Post on 17-Nov-2021
JournalofMolecu
larEndocrinology
ReviewT S NIELSEN and others Dissecting adipose tissue
lipolysis52 :3 R199–R222
Dissecting adipose tissue lipolysis:molecular regulation andimplications for metabolic disease
Thomas Svava Nielsen1,2, Niels Jessen2,3, Jens Otto L Jørgensen2,
Niels Møller2 and Sten Lund2
1The Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Integrative Physiology, Faculty of
Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 6.6.30, DK-2200 N Copenhagen, Denmark2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Nørrebrogade 44, Bldg. 3.0,
8000 Aarhus C, Denmark3Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgardsvej 100, 8200 Aarhus N, Denmark
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Published by Bioscientifica Ltd.
Downloa
Correspondence
should be addressed
to T S Nielsen
thomas.nielsen@sund.ku.dk
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 (ATGL),
hormone-sensitive lipase (HSL), and monoglyceride lipase. The activity in the lipolytic
pathway is tightly regulated by hormonal and nutritional factors. Under conditions of
negative energy balance such as fasting and exercise, stimulation of lipolysis results in a
profound increase in FFA release from adipose tissue (AT). This response is crucial in order to
provide the organism with a sufficient supply of substrate for oxidative metabolism.
However, failure to efficiently suppress lipolysis when FFA demands are low can have 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, protein–protein interactions, and protein stability/
degradation. Here, we provide an overview of the recent advances in the field of AT 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.
Key Words
" lipolysis
" adipose tissue
" ATGL
" HSL
" free fatty acids
" type 2 diabetes
ded
Journal of Molecular
Endocrinology
(2014) 52, R199–R222
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
(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 post-
absorptive 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
from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
TG DG MG GlycerolATGL HSL MGL
FFA FFA 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.
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R200
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 cardiovas-
cular 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 accumu-
lation 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 insulin-mediated suppression of hepatic
glucose production contributing to the impairment of
whole-body glucose tolerance (Roden et al. 2000). Consist-
ently, improvements in whole-body insulin sensitivity
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
and oral glucose tolerance can be obtained by pharma-
cological 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 concomi-
tant 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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R201
(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-AR-associated
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 phosphory-
lates the LD-associated protein PLIN1 (Greenberg
et al. 1991) and cytoplasmic HSL (Stralfors et al. 1984,
PLIN1
5′-AMP
PDE3BPKB/Akt
IRS1/2
PDK
PI3K
PIP2
PIP3
ATP
cAMP
HSL
ATGL
CGI-58 DG
TG
PP P
CGI-58
AC
α2-AR
Gi
IR
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 inhi-
bition. 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-
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
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Garton et al. 1988, Anthonsen et al. 1998). Phosphoryl-
ation 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
PLIN1
Lipid droplet
PLIN1
5′-GMP
PDE5
GTP
cGMP
PKGPKA
MGLHSL
P P PPP
PP
P
P
Three FFA+ glycerol
MG
Cytosol
β1/2-AR
Gs
NPR-A
GC
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, hormone-sensitive 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, phosphoinositide-dependent kinase; PI3K,
phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB/Akt, protein
kinase B; PLIN1, perilipin 1.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R202
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 cAMP-dependent
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 insufficient 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 sub-
sequent phosphorylation of the IRS1/2 (White 1998).
This promotes the activation of phosphatidylinositol
3-kinase (PI3K), which converts phosphatidylinositol-
4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-
triphosphate (PIP3) (Whitman et al. 1988, Carpenter et al.
1990). Generation of PIP3 activates the phosphoinositide-
dependent 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 5 0-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-
strated that besides the inhibitory effect on PKA-mediated
signaling, insulin also acts to reduce lipolysis in primary
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
rat adipocytes by a cAMP-independent mechanism
(Londos et al. 1985). By carefully measuring PKA activity
ratios in response to increasing concentrations of iso-
prenaline (a b-AR agonist), the authors found that when
insulin was added to the cells at submaximal lipolytic
stimulation, the insulin-mediated 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
insulin-mediated antilipolysis at submaximal b-AR stimu-
lation (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 HSL-mediated 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 receptor-
mediated 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 particu-
larly numerous, emphasizing the central role of the cAMP-
dependent pathway in the regulation of TG hydrolysis.
Thyroid-stimulating hormone (TSH) and the melano-
cortins (MCs) adrenocorticotrophic hormone (ACTH) and
melanocyte-stimulating hormone stimulate AC by acti-
vation of the Gs-coupled TSH receptor (Laugwitz et al.
1996, Endo & Kobayashi 2012) and MC receptors
(Cho et al. 2005, Rodrigues et al. 2013) respectively (Fig. 3).
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
cAMP
IR
PLIN1
Lipid droplet
PLIN1
PLIN1
ATGL
CGI-58 DG
TG
MGL
Three FFA+ glycerol
MG
HSLP P
ATP
ACGi Gs
A1-R
TSH-rMC
NPY-Y1
HM74aGPR81
ATP
ACGi Gs
PKA
TNFR1
Growth hormoneGlucocorticoids
‘ANGPTL4-r’
ANGPTL4
β1/2-ARα2-AR
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)
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 a2-adrenergic 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.
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R203
TSH-mediated lipolysis has been found to be particularly
important in neonates and newborns because physiologi-
cal levels of TSH, as opposed to adrenaline or nor-
adrenaline, 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 al. 1993),
suggesting that the impact of NPY/PYY on lipolysis is
depot specific. The importance of neuronal regulation of
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 well-established 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
cAMP-mediated 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).
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R204
In rat and human adipocytes, extracellular adenosine
efficiently 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
b-hydroxybutyrate (b-OHB) has been shown to inhibit
lipolysis in vitro by activating the human Gi-coupled
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 concen-
trations 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 ketoaci-
dosis 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 physiologi-
cal 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
b-adrenergic 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 adminis-
tration acutely stimulates lipolysis and causes peripheral
insulin resistance (Nellemann et al. 2013). Also, the in vivo
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 insulin-
mediated 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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R205
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.
Physiological regulation of human AT lipolysis
As discussed earlier, the lipolytic rate in human AT is
determined by a delicate balance between several regulat-
ory pathways. In healthy subjects, this regulation facili-
tates 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 efficiently 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 pattern of GH, and the nocturnal increase in
FFA during sleep is virtually absent in GH-deficient
patients (Jorgensen et al. 1990).
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 b-adrenergic
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 adre-
nergic responsiveness (Kanaley et al. 2004). The primary
adrenergic stimulus of AT during exercise originates from
circulating catecholamines, with only a minor contri-
bution 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 catechol-
amines 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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R206
lipolysis further (Nellemann et al. 2012). Another import-
ant difference between upper- and lower-body subcu-
taneous 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. hypertro-
phy), 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 lower-
body 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 andco-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
The important function of ATGL as a TG hydrolase was
discovered simultaneously in 2004 by three different
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 ago-
nists) 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 transcrip-
tion 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). The two
serine residues Ser404 and Ser428 in the C-terminal part of
the human ATGL sequence (corresponding to Ser406 and
Ser430 in murine ATGL) have been identified as phos-
phorylation sites (Bartz et al. 2007). However, the role of
these sites in the regulation of ATGL activity, and the
identity of the upstream kinases is somewhat unclear.
