACTH) and
melanocyte-stimulating hormone stimulate AC by activation of the Gs-coupled TSH receptor (Laugwitz et al.
1996, End o & Kobayashi 2012) and MC receptors
(Cho et al. 2005, Rodrigues et al. 2013) respectively (Fig. 3).
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lipolysis
Growth hormone
A1-R
HM74a GPR81
2-AR
MC
TSH-r
1/2-AR
Gi
TNFR1
AC
Gi
Gs
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ANGPTL4
NPY-Y 1
Glucocorticoids
52 :3
AC
ANGPTL4-r
Gs
ATP
ATP
cAMP
PKA
IR
HSL
Three FFA
+ glycerol
MGL
DG
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TG
Figure 3
Alternative signaling pathways in lipolysis. Black and red lines indicate
pro- lipolytic and anti-lipolytic signaling events, respectively. Arrows
indicate
stimulation and blunt lines indicate inhibition. Dashed lines illustrate the
indirect lipolytic effects of growth hormone and glucocorticoids by
modulation of receptor sensitivities and ANGPTL4-mediated signaling.
Although the identity of the ANGPTL4 receptor is unknown, the
intracellular signaling has been shown to involve activation of AC.
Stimulation of the Gs-protein-coupled melanocortin (MC) receptor and TSH
receptor (TSH-r) also increases intracellular cAMP levels through activation
of AC. Conversely, the Gi-protein-coupled receptors for NPY/PYY (NPY-Y1),
adenosine (A1-R), b-hydroxybutyrate (HM74a), and lactate (GPR81)
TSH-mediated lipolysis has been found to be particularly

important in neonates and newborns because physiological levels of TSH, as opposed to adrenaline or noradrenaline, potently stimulate human lipolysis at this
developmental stage (Marcus et al. 1988, Janson et al.
1995). By contrast, although a strong lipolytic potential
of the MCs has been observed in several animal species,
including rodents, hamsters, guinea pigs, and rabbits
(Richter & Schwandt 1983, Ng 1990), they seem to have
limited effects on human lipolysis (Bousquet-Melou et al.
1995, Kiwaki & Levine 2003).
Neuropeptide Y (NPY) and peptide YY (PYY) are
released from sympathetic neurons and inhibit AC by
binding to the Gi-protein-coupled NPY-receptor (NPY-Y1;
Fig. 3) on human adipocytes (Serradeil-Le et al. 2000).
Also, in humans, the highest expression of NPY
receptors has been found in subcutaneous AT (Castan et
MG
Lipid droplet
suppress lipolysis by inhibition of AC. Pro-inflammatory signaling through
the TNF-a receptor (TNFR-1) increases lipolysis by suppressing
antilipolytic signaling mediated by the insulin receptor (IR) and a2adrenergic receptors (a2-ARs). For clarity, the intermediate intracellular
steps in the different
signaling pathways have been omitted. AC, adenylyl cyclase;
ANGPTL4, angiopoietin-like protein 4; ATGL, adipose triglyceride
lipase; b1/2-ARs, b1- and b2-adrenergic receptors; CGI-58, comparative
gene
identification-58; DG, diacylglycerol; FFA, free fatty acid; Gi, inhibitory
G-protein; Gs, stimulating G-protein; HSL, hormone-sensitive lipase; MG,
monoacylglycerol; MGL, monoglyceride lipase; PKA, protein kinase A;
PLIN1, perilipin 1; TG, triglyceride; TSH, thyroid-stimulating hormone.
al. 1993), suggesting that the impact of NPY/PYY on

lipolysis is depot specific. The importance of neuronal
regulation of
lipolysis has been underscored by elegant studies in

rodents demonstrating that isolated stimulation of the
hypothalamus with insulin suppresses peripheral AT
lipolysis (Scherer et al. 2011).
The
fasting-induced
circulating
factor
angiopoietin- like protein 4 (ANGPTL4) is a wellestablished negative regulator of lipid uptake in
rodent adipocytes through inhibition of extracellular
lipoprotein lipase activity (Koster et al. 2005,
Sukonina et al. 2006, Lafferty et al. 2013). Recently,
however, ANGPTL4 has also been found to be intimately

involved in the regulation of intracellular cAMPmediated lipolysis in mice (Gray et al. 2012). By an as yet
unidentified mechanism, extracellular ANGPTL4 was
shown to act independently of b-AR activation to
increase intracellular cAMP production via activation of
AC (Gray et al. 2012). The identity of the putative
ANGPTL4 receptor responsible for this effect in
adipocytes is unknown and is currently under
investigation (Koliwad et al. 2012).
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In rat and human adipocytes, extracellular adenosine

efciently inhibits lipolysis via the Gi-coupled adenosine
receptor (A1-R; Fig. 3; Lonnroth et al. 1989, Liang et al.
2002). However, in humans, the concentrations required
in the interstitial fluid for a significant reduction of
lipolysis have been found to be at the very high end of
the physiological range and therefore of uncertain
significance (Lonnroth et al. 1989). The ketone body bhydroxybutyrate (b-OHB) has been shown to inhibit
lipolysis in vitro by activating the human Gi-coupled
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receptor HM74a (Fig. 3; Taggart et al. 2005). HM74a,

which is the ortholog of the mouse PUMA-G receptor, is
also the target of the lipid-lowering drug nicotinic acid
(niacin; Tunaru et al. 2003). Importantly, the observed
inhibition of lipolysis by b-OHB was obtained at concentrations similar to those seen in humans during fasting,
suggesting a feedback mechanism by which b-OHB can
regulate its own production in order to prevent ketoacidosis during starvation (Taggart et al. 2005). Similarly, the
receptor responsible for the antilipolytic effect of lactate
has been identified as GPR81 (Fig. 3; Cai et al. 2008, Liu
et al. 2009a), which is a Gi-coupled receptor highly
homologous to HM74a (Cai et al. 2008). Like b-OHB,
lactate inhibits lipolysis in adipocytes from several
mammalian species including primates, rodents, and
humans at concentrations within the normal physiological range (Liu et al. 2009a). Consequently, it has been
hypothesized that GPR81 could act as a sensor of hypoxia
by suppressing lipolysis in response to increased lactate
production (Cai et al. 2008).
Growth hormone
Growth hormone (GH) potently and dose dependently
stimulates lipolysis in humans (Hansen et al. 2002). In
mice, knockout (KO) of the GH receptor renders the
animals susceptible to obesity, while GH over-expression
results in a lean phenotype (Berryman et al. 2004, 2006).
The nature of the molecular pathway involved in
GH-mediated lipolysis is not entirely clear. However,
results from animal studies indicate that it involves
remodeling of the cAMP-dependent regulatory signaling
pathways such that the responsiveness toward badrenergic signaling is increased (Doris et al. 1994, Yang
et al. 2004) while insulin sensitivity is reduced (Chen et
al. 2001, Johansen et al. 2003; Fig. 3). Although
definitive mechanistic evidence is lacking, this model has
been supported by human studies. Thus, GH administration acutely stimulates lipolysis and causes peripheral