Thus, Ser406 has been suggested to be a consensus site for
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
Acute stimulation
Prolonged stimulation
PLIN1
Lipid dropletPLIN
1CGI-5
8
DGTG
CGI-58ATG
LG
0S2
ATGL
PKA
ATGL
G0S2
DGTGPLIN
1P
P
P
CGI-58PLIN1
PPPATGL
CG
I-58
Degradation
A
B
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R207
AMP-activated protein kinase (AMPK), and in murine 3T3-
L1 adipocytes, it was shown that pharmacological stimu-
lation of lipolysis with the AMPK agonist AICAR was
dependent on ATGL Ser406 phosphorylation (Ahmadian
et al. 2011). However, another study found that phos-
phorylation of Ser404 in human ATGL was increased by
b-adrenergic stimulation, while AICAR treatment had no
effect (Pagnon et al. 2012). Additionally, in mouse AT,
Ser406 phosphorylation was increased with fasting, exer-
cise, 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 human skeletal muscle (SM), Ser404
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
Ser430 is currently unknown, and so far no reports have
been published on the functional role of this site.
DGTGPLIN
1P
P
P
PLIN1PPP
ATGL
CG
I-58
DG
TG ATGL
CGI-58
G0S2C
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.
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 protein–protein
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 lysopho-
sphatidic 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-58-derived
phospholipids are essential second messengers in murine
liver and AT when exposed to pro-inflammatory cytokines
like TNFa, interleukin 1b (IL1b), and IL6 (Lord et al. 2012).
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Consequently, as downstream inflammatory stress kinases
can impair insulin signaling, CGI-58 seems to be involved
in cross talk between insulin sensitivity and inflammation,
at least in mice.
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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R208
the catalytic patatin domain of ATGL (Yang et al. 2010,
Cornaciu et al. 2011), but the ATGL–G0S2 interaction is
independent of the ATGL–CGI-58 interaction, and inhi-
bition 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 signi-
ficantly reduces the TNFa mediated lipolytic response.
Murine G0S2 is a short-lived 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, conse-
quently, 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.
2013). Furthermore, the normal fasting- or exercise-
induced rise in plasma FFA is absent in ATGL-KO animals
indicating a failure to increase lipolysis in WAT (Huijsman
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 8–12 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 defec-
tive cold adaptation, and the fasting-induced 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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R209
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 subcu-
taneous 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 extensive pancreatic steatosis
generally have an impaired insulin response to an oral
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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-of-function
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 Chanarin–Dorfman
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 (Jenkins-Kruchten et al. 2003,
Smith et al. 2007). Consistently, in FABP4-KO mice, the
lipolytic capacity is reduced, and the intracellular FFA
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
Table 1 Overview of genetic studies on ATGL and CGI-58 function
Species
Diagnosis/genetic
model
Affected
protein Highlights of the study Reference
Human NLSDI CGI-58 Case report: clinical manifestations and proposalof diagnostic criteria
Igal et al. (1997)
Human NLSDI CGI-58 Identification of defects in CGI-58 as causative forNLSDI
Lefevre et al. (2001)
Human NLSDI CGI-58 Activation of ATGL and rescue of NLSDI by CGI-58 Lass et al. (2006)Human NLSDM ATGL Case report: identification of truncations in
human ATGLFischer et al. (2007)
Human NLSDM ATGL Identification of biochemical defects in truncatedATGL
Kobayashi et al. (2008)
Human NLSDM ATGL Case report: magnetic resonance imaging ofmuscles and metabolic characterization
Laforet et al. (2013)
Human NLSDM ATGL Case report: body composition and glucose/lipidmetabolism
Natali et al. (2013)
Mouse KO ATGL andHSL
Measurement of lipolysis in AT explants from KOanimals
Schweiger et al. (2006)
Mouse KO ATGL Phenotyping of KO animals Haemmerle et al. (2006)Mouse KO ATGL Insulin sensitivity and glucose/lipid metabolism Kienesberger et al. (2009)Mouse KO ATGL and
HSLSubstrate partitioning and metabolism during rest
and exerciseHuijsman et al. (2009)
Mouse KO ATGL Evaluation of effects on insulin secretion Peyot et al. (2009)Mouse KO CGI-58 Phenotyping of KO animals Radner et al. (2009)Mouse KO with cardio-specific
expressionATGL Lipid/glucose metabolism during exercise Schoiswohl et al. (2010)
Mouse AT-specific KO ATGL Phenotyping and fed/fasting metabolism Wu et al. (2012)Mouse KO with cardio-specific
expressionATGL Cardiac metabolism Schrammel et al. (2013)
Mouse KO G0S2 Phenotyping of transgenic animals Zhang et al. (2013)Mouse AT-specific overexpression G0S2 Phenotyping of transgenic animals Heckmann et al. (2014)
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R210
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,
these sites are Ser563, Ser659, and Ser660 (Stralfors et al. 1984,
Garton et al. 1988, Anthonsen et al. 1998) corresponding
to the human residues Ser552, Ser649, and Ser650 (Contreras
et al. 1998, Watt et al. 2006). The functional role of these
sites is different; phosphorylation of Ser563 is thought to
promote the translocation of HSL from the cytosol to LDs
(Daval et al. 2005), while phosphorylation of Ser659 and
Ser660 is critical for activation of the intrinsic enzymatic
activity (Anthonsen et al. 1998). Conversely, phosphoryl-
ation of rat HSL on Ser565 (human Ser554) by AMPK inhibits
HSL activation, most likely by steric hindrance of
phosphorylation of the adjacent Ser563, thus preventing
the translocation of HSL to the LDs (Daval et al. 2005)
(Fig. 5B). In terms of specificity, 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).
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Animal models of HSL deficiency
The key role of HSL as a DG hydrolase in vivo was 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 diet-induced obesity and peripheral insulin resistance
(Osuga et al. 2000, Harada et al. 2003, Park et al. 2005). This
unexpected observation was found to be caused by a
compensatory reduction in fatty acid esterification and
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 thermo-
genesis, 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.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
A B
FABP4
PLIN1
Lipid droplet
PLIN1
PKA
FABP4FFA-
FFA
DG MG
HSLP PP
PFABP4
Ser64
9
Ser65
0
Ser55
2
HSLP PP
PLIN1
Lipid droplet
PLIN1
PKA
cAMP
AMPK
5′-AMP
PDE3B
DG MG
HSLP PP
HSLP PP
Ser55
4
Ser55
2
PP
P PP
PP
P PP
P
Figure 5
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
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, phosphodi-
esterase 3B; PKA, protein kinase A.
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R211
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 correspond-
ing 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 subcu-
taneous 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
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.
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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
specific inhibition of HSL in cultured fat pads, the
MG-hydrolase 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 constitu-
tively 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 adipo-
cytes. The pro-apoptotic CIDE proteins (cell-death indu-
cing 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).