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52 :3
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insulin resistance (Nellemann et al. 2013). Also, the in vivo
lipolytic effect of GH is counteracted by the AC

inhibitor acipimox (a niacin derivative; Nielsen et al.
2001, 2002). Notably, stimulation with GH does not
increase lipolysis in explants of human AT (Fain et al.
2008) or isolated human adipocytes (Marcus et al.
1994), but the sensitivity toward b-adrenergic agonists is
enhanced by the presence of GH in the culture medium
(Marcus et al. 1994). In line with this, it has recently
been demonstrated that GH administration in human
subjects increases ANGPTL4 levels in plasma (Clasen et
al. 2013). Given the permissive effect of this protein on
cAMP-mediated lipolysis, it seems likely that elevations
in systemic ANGPTL4 levels could be one of the
mechanisms by which GH stimulates AT lipolysis.
Interestingly,
the
responsiveness
toward
GH
stimulation varies among human AT depots, and
visceral AT has been shown to be particularly
sensitive to the lipolytic effects of GH (Nam et al. 2001,
Pasarica et al. 2007, Plockinger & Reuter 2008).
Glucocorticoids
In a manner similar to GH, the lipolytic effects of
glucocorticoids have been attributed to an increased
b-adrenergic responsiveness and a reduction of
insulinmediated antilipolysis (Fig. 3). Thus, in rat
adipocytes, dexamethasone treatment has been shown

to promote PKA-mediated lipolysis by reducing the
mRNA and protein expression levels of PDE3B (Xu et
al. 2009). Also, dexamethasone potentiates the response
toward b-AR agonists both by inducing an increase in
the number of b-ARs and by increasing the catalytic
response of AC toward receptor-mediated activation
(Lacasa et al. 1988). In agreement with this, elevated
cortisol levels in humans have been found to reduce the
postprandial suppression of FFA release, suggesting a
decreased antilipolytic effect of insulin (Dinneen et al.
1993). As for GH, glucocorticoid- mediated lipolysis in
rodents is partially dependent on an increase in
ANGPTL4 (Koliwad et al. 2009, Gray et al. 2012),
indicating that these hormones share some of the
mechanisms by which they stimulate lipolysis.
However, acute in vivo studies on humans have also
demonstrated additive independent effects of GH and
cortisol on lipolysis, suggesting that alternative, and
distinct, lipolytic pathways exist for these hormones
(Djurhuus et al. 2004).
Tumor necrosis factor a
Multiple effects of the pro-inflammatory cytokine tumor
necrosis factor-a (TNFa) on the lipolytic pathway have
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lipolysis
been described. Acting through TNF receptor 1 ( Fig. 3) in

adipocytes from mice (Sethi et al. 2000) and humans
(Ryden et al. 2002), TNFa activates the three MAPKs
p42/44, JNK, and p38 of which p42/44 and JNK are
involved in the induction of lipolysis (Ryden et al. 2002).
In human fat cells, PDE3B protein expression is
decreased dramatically by TNFa (Zhang et al. 2002) and
in rat adipocytes antilipolytic signaling via the a2-AR is
blunted by TNFa by specific proteasomal degradation of
Gi (Gasic et al. 1999, Botion et al. 2001). The combined
effect of these alterations of the insulin and a2-AR
signaling pathway is an increased intracellular cAMP
level and a resulting activation of PKA-mediated
lipolysis. In addition to modulation of antilipolytic
signaling, exposure to TNFa increases ATGL activity
due to remodeling of core components of the lipolytic
machinery. This is discussed in the following section.
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Physiological
lipolysis
regulation
of
human
AT
As discussed earlier, the lipolytic rate in human AT is

determined by a delicate balance between several regulatory pathways. In healthy subjects, this regulation facilitates a proper lipolytic response to changes in systemic
nutrient demand.
Feeding/fasting
Following the ingestion of a meal, the post-prandial
increase in plasma insulin efciently suppresses lipolysis
to promote the storage of dietary lipids (Roust & Jensen
1993, Jensen 1995). Conversely, in the fasting state, FFA
mobilization is promoted by the combined effects of
reduced plasma insulin and increased release of
adrenaline and noradrenaline (Gjedsted et al. 2007). Also,
it has been demonstrated that lipolysis is further
promoted by a combination of increased b-adrenergic
sensitivity and decreased insulin sensitivity in AT
during fasting (Jensen et al. 1987). Similarly, in obese
individuals subjected to a hypocaloric diet (!3 MJ/day)
for 28 days, lipolytic stimulation by b-adrenergic
agonists as well as by ANP and BNP was enhanced
significantly (Sengenes et al. 2002). These fasting-induced
changes in hormonal sensitivity are mediated, at least
in part, by GH, which is elevated significantly during
prolonged fasting (Norrelund et al. 2001, 2003,
Vendelbo et al. 2010). Likewise, the diurnal fluctuations
in serum FFA levels mirror the pulsatile secretion
52 :3
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pattern of GH, and the nocturnal increase in FFA

during sleep is virtually absent in GH-defi ient patients
(Jorgensen et al. 1990).
Exercise
Physical exercise is the other major situation in
which lipolysis is stimulated in humans and this is
believed to involve the concerted action of several
signaling pathways (Frayn 2010). Thus, circulating
levels of adrenaline, noradrenaline, ANP, GH, and
cortisol increase and insulin decreases in proportion to
exercise intensity, and these gradual changes are
reflected in the magnitude of the resulting lipolytic
response (Moro et al. 2007b). Further- more, the
adrenergic responsiveness of subcutaneous AT is
altered with a shift from predominant a-adrenergic
suppression during rest toward predominant badrenergic stimulation during exercise (Arner et al.
1990), and in the post-exercise recovery phase, b-AR
blockade has been shown to dramatically reduce
plasma levels of FFA and glycerol (Wijnen et al. 1993).
Similar to fasting conditions, GH and cortisol are likely
to be some of the hormonal mediators of these
exercise-induced
alterations
in
adrenergic
responsiveness (Kanaley et al. 2004). The primary
adrenergic stimulus of AT during exercise originates
from circulating catecholamines, with only a minor
contribution from noradrenaline released from
sympathetic neurons (Stallknecht et al. 2001, de
Glisezinski et al. 2009). Additionally, the NPs have
been found to play a prominent role in exercise-
induced lipolysis in humans (Moro et al. 2004b, de

Glisezinski et al. 2009), and they have been suggested to
account for most of the non- adrenergic lipolytic
signaling in AT during exercise (Moro et al. 2006,
Lafontan et al. 2008).
Depot-specific regulation of lipolysis
AT is not a homogenous organ, and significant regional
differences exist between depots in terms of hormonal
responsiveness and metabolic activity. Also, the
distribution of body fat is gender specific, with men
generally having a more central (upper-body) and women
a more peripheral (lower-body) fat deposition (Demerath
et al. 2007).
Regarding the lipolytic activity of the different
depots, visceral and subcutaneous abdominal ATs are
generally more responsive toward lipolytic stimuli like
catecholamines
or
prolonged
fasting
than
subcutaneous gluteal and femoral fat (Gjedsted et al.
2007, Manolopoulos et al. 2012). The reduced lipolytic
effect of catecholamines in lower-body fat depots is
caused by enhanced a2-AR and reduced b-AR
responsiveness compared with upper-body depots
(Manolopoulos et al. 2012). Additionally, in upper- body
obese women, the antilipolytic effect of insulin is
blunted in the abdominal depots, which enhances
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lipolysis further (Nellemann et al. 2012). Another important difference between upper- and lower-body subcutaneous AT is the primary way by which adipogenesis
occurs as obesity develops. Thus, AT can expand either
via an increase in the number of fat cells (i.e.
hyperplasia) or by enlargement of the existing
adipocytes (i.e. hypertrophy), of which the latter has
been found to be an independent marker for increased
metabolic risk (Weyer et al. 2000, Lundgren et al. 2007).
Importantly, irrespective of gender, subcutaneous
abdominal AT is more prone to expansion by
hypertrophy than subcutaneous femoral AT, which
preferentially undergoes hyperplasia (Tchoukalova et al.
2010).
As a consequence of these regional differences in
adipogenesis and lipolytic responsiveness, it has been
found repeatedly that upper-body obesity, but not lowerbody obesity, is associated with elevated systemic FFA
levels and metabolic dysfunction (Nielsen et al. 2004,
Piche et al. 2008, Lapointe et al. 2009, Amati et al. 2012).
In fact, it has been suggested that the preference of
gluteofemoral fat for trapping lipids serves as a
metabolic sink providing metabolic and cardiovascular
protection from the deleterious effects of an excessive
daily influx of dietary lipids (Manolopoulos et al. 2010).
The regulation and implications of these gender- and
depot-specific differences in terms of AT metabolism
and signaling has been covered in great detail in a
recent review (White & Tchoukalova 2014).
The lipolytic pathway: enzymes