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
Table 2 Overview of genetic studies on HSL, MGL, and FABP4
function
Species
Genetic
model
Affected
protein
Highlights
of the study Reference
Mouse KO FABP4 Phenotyping ofKO animals
Coe et al.(1999)
Mouse KO HSL Phenotyping ofKO animals
Osuga et al.(2000)
Mouse KO HSL Involvement ofHSL inwhole-bodyDG catabolism
Haemmerleet al. (2002)
Mouse KO HSL Lipid metab-olism indiet-inducedobesity
Harada et al.(2003)
Mouse KO HSL AT adaptationsto HSLdeficiency
Zimmermannet al. (2003)
Mouse KO HSL Insulin sensi-tivity andglucose/lipidmetabolism
Park et al.(2005)
Mouse KO MGL Phenotyping ofKO animals
Taschler et al.(2011)
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R212
CIDEA and CIDEC from mice and humans have recently
been shown to be negative regulators of lipolysis (Nord-
strom et al. 2005, Puri et al. 2008, Christianson et al. 2010),
although their specific role is not well characterized yet.
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 LD’s 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, adipo-
philin, and tail-interacting protein of 47 kDa (TIP-47), and
the family also includes the proteins S3-12 and myocyte
LD protein (MLDP, also known as OXPAT) (Bickel et al.
2009). However, due to their evolutionary, structural, and
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 PKA-
stimulated 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.
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 phosphory-
lated and translocated (Miyoshi et al. 2006). In other
words, the lipolytic action of LD-associated and phos-
phorylated HSL are critically dependent on PLIN1 phos-
phorylation 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 efficiently
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- and ATGL-mediated
lipolysis, as mutation of Ser517 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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R213
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 liver-specific
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 brown-like
phenotype (Toh et al. 2008). Thus, in spite of tissue-specific
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).
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.
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 deficiency 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 LD-associated
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,
including the crucial Ser517. 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 loss-of-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 CIDEC-deficient AT had an
unusually high occurrence of multilocular adipocytes
supporting a role for CIDEC in the formation and
stabilization of large LD’s (Rubio-Cabezas et al. 2009). An
overview of studies on genetic deficiencies affecting
LD-associated proteins in humans and animal models is
listed in Table 3.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
Table 3 Overview of genetic studies on LD-associated proteins
Species Diagnosis/genetic model
Affected
protein Highlights of the study Reference
Human Partial lipodystrophy CIDEC Identification of CIDEC truncation asthe causative mutation
Rubio-Cabezas et al. (2009)
Human Partial lipodystrophy PLIN1 Identification of two PLIN1 truncationsas causative mutations
Gandotra et al. (2011a)
Human Partial lipodystrophy PLIN1 Characterization of PLIN1 mutants inregulation of lipolysis in cell culture
Gandotra et al. (2011b)
Mouse KO PLIN1 Phenotyping of KO animals Martinez-Botas et al. (2000)Mouse KO PLIN1 Phenotyping of KO animals Tansey et al. (2001)Mouse KO CIDEA Phenotyping of KO animals Zhou et al. (2003)Mouse KO CIDEB Phenotyping of KO animals Li et al. (2007)Mouse KO CIDEC Phenotyping of KO animals Nishino et al. (2008)Mouse KO CIDEC Analysis of WAT ‘browning’ in KO
animalsToh et al. (2008)
Mouse KO CIDEA Characterization of the role of CIDEAin hepatic metabolism
Zhou et al. (2012)
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R214
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
takingup and esterifyingFFA 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 deficient lipase activity, particu-
larly 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 diabetes-
induced cardiomyopathy (Pulinilkunnil et al. 2013), sup-
porting 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-specific KO or
overexpression of ATGL only has minor effects on hepatic
insulin sensitivity and whole-body metabolic parameters
(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
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
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 intramyocel-
lular 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 character-
ization 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 lipo-
lytic 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.
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
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R215
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).
References
Ahmadian M, Abbott MJ, Tang T, Hudak CS, Kim Y, Bruss M, Hellerstein
MK, Lee HY, Samuel VT, Shulman GI et al. 2011 Desnutrin/ATGL is
regulated by AMPK and is required for a brown adipose phenotype.
Cell Metabolism 13 739–748. (doi:10.1016/j.cmet.2011.05.002)
Ahn J, Oh SA, Suh Y, Moeller SJ & Lee K 2013 Porcine G(0)/G(1) switch
gene 2 (G0S2) expression is regulated during adipogenesis and short-
term in-vivo nutritional interventions. Lipids 48 209–218. (doi:10.1007/
s11745-013-3756-8)
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA,
Fruchart JC, James WP, Loria CM & Smith SC Jr 2009 Harmonizing the
metabolic syndrome: a joint interim statement of the International
Diabetes Federation Task Force on Epidemiology and Prevention;
National Heart, Lung, and Blood Institute; American Heart Association;
World Heart Federation; International Atherosclerosis Society; and
International Association for the Study of Obesity. Circulation 120
1640–1645. (doi:10.1161/CIRCULATIONAHA.109.192644)
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB &
Cohen P 1997 Characterization of a 3-phosphoinositide-dependent
protein kinase which phosphorylates and activates protein kinase Ba.
Current Biology 7 261–269. (doi:10.1016/S0960-9822(06)00122-9)
Alsted TJ, Nybo L, Schweiger M, Fledelius C, Jacobsen P, Zimmermann R,
Zechner R & Kiens B 2009 Adipose triglyceride lipase in human skeletal
muscle is upregulated by exercise training. American Journal of
Physiology. Endocrinology and Metabolism 296 E445–E453. (doi:10.1152/
ajpendo.90912.2008)
Amati F, Pennant M, Azuma K, Dube JJ, Toledo FG, Rossi AP, Kelley DE &
Goodpaster BH 2012 Lower thigh subcutaneous and higher visceral
abdominal adipose tissue content both contribute to insulin resistance.
Obesity 20 1115–1117. (doi:10.1038/oby.2011.401)
Anthonsen MW, Ronnstrand L, Wernstedt C, Degerman E & Holm C 1998
Identification of novel phosphorylation sites in hormone-sensitive
lipase that are phosphorylated in response to isoproterenol and govern
activation properties in vitro. Journal of Biological Chemistry 273
215–221. (doi:10.1074/jbc.273.1.215)
Armani A, Marzolla V, Rosano GM, Fabbri A & Caprio M 2011
Phosphodiesterase type 5 (PDE5) in the adipocyte: a novel player in fat
metabolism? Trends in Endocrinology and Metabolism 22 404–411.
(doi:10.1016/j.tem.2011.05.004)
Arner P, Kriegholm E, Engfeldt P & Bolinder J 1990 Adrenergic regulation of
lipolysis in situ at rest and during exercise. Journal of Clinical Investigation
85 893–898. (doi:10.1172/JCI114516)
Aversa A, Caprio M, Antelmi A, Armani A, Brama M, Greco EA,
Francomano D, Calanchini M, Spera G, Di Luigi L et al. 2011 Exposure
to phosphodiesterase type 5 inhibitors stimulates aromatase expression
in human adipocytes in vitro. Journal of Sexual Medicine 8 696–704.