and co-regulators
The core enzymatic machinery for TG hydrolysis in AT
consists of ATGL and HSL. Studies of ATGL-KO mice
have revealed that the absence of ATGL reduces the
lipolytic response of adipocytes to b-AR stimulation by
w70%, and by adding a specific HSL inhibitor lipolysis is
reduced by more than 95% (Schweiger et al. 2006).
Furthermore, both the basal and stimulated lipolytic
capacity of human and mouse adipocytes are increased
by ATGL overexpression and deceased by ATGL
silencing (Kershaw et al. 2006, Bezaire et al. 2009). By
contrast, HSL overexpression or silencing does not affect
the basal lipolytic rates in human adipocytes, but the
maximal stimulated lipolytic rate is decreased by
reduced HSL levels (Bezaire et al. 2009).
Adipose TG lipase

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The important function of ATGL as a TG hydrolase was

discovered simultaneously in 2004 by three different
groups (Jenkins et al. 2004, Villena et al. 2004,

Zimmer- mann et al. 2004). Initially named ATGL
(Zimmermann et al. 2004), phospholipase A2x (Jenkins
et al. 2004), and desnutrin (Villena et al. 2004), the
enzyme is now formally annotated as patatin-like
phospholipase domain- containing protein 2 (Wilson
et al. 2006). Expectedly, the expression of ATGL in
mice has been found to be highest in white AT (WAT)
and brown AT (BAT), but the transcript has been
identified at lower levels in virtually all tissues studied
(Villena et al. 2004, Kershaw et al. 2006).
The transcriptional control of ATGL gene expression
is complex. A peroxisome proliferator-activated
receptor g (PPARg)-responsive element has been
identified in the promoter sequence of the mouse
Atgl gene (Kim et al. 2006), and accordingly
thiazolidinediones
(PPARg
agonists)
like
rosiglitazone increase Atgl expression (Kim et al. 2006,
Liu et al. 2009b). Furthermore, Atgl mRNA
expression in 3T3-L1 adipocytes is negatively
regulated by insulin as well as by TNFa-mediated
p42/44 MAPK activation (Kim et al. 2006). Several
additional studies have addressed the regulation of
ATGL expression, and it has been found that in
humans, ATGL protein is upregulated by fasting
(Nielsen et al. 2011), while in mice, the mRNA is
suppressed by feeding (Kershaw et al. 2006), but
upregulated by glucocorticoids (Villena et al. 2004), and

by SIRT1-mediated activation of the transcription factor
Foxo1 (Chakrabarti et al. 2011, Shan et al. 2013). However,
numerous studies have found that changes in
mammalian ATGL mRNA and protein levels are often
reciprocal, suggesting that ATGL is subject to extensive
post-transcriptional regulation (Steinberg et al. 2007, Li
et al. 2010, Nielsen et al. 2011, 2012).
ATGL is a specific TG hydrolase, and the activity
toward other lipid substrates like DG, MG, retinylesters
(RE), or cholesterylesters (CE) is very limited
(Zimmermann et al. 2004). Although the 3D structure of
ATGL has not been reported, studies on mutated and
truncated human and murine ATGL have revealed that
the N-terminal half of the enzyme contains the catalytic
patatin domain (Duncan et al. 2010), while the C-terminal
part is believed to be involved in regulation of enzymatic
activity and to mediate the interaction between ATGL
and LDs (Kobayashi et al. 2008, Schweiger et al. 2008).
404
428
The two serine residues Ser

and Ser
in the Cterminal part of the human ATGL sequence
406
430
(corresponding to Ser
and Ser
in murine ATGL)
have been identified as phosphorylation sites (Bartz
et al. 2007). However, the role of these sites in the
regulation of ATGL activity, and the identity of the
406
upstream kinases is somewhat unclear. Thus, Ser

been suggested to be a consensus site for
has
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AMP-activated protein kinase (AMPK), and in murine

3T3- L1 adipocytes, it was shown that pharmacological
stimulation of lipolysis with the AMPK agonist
406
AICAR was dependent on ATGL Ser phosphorylation

(Ahmadian et al. 2011). However, another study found
A
TG
404
that phosphorylation of Ser in human ATGL was

increased by b-adrenergic stimulation, while AICAR
treatment had no effect (Pagnon et al. 2012).
Lipid droplet
406
Additionally, in mouse AT, Ser phosphorylation was

increased with fasting, exercise, and ex vivo stimulation
of the cAMP-dependent pathway in a PKA-dependent
manner, thereby implicating this kinase in the
phosphorylation of ATGL (Pagnon et al. 2012). Notably, in
Acute stimulation
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human skeletal muscle (SM), Ser

phosphorylation is
also associated with PKA signaling and not with AMPK
signaling, indicating that PKA is indeed the upstream
kinase for this site (Mason et al. 2012). Whether PKA
and/or AMPK are responsible for phosphorylation of
DG
TG
DG
Prolonged stimulation
Degradation
430
Ser is currently unknown, and so far no reports have

been published on the functional role of this site.
ATGL: activation by CGI-58
The primary way by which ATGL activity is increased

under acute lipolytic stimulation is via interaction with
the co-activator CGI-58 (also known as a/b hydrolase
domain-containing protein 5; Fig. 4A and B; Lass et al.
2006). Activation depends on the interaction of CGI-58
with the patatin domain of ATGL (Schweiger et al. 2008,
Cornaciu et al. 2011) and requires direct proteinprotein
interactions between ATGL and CGI-58 (Granneman et al.
2007, Cornaciu et al. 2011). Also, mutational studies have
shown that additional binding of CGI-58 to the LD is
crucial in order to activate ATGL (Gruber et al. 2010). The
molecular mechanism by which CGI-58 activates ATGL
is unclear, but it could potentially involve induction
of conformational changes, presentation of substrate, or
removal of reaction products. Interestingly, in addition to
its role in regulating lipolysis, both mouse and human
CGI-58 has been identified as a CoA-dependent lysophosphatidic acid acyltransferase (LPAAT; Ghosh et al. 2008,
Gruber et al. 2010, Montero-Moran et al. 2010), and it has
been speculated that it promotes lipolysis by channeling
fatty acids released from TG hydrolysis into
phospholipids to reduce end product inhibition of ATGL
and HSL (Montero-Moran et al. 2010). Although the
potential relevance of this LPAAT activity of CGI-58 in
lipolytic regulation remains to be investigated, CGI-58derived phospholipids are essential second messengers
TG
DG
TG
DG
in murine liver and AT when exposed to pro-inflammatory

cytokines like TNFa, interleukin 1b (IL1b), and IL6 (Lord et
al. 2012).
and inflammation, at least in mice.
Figure 4
Regulation of ATGL. (A) In the basal state, CGI-58 is complexed with
PLIN1 and ATGL activity is low. (B) Upon phosphorylation of PLIN1,
CGI-58 is released and associates with ATGL, which increases ATGL
activity. In this
phase, a fraction of the ATGL pool is dominantly inhibited by G0S2.
(C) If the lipolytic stimulation persists, gradual degradation of G0S2
promotes a further increase in ATGL activity. TG, triglyceride; ATGL,
adipose TG lipase; CGI-58, comparative gene identification-58; DG,
diacylglycerol; G0S2, G0/G1 switch gene 2; PKA, protein kinase A;
PLIN1, perilipin 1.
Consequently, as downstream inflammatory stress

kinases can impair insulin signaling, CGI-58 seems to
be involved in cross talk between insulin sensitivity
ATGL: inhibition by G0S2

Recently, the protein product of G0/G1 switch gene 2
(G0S2) was identified as an inhibitor of ATGL (Yang et al.
2010). In mice, G0S2 is primarily expressed in brown
and white adipocytes, but a significant expression has
also been detected in liver, heart, and SM (Zandbergen
et al. 2005). Murine G0S2 mRNA and protein expression
has been shown to be induced by insulin and PPARg
and suppressed by lipolytic agents like TNFa and
the b-AR agonist isoprenaline (Zandbergen et al. 2005,
Yang et al. 2010). Like CGI-58, G0S2 interacts directly with
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the catalytic patatin domain of ATGL (Yang et al. 2010,

Cornaciu et al. 2011), but the ATGLG0S2 interaction is
independent of the ATGLCGI-58 interaction, and inhibition by G0S2 appears to be dominant to activation by
CGI-58 (Fig. 4B; Yang et al. 2010, 2011, Schweiger et al.
2012). Human G0S2, like the murine ortholog, inhibits
ATGL in a dose-dependent manner and is also involved
in regulating the intracellular localization of ATGL by
recruiting it to LDs (Schweiger et al. 2012).
It has been proposed that G0S2 acts as a long-term
regulator of lipolysis, as G0S2 protein levels are gradually
reduced during prolonged lipolytic stimulation resulting
in increased ATGL activity (Fig. 4C; Yang et al. 2010).
Notably, G0S2 protein and mRNA expression is
dramatically reduced in human AT by prolonged
physiological stimulation of lipolysis with a 72-h fast
(Nielsen et al. 2011) and similar effects have been
observed in birds (Oh et al. 2011) and pigs (Ahn et al.
2013). However, it is currently not known if the
association between ATGL and G0S2 is dynamic and
subject to regulation or if G0S2-mediated ATGL
inhibition primarily depends on the intracellular levels
of G0S2. Recent evidence has suggested the latter
although. Thus, in 3T3-L1 adipocytes, stimulation with
TNFa for up to 16 h reduces G0S2 levels gradually,
while the rate of lipolysis increases nearly proportionally
to the G0S2 reduction (Yang et al. 2011). Conversely,
overexpression of G0S2 significantly reduces the TNFa
mediated lipolytic response. Murine G0S2 is a shortlived protein with a half-life of
!1 h, and its stability can be greatly improved by
inhibition of the proteasomal pathway (Yang et al.
2011). Hence, it appears that one of the mechanisms by
which TNFa promotes adipocyte lipolysis is by
suppressing G0S2 mRNA expression leading to
cytosolic
depletion
of
G0S2
protein
through
proteasomal degradation and, consequently, increased
ATGL activity.
Animal models of ATGL deficiency
Insight into the crucial role of ATGL in whole-body TG
metabolism has been provided from the characterization
of ATGL-deficient mice (Haemmerle et al. 2006). These
animals exhibit massive ectopic lipid accumulation in
virtually all tissues and especially in AT, liver, SM, and
heart (Haemmerle et al. 2006). Accordingly, the animals
become obese even on a low-fat diet, and they suffer from
premature death due to severe cardiac steatosis and
dysfunction (Haemmerle et al. 2006, Schrammel et al.

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2013). Furthermore, the normal fasting- or exerciseinduced rise in plasma FFA is absent in ATGL-KO animals
indicating a failure to increase lipolysis in WAT (Huijsman
et al. 2009, Schoiswohl et al. 2010). Without sufficient fuel
from lipid substrates, they rely primarily on carbohydrate
metabolism for energy conversion resulting in rapid
depletion of hepatic and SM glycogen stores (Huijsman
et al. 2009, Schoiswohl et al. 2010). Consequently, when
subjected to moderate exercise or short-term fasting, the
mice become hypoglycemic, and if fasting is extended
beyond a modest 812 h, they develop signs of severe
energy starvation like hypothermia, lethargy, reduced
oxygen consumption, and loss of lean mass (Haemmerle
et al. 2006, Schoiswohl et al. 2010, Wu et al. 2012).
Similarly, in spite of massively increased BAT mass,
ATGL- KO mice are unable to increase thermogenesis in
response to cold exposure, indicating that the
mobilization of lipid fuel in BAT is defective
(Haemmerle et al. 2006). In addition to the abnormal
substrate
metabolism,
ATGL deficiency causes
pancreatic steatosis leading to impaired insulin secretion
and hypoinsulinemia (Peyot et al. 2009). Interestingly,
however, despite the massive ectopic lipid accumulation
and b-cell dysfunction, the ATGL-deficient mice have
improved whole-body insulin sensitivity and glucose
tolerance compared with WT animals (Haemmerle et al.
2006, Peyot et al. 2009). Specifically, muscle and WAT
insulin signaling is improved, although in BAT and liver
it is reduced (Kienesberger et al. 2009).
The key role of defective TG catabolism in the
phenotype of ATGL-KO mice has recently been
supported with the generation of transgenic mice with
AT-specific overexpression of G0S2 (Heckmann et al.
2014). Like ATGL-deficient mice, WAT and BAT mass is
increased in these animals due to impaired basal and
stimulated lipolysis, but glucose and insulin tolerance is
improved. Moreover, thermogenesis is attenuated
leading to defective cold adaptation, and the fastinginduced switch from carbohydrate to fatty acid
metabolism is severely impaired (Heckmann et al. 2014).
Conversely, mice with global G0S2 KO are lean and
resistant to high-fat diet-induced obesity and hepatic
steatosis (Zhang et al. 2013). Further- more, hepatic fatty
acid metabolism is enhanced as G0S2 ablation
accelerates ketogenesis and gluconeogenesis while
glycogen breakdown is impaired (Zhang et al. 2013).
Combined with the observations from Atgl-KO mice,
these results support a defining role for ATGL- mediated
lipolysis in whole-body substrate partitioning and
metabolism, at least in mice.

ATGL in human obesity and metabolic disease
The available literature on the expression patterns of

ATGL in human obesity is somewhat conflicting. In a
study
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among lean and obese women, no difference in ATGL

protein levels were found in subcutaneous abdominal AT
(Ryden et al. 2007). Conversely, in mixed populations of
men and women, ATGL mRNA was increased in subcutaneous abdominal AT in obesity, but the protein levels
were reduced (Steinberg et al. 2007, Yao-Borengasser et al.
2011) and a negative correlation was found between BMI
and ATGL protein expression (Yao-Borengasser et al. 2011).
Furthermore, in paired biopsies, ATGL mRNA expression
was lower in visceral than in subcutaneous abdominal AT
(Yao-Borengasser et al. 2011), and when comparing visceral
AT from obese and lean subjects, ATGL mRNA was
increased in obesity (Steinberg et al. 2007, Tinahones
et al. 2010), while the protein levels were unaffected
(Steinberg et al. 2007). Similarly, in a recent comparison
of lean and obese men, only the mRNA of ATGL was
increased in visceral fat in obesity, but in subcutaneous
abdominal fat, ATGL protein was increased in the obese
subjects (De Naeyer et al. 2011). Furthermore, among obese
males and females with either normal or impaired insulin
sensitivity, insulin resistance has been shown to be
associated with reduced ATGL protein and mRNA in
subcutaneous abdominal AT (Jocken et al. 2007) and
reduced ATGL mRNA in visceral AT (Berndt et al. 2008).
However, whereas the available data on ATGL expression
in obesity is inconclusive, the expression of CGI-58 seems
to be remarkably stable between depots (Yao-Borengasser
et al. 2011) and in obesity (Steinberg et al. 2007).
Gender-specific differences may explain some of the
discrepancies between the studies on ATGL, but in light
of the substantial body of conflicting data, the role of
human ATGL in the pathogenesis of metabolic disease in
obesity is currently unclear.
By contrast, defective ATGL-mediated lipolysis has
been unequivocally identified as the primary defect in the
inherited monogenic disorder neutral lipid storage
disease (NLSD; Lefevre et al. 2001, Lass et al. 2006,
Fischer et al. 2007). Patients with loss-of-function
mutations affecting ATGL are characterized by ectopic
TG accumulation and visceral obesity, skeletal and
cardiac myopathy, and variable degrees of hepatic and
pancreatic steatosis (Schweiger et al. 2009, Laforet et
al. 2013, Natali et al. 2013). However, the metabolic
phenotype of these patients is heterogeneous. Thus,
some are insulin resistant and develop type 2 diabetes
(Laforet et al. 2013), while others have normal insulin
sensitivity but impaired glucose tolerance (Natali et al.
2013). This probably reflects individual differences in the
pattern of ectopic lipid deposition: patients with