(doi:10.1111/j.1743-6109.2010.02152.x)
Barbe P, Millet L, Galitzky J, Lafontan M & Berlan M 1996 In situ assessment
of the role of the b1-, b2- and b3-adrenoceptors in the control of
lipolysis and nutritive blood flow in human subcutaneous adipose
tissue. British Journal of Pharmacology 117 907–913. (doi:10.1111/
j.1476-5381.1996.tb15279.x)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Bartz R, Zehmer JK, Zhu M, Chen Y, Serrero G, Zhao Y & Liu P 2007
Dynamic activity of lipid droplets: protein phosphorylation and
GTP-mediated protein translocation. Journal of Proteome Research 6
3256–3265. (doi:10.1021/pr070158j)
Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R,
DeFronzo RA & Cusi K 2005 Dose–response effect of elevated
plasma free fatty acid on insulin signaling. Diabetes 54 1640–1648.
(doi:10.2337/diabetes.54.6.1640)
Berndt J, Kralisch S, Kloting N, Ruschke K, Kern M, Fasshauer M, Schon MR,
Stumvoll M & Bluher M 2008 Adipose triglyceride lipase gene
expression in human visceral obesity. Experimental and Clinical
Endocrinology & Diabetes 116 203–210. (doi:10.1055/s-2007-993148)
Berryman DE, List EO, Coschigano KT, Behar K, Kim JK & Kopchick JJ 2004
Comparing adiposity profiles in three mouse models with altered GH
signaling. Growth Hormone & IGF Research 14 309–318. (doi:10.1016/
j.ghir.2004.02.005)
Berryman DE, List EO, Kohn DT, Coschigano KT, Seeley RJ & Kopchick JJ
2006 Effect of growth hormone on susceptibility to diet-induced
obesity. Endocrinology 147 2801–2808. (doi:10.1210/en.2006-0086)
Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J, Laurencikiene J,
Anesia R, Rodriguez AM, Ryden M et al. 2009 Contribution of
adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in
hMADS adipocytes. Journal of Biological Chemistry 284 18282–18291.
(doi:10.1074/jbc.M109.008631)
Bickel PE, Tansey JT & Welte MA 2009 PAT proteins, an ancient family of
lipid droplet proteins that regulate cellular lipid stores. Biochimica et
Biophysica Acta 1791 419–440. (doi:10.1016/j.bbalip.2009.04.002)
Botion LM, Brasier AR, Tian B, Udupi V & Green A 2001 Inhibition of
proteasome activity blocks the ability of TNFa to down-regulate G(i)
proteins and stimulate lipolysis. Endocrinology 142 5069–5075.
(doi:10.1210/endo.142.12.8518)
Boura-Halfon S & Zick Y 2009 Phosphorylation of IRS proteins, insulin action,
and insulin resistance. American Journal of Physiology. Endocrinology and
Metabolism 296 E581–E591. (doi:10.1152/ajpendo.90437.2008)
Bousquet-Melou A, Galitzky J, Lafontan M & Berlan M 1995 Control of
lipolysis in intra-abdominal fat cells of nonhuman primates:
comparison with humans. Journal of Lipid Research 36 451–461.
Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, Wright SD, Taggart AK &
Waters MG 2008 Role of GPR81 in lactate-mediated reduction of
adipose lipolysis. Biochemical and Biophysical Research Communications
377 987–991. (doi:10.1016/j.bbrc.2008.10.088)
Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS &
Cantley LC 1990 Purification and characterization of phosphoinositide
3-kinase from rat liver. Journal of Biological Chemistry 265 19704–19711.
Castan I, Valet P, Larrouy D, Voisin T, Remaury A, Daviaud D, Laburthe M
& Lafontan M 1993 Distribution of PYY receptors in human fat cells: an
antilipolytic system alongside the a2-adrenergic system. American
Journal of Physiology 265 E74–E80.
Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, Luo Z, Farmer SR &
Kandror KV 2011 SIRT1 controls lipolysis in adipocytes via
FOXO1-mediated expression of ATGL. Journal of Lipid Research 52
1693–1701. (doi:10.1194/jlr.M014647)
Chanarin I, Patel A, Slavin G, Wills EJ, Andrews TM & Stewart G 1975
Neutral-lipid storage disease: a new disorder of lipid metabolism.
BMJ 1 553–555. (doi:10.1136/bmj.1.5957.553)
Chen XL, Lee K, Hartzell DL, Dean RG, Hausman GJ, McGraw RA,
Della-Fera MA & Baile CA 2001 Adipocyte insensitivity to insulin in
growth hormone-transgenic mice. Biochemical and Biophysical Research
Communications 283 933–937. (doi:10.1006/bbrc.2001.4882)
Cho KJ, Shim JH, Cho MC, Choe YK, Hong JT, Moon DC, Kim JW &
Yoon DY 2005 Signaling pathways implicated in a-melanocyte
stimulating hormone-induced lipolysis in 3T3-L1 adipocytes. Journal of
Cellular Biochemistry 96 869–878. (doi:10.1002/jcb.20561)
Choi YH, Park S, Hockman S, Zmuda-Trzebiatowska E, Svennelid F,
Haluzik M, Gavrilova O, Ahmad F, Pepin L, Napolitano M et al. 2006
Alterations in regulation of energy homeostasis in cyclic nucleotide
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R216
phosphodiesterase 3B-null mice. Journal of Clinical Investigation 116
3240–3251. (doi:10.1172/JCI24867)
Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS,
Monks BR & Birnbaum MJ 2010 Insulin regulates adipocyte lipolysis via
an Akt-independent signaling pathway. Molecular and Cellular Biology
30 5009–5020. (doi:10.1128/MCB.00797-10)
Christianson JL, Boutet E, Puri V, Chawla A & Czech MP 2010
Identification of the lipid droplet targeting domain of the Cidea protein.
Journal of Lipid Research 51 3455–3462. (doi:10.1194/jlr.M009498)
Clasen BF, Krusenstjerna-Hafstrom T, Vendelbo MH, Thorsen K, Escande C,
Moller N, Pedersen SB, Jorgensen JO & Jessen N 2013 Gene expression
in skeletal muscle after an acute intravenous GH bolus in human
subjects: identification of a mechanism regulating ANGPTL4. Journal of
Lipid Research 54 1988–1997. (doi:10.1194/jlr.P034520)
Clerico A, Giannoni A, Vittorini S & Passino C 2011 Thirty years of the heart
as an endocrine organ: physiological role and clinical utility of cardiac
natriuretic hormones.American Journal of Physiology. Heart andCirculatory
Physiology 301 H12–H20. (doi:10.1152/ajpheart.00226.2011)
Coe NR, Simpson MA & Bernlohr DA 1999 Targeted disruption of the
adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell
lipolysis and increases cellular fatty acid levels. Journal of Lipid Research
40 967–972.
Contreras JA, Danielsson B, Johansson C, Osterlund T, Langin D & Holm C
1998 Human hormone-sensitive lipase: expression and large-scale
purification from a baculovirus/insect cell system. Protein Expression and
Purification 12 93–99. (doi:10.1006/prep.1997.0821)
Copps KD & White MF 2012 Regulation of insulin sensitivity by
serine/threonine phosphorylation of insulin receptor substrate
proteins IRS1 and IRS2. Diabetologia 55 2565–2582. (doi:10.1007/
s00125-012-2644-8)
Cornaciu I, Boeszoermenyi A, Lindermuth H, Nagy HM, Cerk IK, Ebner C,
Salzburger B, Gruber A, Schweiger M, Zechner R et al. 2011 The minimal
domain of adipose triglyceride lipase (ATGL) ranges until leucine 254
and can be activated and inhibited by CGI-58 and G0S2, respectively.