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52 :3
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extensive pancreatic steatosis generally have an impaired

insulin response to an oral
glucose challenge (Natali et al. 2013), while insulin

resistance is more common in patients with severe
muscular involvement and hepatic steatosis (Laforet
et al. 2013). The clinical manifestations of loss-offunction mutations in CGI-58 are similar to those
observed in functional ATGL deficiency except that
these patients do not develop myopathy (Igal et al.
1997). Instead, they suffer from severe ichthyosis
(Chanarin et al. 1975, Lefevre et al. 2001) and,
accordingly, the two types of NLSD are known as
NLSD with myopathy (NLSDM) and NLSD with
ichthyosis (NLSDI, also known as ChanarinDorfman
syndrome) (Fischer et al. 2007). The epidermal
defects observed in NLSDI are not present in NLSDM,
suggesting an ATGL-independent function of CGI-58,
possibly as a LPAAT in the synthesis pathway of
glycerophospholipids and acylceramides required for
the formation and maintenance of the skin
permeability barrier (Igal & Coleman 1996, Radner et
al. 2009). Consistently, KO of CGI-58 in mice results
in a neonatal lethal phenotype caused by leaky skin,
and the pups die from desiccation within hours after
birth (Radner et al. 2009). An overview of studies on
genetic deficiencies affecting ATGL function in humans
and animal models is listed in Table 1.
Hormone-sensitive lipase
HSL was discovered in rat AT in the early 1960s as a
lipolytic enzyme, which was inducible by fasting
and stimulation with ACTH or adrenaline and inhibited
by insulin (Hollenberg et al. 1961, Rizack 1964, Vaughan
et al. 1964).
Like ATGL, HSL is expressed in most tissues examined,
with the highest expression found in WAT and BAT
(Kraemer et al. 1993). The mRNA is generated from a
single gene controlled by a number of alternative
promoters that produce several different tissue-specific
isoforms of the HSL protein that range in size from
w85 kDa and up to 130 kDa (Langin et al. 1993, Mairal
et al. 2002). The HSL isoform found in human AT is a
786 aa protein with an apparent molecular weight of
w88 kDa (Langin et al. 1993).
Efficient lipid hydrolysis by HSL requires the lipase
to form a complex with cytosolic fatty acid-binding
protein 4 (FABP4), which acts as a molecular chaperone
by shuttling the FFA generated by HSL out of the cell
(Fig. 5A; Furuhashi & Hotamisligil 2008). Upon
stimulation of lipolysis, HSL and FABP4 associate in the
cytosol and the complex translocate to LDs (JenkinsKruchten et al. 2003, Smith et al. 2007). Consistently, in
FABP4-KO mice, the lipolytic capacity is reduced, and
the intracellular FFA
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Table 1
and others
Affected
protein
Human
NLSDI
CGI-58
Human
NLSDI
CGI-58
Human
Human
NLSDI
NLSDM
CGI-58
ATGL
Human
NLSDM
ATGL
Human
NLSDM
ATGL
Human
NLSDM
ATGL
Mouse
and
KO
ATGL
Mouse
Mouse
Mouse
and
KO
KO
KO
HSL
ATGL
ATGL
ATGL
Mouse
Mouse
Mouse
specific
KO
KO
KO with cardio-
Mouse
Mouse
specific
Mouse
Mouse

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Overview of genetic studies on ATGL and CGI-58 function

Diagnosis/genetic
model
Specie
s
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Highlights of the study
Reference
Case report: clinical manifestations and

proposal of diagnostic criteria
Igal et al. (1997)
Identification of defects in CGI-58 as causative for
NLSDI
Lefevre et al. (2001)
Activation of ATGL and rescue of NLSDI by CGI-58
Case report: identification of truncations in
human ATGL
Identification of biochemical defects in truncated
ATGL
Case report: magnetic resonance imaging of
muscles and metabolic characterization
Case report: body composition and glucose/lipid
metabolism
Lass et al. (2006)

Fischer et al. (2007)
Measurement of lipolysis in AT explants from

KO animals
Schweiger et al. (2006)
Phenotyping of KO animals
Insulin sensitivity and glucose/lipid metabolism
Substrate partitioning and metabolism during
rest and exercise
Haemmerle et al. (2006)

Kienesberger et al. (2009)
Huijsman et al. (2009)
HSL
ATGL
CGI-58
ATGL
Evaluation of effects on insulin secretion

Lipid/glucose metabolism during exercise
Peyot et al. (2009)

Radner et al. (2009)
Schoiswohl et al. (2010)
expression
AT-specific KO
KO with cardio-
ATGL
ATGL
Phenotyping and fed/fasting metabolism

Cardiac metabolism
Wu et al. (2012)
Schrammel et al. (2013)
KOexpression
AT-specific overexpression
G0S2
G0S2
Phenotyping of transgenic animals

Phenotyping of transgenic animals
Zhang et al. (2013)

Heckmann et al. (2014)
levels in adipocytes are increased (Coe et al. 1999).

Activation of HSL requires phosphorylation by PKA or
PKG on specific regulatory serine residues. In rat HSL,
563
659
660
these sites are Ser , Ser , and Ser (Stralfors et al. 1984,
Garton et al. 1988, Anthonsen et al. 1998) corresponding
552
649
650
to the human residues Ser , Ser , and Ser (Contreras

et al. 1998, Watt et al. 2006). The functional role of these
563
sites is different; phosphorylation of Ser is thought to

promote the translocation of HSL from the cytosol to LDs
659
(Daval et al. 2005), while phosphorylation of Ser
and
660
Ser is critical for activation of the intrinsic enzymatic

activity (Anthonsen et al. 1998). Conversely, phosphoryl565
554
ation of rat HSL on Ser

(human Ser ) by AMPK
inhibits HSL activation, most likely by steric
563
hindrance of phosphorylation of the adjacent Ser ,

thus preventing the translocation of HSL to the LDs
(Daval et al. 2005) (Fig. 5B). In terms of specificity,
Kobayashi et al. (2008)

Laforet et al. (2013)
Natali et al. (2013)
HSL is a much more promiscuous lipase than ATGL

and readily hydrolyze several lipid substrates, including
TG, DG, MG, RE, and CE in vitro (Fredrikson et al. 1981,
Wei et al. 1997). Among the substrates and intermediates
in TG lipolysis, the affinity for DG is approximately
tenfold higher than for TG and MG (Fredrikson et al.
1981, 1986).
Animal models of HSL deficiency
(Osuga et al. 2000, Harada et al. 2003, Park et al. 2005). This
The key role of HSL as a DG hydrolase in vivo was
unexpected observation was found to be caused by a

compensatory reduction in fatty acid esterification and
revealed with the generation of HSL-KO mice, which

were found to accumulate intracellular DG in AT, SM,
cardiac muscle, and testis (Haemmerle et al. 2002).
However, in contrast to ATGL-KO mice, HSL-deficient
mice do not suffer from severe systemic lipid
accumulation, although they tend to have enlargement
of internal organs like liver, heart, pancreas, and spleen
(Harada et al. 2003). Surprisingly, the WAT mass is
slightly reduced, and they are resistant to high- fat dietinduced obesity and peripheral insulin resistance
de novo lipogenesis to counteract the reduced release of

FFA to the circulation (Zimmermann et
al. 2003).
However, similar to ATGL-KO mice, HSL-KO mice have
increased BAT mass and enlargement of brown
adipocytes (Harada et al. 2003), but this is not
associated with impaired thermogenesis, as they retain
a normal sensitivity to cold exposure (Osuga et al. 2000).
An overview of animal studies on genetic deficiencies
affecting HSL is listed in Table 2.
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FFA
B
FFA- FABP4
cAMP
PDE3B
PKA
P
HSL
5-AMP
FABP4
HSL
P
P
P
P
P
P
DG
MG
Lipid droplet
Figure 5
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AMPK
Regulation of HSL. (A) Phosphorylation of Ser552, Ser649, and Ser650 on

human HSL promotes lipase activation and association with FABP4 in
the cytosol. Subsequent translocation of this complex to the LD surface
is
dependent on both HSL and PLIN1 phosphorylation and results in full
activation of HSL activity. Acting as a molecular chaperone, FABP4
shuttles the FFAs released by HSL from the LD to the plasma membrane
of the
adipocyte where they are secreted. (B) LD-targeting of cytoplasmic HSL
HSL in human obesity and metabolic disease

While changes in ATGL expression patterns in obesity
are of uncertain significance, the importance of HSL
expression is somewhat more well established, although
discrepancies certainly exist. Thus, the expression of HSL
mRNA in subcutaneous abdominal AT in obesity has
been reported to be increased (Ray et al. 2009), reduced
(Large et al. 1999, Mairal et al. 2006), or not affected
(Steinberg et al. 2007, De Naeyer et al. 2011). However,
irrespective of gender, the majority of studies have found
the corresponding HSL protein levels to be reduced in
obesity (Large et al. 1999, Langin et al. 2005, Ryden et al.
2007, Ray et al. 2009). Similarly, in the obese state, insulin
resistance is associated with a reduction in HSL mRNA
and protein in subcutaneous abdominal AT (Jocken et
al. 2007). In visceral AT, HSL mRNA levels have
consistently been found to be upregulated in obesity
(Mairal et al. 2006, Steinberg et al. 2007, Ray et al. 2009,
De Naeyer et al. 2011), but the protein levels seem to be
unaffected (De Naeyer et al. 2011) or possibly reduced
(Ray et al. 2009).
So far, no human examples of loss-of-function
mutations affecting HSL have been reported, and in light
DG
HSL
HSL
PKA
MG
Lipid droplet
requires cAMP-dependent phosphorylation on Ser552 by PKA. Conversely,
AMPK is activated by 5 0 -AMP and phosphorylate HSL on the adjacent
Ser554. As phosphorylation on Ser552 and Ser554 is mutually exclusive, AMPK
reduces the LD association of HSL. AMPK, AMP-activated protein kinase;
DG, diacylglycerol; FABP4, fatty acid-binding protein 4; FFA, free fatty acid;
HSL, hormone-sensitive lipase; MG, monoacylglycerol; PDE3B, phosphodiesterase 3B; PKA, protein kinase A.
of the relatively mild phenotype of HSL-KO mice, it seems

unlikely that HSL deficiency per se is associated with severe
metabolic defects in humans.
Monoglyceride lipase
MGL was identified in rats as an MG-specific lipase
with no affinity toward TG or DG (Tornqvist &
Belfrage 1976). The first MGL-KO mouse model has
recently been generated (Table 2), and these animals
accumulate MG in WAT, brain, and liver (Taschler
et al. 2011). Also, it was found that HSL partially
compensated for the absence of MGL in AT, as the
stimulated glycerol release was reduced by a modest
43% compared with WT mice. However, upon specifi
inhibition of HSL in cultured fat pads, the MGhydrolase activity was almost completely abolished
(Taschler et al. 2011). To date, no reports have been
published indicating that MGL expression and enzymatic

activity in AT is regulated by hormonal signals or
nutritional status, suggesting that the enzyme is constitutively active in the lipolytic cascade.
LD-associated proteins: the CIDE family
The PLIN proteins and the CIDE proteins constitute the
two major families of LD-associated proteins in adipocytes. The pro-apoptotic CIDE proteins (cell-death inducing DNA fragmentation factor-a-like effector) comprise
three members: CIDEA, CIDEB, and CIDEC (also known
as fat-specific protein of 27 kDa, Fsp27) (Yonezawa et al.
2011).
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and others
Table 2 Overview of genetic studies on HSL, MGL, and

FABP4 function
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Specie
s
Geneti
c
model
Affecte
d
protein
Mouse
KO
FABP4
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
MGL
Coe et al.
(1999)
Osuga et al. (2000)
Highlights
of the study
Reference
Phenotyping of
KO animals
Phenotyping of
KO animals
Involvement of
HSL in
whole-body
DG catabolism
Lipid metabolism in
diet-induced
obesity
AT adaptations
to HSL
deficiency
Insulin sensitivity and
glucose/lipid
metabolism
Phenotyping of
KO animals
Haemmerle
et al. (2002)
Harada et al.
(2003)
Zimmermann
et al. (2003)
Park et al.
(2005)
Taschler et al.
(2011)

lipolysis
52 :3
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functional relationship, they are now annotated as PLIN1

(perilipin A), PLIN2 (adipophilin), PLIN3 (TIP-47),
PLIN4 (S3-12), and PLIN5 (MLDP/OXPAT) (Kimmel et
al. 2010).
Of the PLIN proteins, PLIN1 is particularly important in
the regulation of AT lipolysis, while the other family
members are involved in adipogenesis and LD formation
(PLIN2), LD biosynthesis and stabilization (PLIN3),
LD maturation (PLIN4) and regulation of lipolysis in
oxidative tissues not expressing PLIN1 (PLIN5) (Bickel
et al. 2009).
Multiple regulatory roles of murine PLIN1 have been
described in the lipolytic cascade, and it has been
suggested that PLIN1 is the master regulator of PKAstimulated lipolysis in mice (Miyoshi et al. 2007). As such,
PLIN1 either directly or indirectly regulates the activity
of ATGL and HSL as well as their access to lipid
substrates in the LDs. The LD targeting of HSL is partly
governed by PLIN1; in the basal state, as much as
half of the total cellular HSL content is located in the
cytoplasm, but PKA- mediated PLIN1 and HSL
phosphorylation has been shown to significantly
enhance the co-localization and association of the two
proteins on LDs (Miyoshi et al.
CIDEA and CIDEC from mice and humans have recently

been shown to be negative regulators of lipolysis (Nord-
the family also includes the proteins S3-12 and myocyte

LD protein (MLDP, also known as OXPAT) (Bickel et al.
strom et al. 2005, Puri et al. 2008, Christianson et al. 2010),

although their specific role is not well characterized yet.
2009). However, due to their evolutionary, structural, and