PLoS ONE 6 e26349. (doi:10.1371/journal.pone.0026349)
CusiK, Kashyap S,Gastaldelli A, Bajaj M & Cersosimo E 2007 Effects on insulin
secretion and insulin action of a 48-h reduction of plasma free fatty acids
with acipimox in nondiabetic subjects genetically predisposed to type 2
diabetes. American Journal of Physiology. Endocrinology and Metabolism 292
E1775–E1781. (doi:10.1152/ajpendo.00624.2006)
Czech MP, Tencerova M, Pedersen DJ & Aouadi M 2013 Insulin signalling
mechanisms for triacylglycerol storage. Diabetologia 56 949–964.
(doi:10.1007/s00125-013-2869-1)
Daval M, Diot-Dupuy F, Bazin R, Hainault I, Viollet B, Vaulont S, Hajduch E,
Ferre P & Foufelle F 2005 Anti-lipolytic action of AMP-activated protein
kinase in rodent adipocytes. Journal of Biological Chemistry 280
25250–25257. (doi:10.1074/jbc.M414222200)
Demerath EW, Sun SS, Rogers N, Lee M, Reed D, Choh AC, Couch W,
Czerwinski SA, Chumlea WC, Siervogel RM et al. 2007 Anatomical
patterning of visceral adipose tissue: race, sex, and age variation. Obesity
15 2984–2993. (doi:10.1038/oby.2007.356)
De Naeyer H, Ouwens DM, Van Nieuwenhove Y, Pattyn P, ’t Hart LM,
Kaufman JM, Sell H, Eckel J, Cuvelier C, Taes YE et al. 2011 Combined
gene and protein expression of hormone-sensitive lipase and adipose
triglyceride lipase, mitochondrial content, and adipocyte size in
subcutaneous and visceral adipose tissue of morbidly obese men.
Obesity Facts 4 407–416. (doi:10.1159/000333445)
Dinneen S, Alzaid A, Miles J & Rizza R 1993 Metabolic effects of the
nocturnal rise in cortisol on carbohydrate metabolism in normal
humans. Journal of Clinical Investigation 92 2283–2290. (doi:10.1172/
JCI116832)
Djurhuus CB, Gravholt CH, Nielsen S, Pedersen SB, Moller N & Schmitz O
2004 Additive effects of cortisol and growth hormone on regional
and systemic lipolysis in humans. American Journal of Physiology.
Endocrinology and Metabolism 286 E488–E494. (doi:10.1152/ajpendo.
00199.2003)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Doris R, Vernon RG, Houslay MD & Kilgour E 1994 Growth hormone
decreases the response to anti-lipolytic agonists and decreases the levels
of Gi2 in rat adipocytes. Biochemical Journal 297 41–45.
Duncan RE, Wang Y, Ahmadian M, Lu J, Sarkadi-Nagy E & Sul HS 2010
Characterization of desnutrin functional domains: critical residues for
triacylglycerol hydrolysis in cultured cells. Journal of Lipid Research 51
309–317. (doi:10.1194/jlr.M000729)
Egan JJ, Greenberg AS, Chang MK, Wek SA, Moos MC Jr & Londos C 1992
Mechanism of hormone-stimulated lipolysis in adipocytes: transloca-
tion of hormone-sensitive lipase to the lipid storage droplet. PNAS 89
8537–8541. (doi:10.1073/pnas.89.18.8537)
Endo T & Kobayashi T 2012 Expression of functional TSH receptor in white
adipose tissues of hyt/hyt mice induces lipolysis in vivo. American
Journal of Physiology. Endocrinology and Metabolism 302 E1569–E1575.
(doi:10.1152/ajpendo.00572.2011)
Fain JN, Cheema P, Tichansky DS & Madan AK 2008 Stimulation of human
omental adipose tissue lipolysis by growth hormone plus dexametha-
sone. Molecular and Cellular Endocrinology 295 101–105. (doi:10.1016/
j.mce.2008.05.014)
Fischer J, Lefevre C, Morava E, Mussini JM, Laforet P, Negre-Salvayre A,
Lathrop M & Salvayre R 2007 The gene encoding adipose triglyceride
lipase (PNPLA2) is mutated in neutral lipid storage disease with
myopathy. Nature Genetics 39 28–30. (doi:10.1038/ng1951)
Frayn KN 2002 Adipose tissue as a buffer for daily lipid flux. Diabetologia 45
1201–1210. (doi:10.1007/s00125-002-0873-y)
Frayn KN 2010 Fat as a fuel: emerging understanding of the adipose
tissue–skeletal muscle axis. Acta Physiologica 199 509–518.
(doi:10.1111/j.1748-1716.2010.02128.x)
Fredrikson G, Stralfors P, Nilsson NO & Belfrage P 1981 Hormone-sensitive
lipase of rat adipose tissue. Purification and some properties. Journal of
Biological Chemistry 256 6311–6320.
Fredrikson G, Tornqvist H & Belfrage P 1986 Hormone-sensitive lipase and
monoacylglycerol lipase are both required for complete degradation of
adipocyte triacylglycerol. Biochimica et Biophysica Acta 876 288–293.
(doi:10.1016/0005-2760(86)90286-9)
Furuhashi M & Hotamisligil GS 2008 Fatty acid-binding proteins: role in
metabolic diseases and potential as drug targets. Nature Reviews. Drug
Discovery 7 489–503. (doi:10.1038/nrd2589)
Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y,
Charpentier G, Auclair M, Delepine M, Barroso I et al. 2011a Perilipin
deficiency and autosomal dominant partial lipodystrophy. New England
Journal of Medicine 364 740–748. (doi:10.1056/NEJMoa1007487)
Gandotra S, Lim K, Girousse A, Saudek V, O’Rahilly S & Savage DB 2011b
Human frame shift mutations affecting the carboxyl terminus of
perilipin increase lipolysis by failing to sequester the adipose triglyceride
lipase (ATGL) coactivator AB-hydrolase-containing 5 (ABHD5). Journal of
Biological Chemistry 286 34998–35006. (doi:10.1074/jbc.M111.278853)
Garton AJ, Campbell DG, Cohen P & Yeaman SJ 1988 Primary structure of
the site on bovine hormone-sensitive lipase phosphorylated by cyclic
AMP-dependent protein kinase. FEBS Letters 229 68–72. (doi:10.1016/
0014-5793(88)80799-3)
Gasic S, Tian B & Green A 1999 Tumor necrosis factor a stimulates lipolysis
in adipocytes by decreasing Gi protein concentrations. Journal of
Biological Chemistry 274 6770–6775. (doi:10.1074/jbc.274.10.6770)
Ghosh AK, Ramakrishnan G, Chandramohan C & Rajasekharan R 2008
CGI-58, the causative gene for Chanarin–Dorfman syndrome, mediates
acylation of lysophosphatidic acid. Journal of Biological Chemistry 283
24525–24533. (doi:10.1074/jbc.M801783200)
Gjedsted J, Gormsen LC, Nielsen S, Schmitz O, Djurhuus CB, Keiding S,
ORskov H, Tonnesen E & Moller N 2007 Effects of a 3-day fast on
regional lipid and glucose metabolism in human skeletal muscle and
adipose tissue. Acta Physiologica 191 205–216. (doi:10.1111/j.1748-
1716.2007.01740.x)
de Glisezinski I, Larrouy D, Bajzova M, Koppo K, Polak J, Berlan M, Bulow J,
Langin D, Marques MA, Crampes F et al. 2009 Adrenaline but not
noradrenaline is a determinant of exercise-induced lipid mobilization
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R217
in human subcutaneous adipose tissue. Journal of Physiology 587
3393–3404. (doi:10.1113/jphysiol.2009.168906)
Gormsen LC, Jessen N, Gjedsted J, Gjedde S, Norrelund H, Lund S,
Christiansen JS, Nielsen S, Schmitz O & Moller N 2007 Dose–response
effects of free fatty acids on glucose and lipid metabolism during
somatostatin blockade of growth hormone and insulin in humans.