2006). However, studies on mutant PLIN1 lacking all
phosphosites have revealed that in the absence of
phosphorylation of PLIN1, the PKA-mediated increase in
HSL activity is blunted, although the lipase is phosphorylated and translocated (Miyoshi et al. 2006). In other
words, the lipolytic action of LD-associated and phosphorylated HSL are critically dependent on PLIN1 phosphorylation in mouse adipocytes.
Similarly, the activation of murine ATGL depends
on phosphorylation of PLIN1, although by a different
mechanism. In the basal state, unphosphorylated PLIN1
has been shown to negatively regulate ATGL by
efciently sequestering CGI-58, thereby preventing
activation of ATGL (Granneman et al. 2007, 2009). Upon
stimulation of lipolysis, phosphorylation of PLIN1 causes
the dissoci- ation of CGI-58, which can then bind and
activate ATGL (Granneman et al. 2009; Fig. 4).
Interestingly, a single amino acid in PLIN1 has been
identified as the crucial residue for regulation of HSL-
However, it appears that they promote lipid storage

through their involvement in LD formation, fusion, and
stabilization (Puri et al. 2008, Christianson et al. 2010, Ito
et al. 2010). Accordingly, human CIDEC has been found
to interact with PLIN1 (see below) and the interaction
between these two proteins is critical for the formation of
large LDs and unilocular adipocytes (i.e. cells containing
a single big LD) (Grahn et al. 2013, Sun et al. 2013).
The mechanism by which the CIDE proteins inhibit
lipolysis is incompletely understood but it seems to
involve shielding of the LDs from the action of lipases by
providing a physical barrier around the lipid core
(Christianson et al. 2010, Yang et al. 2013).
LD-associated proteins: the PLIN family
The other family of LD-associated proteins has been
studied in much more detail. The PLIN proteins were
originally called the PAT family after perilipin A, adipophilin, and tail-interacting protein of 47 kDa (TIP-47), and
517
and ATGL-mediated lipolysis, as mutation of Ser in

the mouse sequence almost completely abolishes PKA-
stimulated FFA and glycerol release (Miyoshi et al.

2007).
Animal models of deficiencies in LD-associated
proteins
In mice, the CIDE proteins exhibit a distinct expression

pattern. Thus, while CIDEA is predominantly expressed
in BAT (Zhou et al. 2003), CIDEB is almost
exclusively
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T S NIELSEN
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expressed in the liver (Li et al. 2007), and CIDEC is

primarily found in WAT (Nishino et al. 2008), suggesting
a tissue-specific role of these proteins. Consistently,
CIDEA- deficient mice are characterized by elevations
in body temperature and overall metabolic rate due to
accelerated BAT lipolysis and thermogenesis (Zhou et al.
2003). Consequently, these mice are lean and resistant
to diet- induce obesity and glucose intolerance. A liverspecific function of CIDEA has also been demonstrated,
as hepatic CIDEA knockdown in genetically obese ob/ob
mice reduces hepatic TG accumulation and LD size and
accelerates overall energy expenditure (Zhou et al. 2012).
Similarly, KO of CIDEB results in lean mice with
improved glucose tolerance, insulin sensitivity, and
resistance to hepatic steatosis, but BAT metabolism is
normal in these animals (Li et al. 2007). Instead,
ketogenesis and overall metabolic rate is accelerated,
suggesting an overall shift in substrate utilization toward
lipid metabolism (Li et al. 2007). In terms of metabolic
rate, susceptibility to obesity, hepatic steatosis, and
disturbances in glucose homeostasis and metabolism,
the overall phenotype of CIDEC-KO mice is very similar
to the phenotype of CIDEA- and CIDEB- deficient
animals (Nishino et al. 2008, Toh et al. 2008). Notably,
however, while the metabolic rate in BAT is reduced,
mitochondrial biogenesis, oxygen consumption, and
basal lipolytic rates are increased in WAT (Nishino et al.
2008). Consistently, WAT expression of specific factors
inhibiting BAT differentiation is reduced and a
concomitant increase in the expression of BAT-specific
genes (e.g. UCP1) causes a shift toward a more brownlike phenotype (Toh et al. 2008). Thus, in spite of tissuespecific differences in the expression and regulation of
the CIDE proteins, they seem to share a crucial role in
the regulation of overall substrate partitioning and
metabolism.
In agreement with the role of PLIN1 as a negative
regulator of ATGL activity, PLIN1-deficient mice have
been found to have dramatically decreased fat mass and
increased basal lipolysis (Martinez-Botas et al. 2000,
Tansey et al. 2001). This observation has been supported
by in vitro studies; stimulation of 3T3-L1 cells with TNFa
was found to increase basal lipolysis due to a reduction in
PLIN1 protein levels, and this effect could be reversed by
simultaneous overexpression of PLIN1 (Souza et al. 1998).
Furthermore, PLIN1-KO animals are lean and resistant to
diet-induced obesity, but nevertheless they are prone
to develop glucose intolerance and peripheral insulin
resistance (Martinez-Botas et al. 2000, Tansey et al. 2001).
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Interestingly, in the absence of PLIN1, the expression of

PLIN2 is increased and, consequently, PLIN2 is the major
LD-associated protein in these animals (Tansey et al.
2001). In cultured cells, overexpression of PLIN2 has
been shown to promote lipid storage by negatively
regulating the access of ATGL to LDs (Listenberger et al.
2007), but the underlying mechanism is currently
unknown, and it remains to be determined whether
PLIN1 defi iency is associated with increased PLIN2
expression in humans in vivo.
LD-associated proteins in human obesity and
metabolic disease
As for ATGL and HSL, the available data on the
association between obesity and the expression of LDassociated proteins are rather inconclusive. In the
obese state, PLIN1 mRNA expression has been reported
to be increased in visceral AT (Ray et al. 2009, Tinahones
et al. 2010) but unaffected in subcutaneous abdominal
AT (Ray et al. 2009). However, others have found a
negative correlation between BMI and visceral PLIN1
mRNA levels, suggesting that the expression is reduced
in obesity (Moreno- Navarrete et al. 2013). In obesity,
PLIN1 protein expression is reduced in both visceral and
subcutaneous abdominal AT (Ray et al. 2009), and
among obese subjects, the protein levels in subcutaneous
abdominal AT are lower in insulin-resistant subjects than
in insulin-sensitive subjects (Moreno-Navarrete et al.
2013).
Recently, two different loss-of-function mutations in
PLIN1 have been identified in three patients diagnosed
with a rare autosomal dominant partial lipodystrophy
(Gandotra et al. 2011a). Both mutations introduced a
frameshift causing the loss of three regulatory PKA sites,
517
including the crucial Ser . Consequently, these mutants

fail to sequester CGI-58 leading to permanently elevated
basal lipolysis due to constitutive activation of ATGL
(Gandotra et al. 2011b). The clinical manifestations of
these mutations included dyslipidemia, hypertension,
lipoatrophy, hepatic steatosis, severe insulin resistance,
and type 2 diabetes. Remarkably, a very similar
phenotype has been found in a patient carrying a lossof-function mutation in the LD-targeting domain of
CIDEC, suggesting that the integrity of the interaction
between CIDEC and PLIN1 is crucial for proper LD
dynamics and lipolytic control in humans in vivo
(Rubio-Cabezas et al. 2009). Additionally, the CIDECdefi
AT had an
unusually high occurrence of multilocular adipocytes

supporting a role for CIDEC in the formation and
stabilization of large LDs (Rubio-Cabezas et al. 2009).
An overview of studies on genetic defi iencies affecting

LD-associated proteins in humans and animal models is
listed in Table 3.
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Table 3 Overview of genetic studies on LD-associated proteins
Species
model
Diagnosis/genetic
Affected
protein
Human
Partial lipodystrophy
CIDEC
Human
truncations
PLIN1
Human
Highlights of the study
Reference
Identification of CIDEC truncation as

the causative mutation
Identification of two PLIN1
Rubio-Cabezas et al.
(2009) Gandotra et al.
PLIN1
Mouse
(2000) Mouse
Mouse
Mouse
Mouse
Mouse
KO
KO
KO
KO
KO
KO
PLIN1
PLIN1
CIDEA
CIDEB
CIDEC
CIDEC
Mouse
KO
CIDEA
as causative mutations
Characterization of PLIN1 mutants in
regulation of lipolysis in cell
culture
Analysis of WAT browning in KO
animals
Characterization of the role of
CIDEA in hepatic metabolism
(2011a) Gandotra et al.

(2011b)
Martinez-Botas et al.
Tansey et al. (2001)
Zhou et al. (2003)
Li et al. (2007)
Nishino et al. (2008)
Toh et al. (2008)
Zhou et al.
(2012)
Intracellular lipolysis in non-ATs

In this review, we have focused on lipolysis in AT.
However, the ability to store and re-hydrolyze TG is not
unique for adipocytes, and most cell types are able to
form LDs by taking up and esterifying FFA into TG
(Greenberg et al. 2011). In fact, the importance of tight
lipolytic control in other tissues has become apparent
with the characterization of the phenotypes associated
with defi lipase activity, particularly with respect to
ATGL. Like the myocardial defects observed in Atgl KO
mice, muscle-specific CGI-58 KO mice also suffer from
cardiomyopathy and cardiac steatosis caused by a severe
impairment of TG catabolism (Zierler et al. 2013).
Conversely, myocardial specific ATGL overexpression in
type 1 diabetic mice confers protection against diabetesinduced cardiomyopathy (Pulinilkunnil et al. 2013), supporting a key role of ATGL in the regulation of metabolism
and lipid homeostasis in the heart. Similar results have
been obtained in the liver, where ATGL deficiency causes
hepatic steatosis and reduced b-oxidation (Ong et al. 2011,
Wu et al. 2011) while liver-specific overexpression of
ATGL or HSL reduces obesity-induced steatosis and
increases b-oxidation (Reid et al. 2008, Ong et al. 2011).
Surprisingly although, in spite of these effects of altered
lipase expression on hepatic TG content and substrate
utilization, liver-specifi KO or
overexpression of ATGL only has minor effects on hepatic
insulin sensitivity and whole-body metabolic parameters
DG to TG hydrolase activity (Jocken et al. 2010). Finally, in

obese type 2 diabetic patients, basal SM lipolysis is
elevated and the anti-lipolytic action of insulin is
blunted (Jocken et al. 2013). Whether this impairment is a
result of peripheral insulin resistance or a cause of it is
unclear although, and at present, the mechanistic
connection between intramyocellular lipolysis and
insulin resistance is a matter of intense debate and
research.
In summary, since the discovery of ATGL in 2004
tremendous progress has been made in the characterization of AT lipolysis. However, with the increasing
number of newly identified enzymes and regulatory
proteins, the remarkable complexity of the hormonal
and intracellular signaling network regulating the lipolytic pathway has also become clear. Considering the
severe phenotypes associated with defective lipolysis in
AT, pancreas, liver, heart, and SM, it is evident that the
balance between lipid mobilization, utilization, and
storage is crucial in most tissues. Consequently, by
delineating the processes regulating lipid metabolism in
adipose and non-ATs alike, we can also advance our
understanding of glucose metabolism and identify new
pathways to target in the treatment of metabolic disease
like type 2 diabetes.
(Turpin et al. 2011, Wu et al. 2011). In human SM, ATGL
protein is increased significantly by endurance training,

indicating that mobilization of intramyocellular TG stores
involves ATGL (Alsted et al. 2009). Obesity is also
associated with increased SM content of ATGL, whereas
HSL is decreased, resulting in a substantial decrease in the
ratio of
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Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the review.
Funding
This work was supported by grants from: i) The FOOD Study
Group/Ministry of Food, Agriculture and Fisheries & Ministry of Family
and Consumer
Review
T S NIELSEN
and others
Affairs, Denmark, ii) The Lundbeck Foundation, Denmark, iii) The Novo
Nordisk Foundation, Denmark, iv) Augustinus Fonden, Denmark, and
v) Aase og Ejnar Danielsens Fond, Denmark.
Acknowledgements
The Novo Nordisk Foundation Center for Basic Metabolic Research is an
independent Research Center at the University of Copenhagen partially
funded by an unrestricted donation from the Novo Nordisk Foundation
(www.metabol.ku.dk).
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Received in final form 14 February 2014

Accepted 25 February 2014
Accepted Preprint published online 27 February 2014

Dissecting Adipose Tissue Lipolysis

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Dissecting Adipose Tissue Lipolysis

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with particular focus on the molecular regulation of the two main lipases, ATGL and HSL, and

the intracellular and extracellular signals affecting their activity.

Dissecting adipose tissue

Dissecting adipose tissue lipolysis:

Niels Mller and Sten Lund

, Jens Otto L Jrgensen ,

free fatty acids

serious metabolic consequences and is believed to be a key mechanism in the

2014 Society for

(FFAs). These are delivered to peripheral tissues where

Published by Bioscientifica Ltd.

provides the organism with an FFA-buffering system of

Dissecting adipose tissue

tolerance (Roden et al. 2000). Consist- ently, improvements

and oral glucose tolerance can be obtained by

Major signaling pathways in AT lipolysis

catecholamines and natriuretic peptides (NPs), while

(Robidoux et al. 2004; Fig. 2). Three different b-AR

et al. 1991) and cytoplasmic HSL (Stralfors et al. 1984,

Dissecting adipose tissue

PDE5-mediated conversion of cGMP to 5 0 -GMP, although the upstream

are released from the atrial and ventricular walls of the

Dissecting adipose tissue

strated that besides the inhibitory effect on PKA-mediated

rat adipocytes by a cAMP-independent mechanism

activating a range of pathways involved in the uptake,

Alternative regulatory pathways

Dissecting adipose tissue

TSH-mediated lipolysis has been found to be particularly

al. 1993), suggesting that the impact of NPY/PYY on

lipolysis has been underscored by elegant studies in

however, ANGPTL4 has also been found to be intimately

In rat and human adipocytes, extracellular adenosine

receptor HM74a (Fig. 3; Taggart et al. 2005). HM74a,

Dissecting adipose tissue

insulin resistance (Nellemann et al. 2013). Also, the in vivo

lipolytic effect of GH is counteracted by the AC

adipocytes, dexamethasone treatment has been shown

Dissecting adipose tissue

been described. Acting through TNF receptor 1 ( Fig. 3) in

As discussed earlier, the lipolytic rate in human AT is

pattern of GH, and the nocturnal increase in FFA

induced lipolysis in humans (Moro et al. 2004b, de

The lipolytic pathway: enzymes

Dissecting adipose tissue

The important function of ATGL as a TG hydrolase was

groups (Jenkins et al. 2004, Villena et al. 2004,

upregulated by glucocorticoids (Villena et al. 2004), and

The two serine residues Ser

upstream kinases is somewhat unclear. Thus, Ser

Dissecting adipose tissue

AMP-activated protein kinase (AMPK), and in murine

AICAR was dependent on ATGL Ser phosphorylation

that phos- phorylation of Ser in human ATGL was

Additionally, in mouse AT, Ser phosphorylation was

human skeletal muscle (SM), Ser

Ser is currently unknown, and so far no reports have

ATGL: activation by CGI-58

The primary way by which ATGL activity is increased

in murine liver and AT when exposed to pro-inflammatory

and inflammation, at least in mice.

Consequently, as downstream inflammatory stress

ATGL: inhibition by G0S2

the catalytic patatin domain of ATGL (Yang et al. 2010,