Journal of Clinical Endocrinology and Metabolism 92 1834–1842.
(doi:10.1210/jc.2006-2659)
Grahn TH, Zhang Y, Lee MJ, Sommer AG, Mostoslavsky G, Fried SK,
Greenberg AS & Puri V 2013 FSP27 and PLIN1 interaction promotes the
formation of large lipid droplets in human adipocytes. Biochemical and
Biophysical Research Communications 432 296–301. (doi:10.1016/j.bbrc.
2013.01.113)
Granneman JG, Moore HP, Granneman RL, Greenberg AS, Obin MS &
Zhu Z 2007 Analysis of lipolytic protein trafficking and interactions in
adipocytes. Journal of Biological Chemistry 282 5726–5735. (doi:10.1074/
jbc.M610580200)
Granneman JG, Moore HP, Krishnamoorthy R & Rathod M 2009 Perilipin
controls lipolysis by regulating the interactions of AB-hydrolase
containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). Journal of
Biological Chemistry 284 34538–34544. (doi:10.1074/jbc.M109.068478)
Gray NE, Lam LN, Yang K, Zhou AY, Koliwad S & Wang JC 2012
Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of
intracellular lipolysis in murine adipocytes. Journal of Biological
Chemistry 287 8444–8456. (doi:10.1074/jbc.M111.294124)
Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ & Londos C
1991 Perilipin, a major hormonally regulated adipocyte-specific
phosphoprotein associated with the periphery of lipid storage droplets.
Journal of Biological Chemistry 266 11341–11346.
Greenberg AS, Coleman RA, Kraemer FB, McManaman JL, Obin MS, Puri V,
Yan QW, Miyoshi H & Mashek DG 2011 The role of lipid droplets in
metabolic disease in rodents and humans. Journal of Clinical Investi-
gation 121 2102–2110. (doi:10.1172/JCI46069)
Gruber A, Cornaciu I, Lass A, Schweiger M, Poeschl M, Eder C, Kumari M,
Schoiswohl G, Wolinski H, Kohlwein SD et al. 2010 The N-terminal
region of comparative gene identification-58 (CGI-58) is important for
lipid droplet binding and activation of adipose triglyceride lipase.
Journal of Biological Chemistry 285 12289–12298. (doi:10.1074/jbc.
M109.064469)
Haemmerle G, Zimmermann R, Hayn M, Theussl C, Waeg G, Wagner E,
Sattler W, Magin TM, Wagner EF & Zechner R 2002 Hormone-sensitive
lipase deficiency in mice causes diglyceride accumulation in adipose
tissue, muscle, and testis. Journal of Biological Chemistry 277 4806–4815.
(doi:10.1074/jbc.M110355200)
Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J,
Heldmaier G, Maier R, Theussl C, Eder S et al. 2006 Defective lipolysis
and altered energy metabolism in mice lacking adipose triglyceride
lipase. Science 312 734–737. (doi:10.1126/science.1123965)
Hansen TK, Gravholt CH, ORskov H, Rasmussen MH, Christiansen JS &
Jorgensen JO 2002 Dose dependency of the pharmacokinetics and
acute lipolytic actions of growth hormone. Journal of Clinical
Endocrinology and Metabolism 87 4691–4698. (doi:10.1210/jc.2002-
020563)
Harada K, Shen WJ, Patel S, Natu V, Wang J, Osuga J, Ishibashi S & Kraemer
FB 2003 Resistance to high-fat diet-induced obesity and altered
expression of adipose-specific genes in HSL-deficient mice. American
Journal of Physiology. Endocrinology and Metabolism 285 E1182–E1195.
(doi:10.1152/ajpendo.00259.2003)
Hardy OT, Czech MP & Corvera S 2012 What causes the insulin resistance
underlying obesity? Current Opinion in Endocrinology, Diabetes, and
Obesity 19 81–87. (doi:10.1097/MED.0b013e3283514e13)
Heckmann BL, Zhang X, Xie X, Saarinen A, Lu X, Yang X & Liu J 2014
Defective adipose lipolysis and altered global energy metabolism in
mice with adipose overexpression of the lipolytic inhibitor G0/G1
switch gene 2 (G0S2). Journal of Biological Chemistry 289 1905–1916.
(doi:10.1074/jbc.M113.522011)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Hoeg LD, Sjoberg KA, Jeppesen J, Jensen TE, Frosig C, Birk JB, Bisiani B,
Hiscock N, Pilegaard H, Wojtaszewski JF et al. 2011 Lipid-induced
insulin resistance affects women less than men and is not accompanied
by inflammation or impaired proximal insulin signaling. Diabetes 60
64–73. (doi:10.2337/db10-0698)
Hollenberg CH, Raben MS & Astwood EB 1961 The lipolytic response to
corticotropin. Endocrinology 68 589–598. (doi:10.1210/endo-68-4-589)
Huijsman E, van de Par C, Economou C, van der Poel C, Lynch GS,
Schoiswohl G, Haemmerle G, Zechner R & Watt MJ 2009 Adipose
triacylglycerol lipase deletion alters whole body energy metabolism
and impairs exercise performance in mice. American Journal of
Physiology. Endocrinology and Metabolism 297 E505–E513. (doi:10.1152/
ajpendo.00190.2009)
Igal RA & Coleman RA 1996 Acylglycerol recycling from triacylglycerol to
phospholipid, not lipase activity, is defective in neutral lipid storage
disease fibroblasts. Journal of Biological Chemistry 271 16644–16651.
(doi:10.1074/jbc.271.28.16644)
Igal RA, Rhoads JM & Coleman RA 1997 Neutral lipid storage disease with
fatty liver and cholestasis. Journal of Pediatric Gastroenterology and
Nutrition 25 541–547. (doi:10.1097/00005176-199711000-00011)
Ito M, Nagasawa M, Hara T, Ide T & Murakami K 2010 Differential roles of
CIDEA and CIDEC in insulin-induced anti-apoptosis and lipid droplet
formation in human adipocytes. Journal of Lipid Research 51 1676–1684.
(doi:10.1194/jlr.M002147)
Janson A, Karlsson FA, Micha-Johansson G, Bolme P, Bronnegard M &
Marcus C 1995 Effects of stimulatory and inhibitory thyrotropin
receptor antibodies on lipolysis in infant adipocytes. Journal of Clinical
Endocrinology and Metabolism 80 1712–1716. (doi:10.1210/jcem.80.5.
7745024)
Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B & Gross RW 2004
Identification, cloning, expression, and purification of three novel
human calcium-independent phospholipase A2 family members
possessing triacylglycerol lipase and acylglycerol transacylase activities.
Journal of Biological Chemistry 279 48968–48975. (doi:10.1074/jbc.
M407841200)
Jenkins-Kruchten AE, Bennaars-Eiden A, Ross JR, Shen WJ, Kraemer FB &
Bernlohr DA 2003 Fatty acid-binding protein–hormone-sensitive lipase
interaction. Fatty acid dependence on binding. Journal of Biological
Chemistry 278 47636–47643. (doi:10.1074/jbc.M307680200)
Jensen MD 1995 Gender differences in regional fatty acid metabolism
before and after meal ingestion. Journal of Clinical Investigation 96
2297–2303. (doi:10.1172/JCI118285)
Jensen MD 2003 Fate of fatty acids at rest and during exercise: regulatory
mechanisms. Acta Physiologica Scandinavica 178 385–390. (doi:10.1046/
j.1365-201X.2003.01167.x)
Jensen MD & Nielsen S 2007 Insulin dose response analysis of free fatty acid
kinetics. Metabolism 56 68–76. (doi:10.1016/j.metabol.2006.08.022)
Jensen MD, Haymond MW, Gerich JE, Cryer PE & Miles JM 1987 Lipolysis
during fasting. Decreased suppression by insulin and increased
stimulation by epinephrine. Journal of Clinical Investigation 79 207–213.
(doi:10.1172/JCI112785)
Jocken JW, Langin D, Smit E, Saris WH, Valle C, Hul GB, Holm C, Arner P &
Blaak EE 2007 Adipose triglyceride lipase and hormone-sensitive lipase
protein expression is decreased in the obese insulin-resistant state.
Journal of Clinical Endocrinology and Metabolism 92 2292–2299.
(doi:10.1210/jc.2006-1318)
Jocken JW, Moro C, Goossens GH, Hansen D, Mairal A, Hesselink MK,
Langin D, van Loon LJ & Blaak EE 2010 Skeletal muscle lipase content
and activity in obesity and type 2 diabetes. Journal ofClinical Endocrinology
and Metabolism 95 5449–5453. (doi:10.1210/jc.2010-0776)
Jocken JW, Goossens GH, Boon H, Mason RR, Essers Y, Havekes B, Watt MJ,
van Loon LJ & Blaak EE 2013 Insulin-mediated suppression of lipolysis
in adipose tissue and skeletal muscle of obese type 2 diabetic men and
men with normal glucose tolerance. Diabetologia 56 2255–2265.
(doi:10.1007/s00125-013-2995-9)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R218
Johansen T, Richelsen B, Hansen HS, Din N & Malmlof K 2003 Growth
hormone-mediated breakdown of body fat: effects of GH on lipases in
adipose tissue and skeletal muscle of old rats fed different diets.Hormone
and Metabolic Research 35 243–250. (doi:10.1055/s-2003-39481)
Jorgensen JO, Moller N, Lauritzen T, Alberti KG, ORskov H &
Christiansen JS 1990 Evening versus morning injections of growth
hormone (GH) in GH-deficient patients: effects on 24-hour patterns of
circulating hormones and metabolites. Journal of Clinical Endocrinology
and Metabolism 70 207–214. (doi:10.1210/jcem-70-1-207)
Kanaley JA, Dall R, Moller N, Nielsen SC, Christiansen JS, Jensen MD &
Jorgensen JO 2004 Acute exposure to GH during exercise stimulates the
turnover of free fatty acids in GH-deficient men. Journal of Applied
Physiology 96 747–753. (doi:10.1152/japplphysiol.00711.2003)
Kershaw EE, Hamm JK, Verhagen LA, Peroni O, Katic M & Flier JS 2006
Adipose triglyceride lipase: function, regulation by insulin, and
comparison with adiponutrin. Diabetes 55 148–157. (doi:10.2337/
diabetes.55.01.06.db05-0982)
Kienesberger PC, Lee D, Pulinilkunnil T, Brenner DS, Cai L, Magnes C,
Koefeler HC, Streith IE, Rechberger GN, Haemmerle G et al. 2009
Adipose triglyceride lipase deficiency causes tissue-specific changes in
insulin signaling. Journal of Biological Chemistry 284 30218–30229.
(doi:10.1074/jbc.M109.047787)
Kim JY, Tillison K, Lee JH, Rearick DA & Smas CM 2006 The adipose tissue
triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and
TNF-a in 3T3-L1 adipocytes and is a target for transactivation by
PPARgamma. American Journal of Physiology. Endocrinology and Metab-
olism 291 E115–E127. (doi:10.1152/ajpendo.00317.2005)
Kimmel AR, Brasaemle DL, McAndrews-Hill M, Sztalryd C & Londos C 2010
Adoption of PERILIPIN as a unifying nomenclature for the mammalian
PAT-family of intracellular lipid storage droplet proteins. Journal of Lipid
Research 51 468–471. (doi:10.1194/jlr.R000034)
Kiwaki K & Levine JA 2003 Differential effects of adrenocorticotropic
hormone on human and mouse adipose tissue. Journal of Comparative
Physiology. B, Biochemical, Systemic, and Environmental Physiology 173
675–678. (doi:10.1007/s00360-003-0377-1)
Kobayashi K, Inoguchi T, Maeda Y, Nakashima N, Kuwano A, Eto E, Ueno N
, Sasaki S, Sawada F, Fujii M et al. 2008 The lack of the C-terminal
domain of adipose triglyceride lipase causes neutral lipid storage
disease through impaired interactions with lipid droplets. Journal of
Clinical Endocrinology and Metabolism 93 2877–2884. (doi:10.1210/jc.
2007-2247)
Kolditz CI & Langin D 2010 Adipose tissue lipolysis. Current Opinion in
Clinical Nutrition and Metabolic Care 13 377–381. (doi:10.1097/MCO.
0b013e32833bed6a)
Koliwad SK, Kuo T, Shipp LE, Gray NE, Backhed F, So AY, Farese RV Jr &
Wang JC 2009 Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose
factor) is a direct glucocorticoid receptor target and participates in
glucocorticoid-regulated triglyceride metabolism. Journal of Biological
Chemistry 284 25593–25601. (doi:10.1074/jbc.M109.025452)
Koliwad SK, Gray NE & Wang JC 2012 Angiopoietin-like 4 (Angptl4): a
glucocorticoid-dependent gatekeeper of fatty acid flux during fasting.
Adipocytes 1 182–187. (doi:10.4161/adip.20787)
Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D,
Qiu Y, Fraser CC, Yang DD et al. 2005 Transgenic angiopoietin-like
(angptl)4 overexpression and targeted disruption of angptl4 and
angptl3: regulation of triglyceride metabolism. Endocrinology 146
4943–4950. (doi:10.1210/en.2005-0476)
Kraemer FB, Patel S, Saedi MS & Sztalryd C 1993 Detection of hormone-
sensitive lipase in various tissues. I. Expression of an HSL/bacterial
fusion protein and generation of anti-HSL antibodies. Journal of Lipid
Research 34 663–671.
Lacasa D, Agli B & Giudicelli Y 1988 Permissive action of glucocorticoids on
catecholamine-induced lipolysis: direct “in vitro” effects on the fat cell
b-adrenoreceptor-coupled-adenylate cyclase system. Biochemical and
Biophysical Research Communications 153 489–497. (doi:10.1016/
S0006-291X(88)81121-5)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Lafferty MJ, Bradford KC, Erie DA & Neher SB 2013 Angiopoietin-like
Protein 4 Inhibition of Lipoprotein Lipase: evidence for reversible
complex formation. Journal of Biological Chemistry 288 28524–28534.
(doi:10.1074/jbc.M113.497602)
Lafontan M & Berlan M 1993 Fat cell adrenergic receptors and the control of
white and brown fat cell function. Journal of Lipid Research34 1057–1091.
Lafontan M, Moro C, Berlan M, Crampes F, Sengenes C & Galitzky J 2008
Control of lipolysis by natriuretic peptides and cyclic GMP. Trends in
Endocrinology and Metabolism 19 130–137. (doi:10.1016/j.tem.2007.
11.006)
Laforet P, Stojkovic T, Bassez G, Carlier PG, Clement K, Wahbi K, Petit FM,
Eymard B & Carlier RY 2013 Neutral lipid storage disease with
myopathy: a whole-body nuclear MRI and metabolic study. Molecular
Genetics and Metabolism 108 125–131. (doi:10.1016/j.ymgme.2012.
12.004)
Langin D 2006 Control of fatty acid and glycerol release in adipose tissue
lipolysis. Comptes Rendus Biologies 329 598–607. (doi:10.1016/j.crvi.
2005.10.008)
Langin D, Laurell H, Holst LS, Belfrage P & Holm C 1993 Gene organization
and primary structure of human hormone-sensitive lipase: possible
significance of a sequence homology with a lipase of Moraxella TA144,
an antarctic bacterium. PNAS 90 4897–4901. (doi:10.1073/pnas.90.11.
4897)
Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M, Arner E,
Sicard A, Jenkins CM, Viguerie N et al. 2005 Adipocyte lipases and
defect of lipolysis in human obesity. Diabetes 54 3190–3197.
(doi:10.2337/diabetes.54.11.3190)
Lapointe A, Piche ME, Weisnagel SJ, Bergeron J & Lemieux S 2009
Associations between circulating free fatty acids, visceral adipose tissue
accumulation, and insulin sensitivity in postmenopausal women.
Metabolism 58 180–185. (doi:10.1016/j.metabol.2008.09.011)
Large V, Reynisdottir S, Langin D, Fredby K, Klannemark M, Holm C &
Arner P 1999 Decreased expression and function of adipocyte
hormone-sensitive lipase in subcutaneous fat cells of obese subjects.
Journal of Lipid Research 40 2059–2066.
Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G,
Schweiger M, Kienesberger P, Strauss JG, Gorkiewicz G & Zechner R
2006 Adipose triglyceride lipase-mediated lipolysis of cellular fat stores
is activated by CGI-58 and defective in Chanarin–Dorfman Syndrome.
Cell Metabolism 3 309–319. (doi:10.1016/j.cmet.2006.03.005)
Laugwitz KL, Allgeier A, Offermanns S, Spicher K, Van Sande J, Dumont JE
& Schultz G 1996 The human thyrotropin receptor: a heptahelical
receptor capable of stimulating members of all four G protein families.
PNAS 93 116–120. (doi:10.1073/pnas.93.1.116)
Lefevre C, Jobard F, Caux F, Bouadjar B, Karaduman A, Heilig R, Lakhdar H,
Wollenberg A, Verret JL, Weissenbach J et al. 2001 Mutations in CGI-58,
the gene encoding a new protein of the esterase/lipase/thioesterase
subfamily, in Chanarin–Dorfman syndrome. American Journal of Human
Genetics 69 1002–1012. (doi:10.1086/324121)
Li JZ, Ye J, Xue B, Qi J, Zhang J, Zhou Z, Li Q, Wen Z & Li P 2007 Cideb
regulates diet-induced obesity, liver steatosis, and insulin sensitivity
by controlling lipogenesis and fatty acid oxidation. Diabetes 56
2523–2532. (doi:10.2337/db07-0040)
Li YC, Zheng XL, Liu BT & Yang GS 2010 Regulation of ATGL expression
mediated by leptin in vitro in porcine adipocyte lipolysis. Molecular and
Cellular Biochemistry 333 121–128. (doi:10.1007/s11010-009-0212-4)
Liang HX, Belardinelli L, Ozeck MJ & Shryock JC 2002 Tonic activity of the
rat adipocyte A1-adenosine receptor. British Journal of Pharmacology 135
1457–1466. (doi:10.1038/sj.bjp.0704586)
Listenberger LL, Ostermeyer-Fay AG, Goldberg EB, Brown WJ & Brown DA
2007 Adipocyte differentiation-related protein reduces the lipid droplet
association of adipose triglyceride lipase and slows triacylglycerol
turnover. Journal of Lipid Research 48 2751–2761. (doi:10.1194/jlr.
M700359-JLR200)
Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Yun SJ,
Mirzadegan T et al. 2009a Lactate inhibits lipolysis in fat cells through
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R219
activation of an orphan G-protein-coupled receptor, GPR81. Journal of
Biological Chemistry 284 2811–2822. (doi:10.1074/jbc.M806409200)
Liu LF, Purushotham A, Wendel AA, Koba K, Deiuliis J, Lee K & Belury MA
2009b Regulation of adipose triglyceride lipase by rosiglitazone.
Diabetes, Obesity & Metabolism 11 131–142. (doi:10.1111/j.1463-1326.
2008.00916.x)
Londos C, Honnor RC & Dhillon GS 1985 cAMP-dependent protein kinase
and lipolysis in rat adipocytes. III. Multiple modes of insulin regulation
of lipolysis and regulation of insulin responses by adenylate cyclase
regulators. Journal of Biological Chemistry 260 15139–15145.
Lonnroth P, Jansson PA, Fredholm BB & Smith U 1989 Microdialysis of
intercellular adenosine concentration in subcutaneous tissue in
humans. American Journal of Physiology 256 E250–E255.
Lord CC, Betters JL, Ivanova PT, Milne SB, Myers DS, Madenspacher J,
Thomas G, Chung S, Liu M, Davis MA et al. 2012 CGI-58/ABHD5-
derived signaling lipids regulate systemic inflammation and insulin
action. Diabetes 61 355–363. (doi:10.2337/db11-0994)
Lundgren M, Svensson M, Lindmark S, Renstrom F, Ruge T & Eriksson JW
2007 Fat cell enlargement is an independent marker of insulin
resistance and ‘hyperleptinaemia’. Diabetologia 50 625–633.
(doi:10.1007/s00125-006-0572-1)
Mairal A, Melaine N, Laurell H, Grober J, Holst LS, Guillaudeux T, Holm C,
Jegou B & Langin D 2002 Characterization of a novel testicular form of
human hormone-sensitive lipase. Biochemical and Biophysical Research
Communications 291 286–290. (doi:10.1006/bbrc.2002.6427)
Mairal A, Langin D, Arner P & Hoffstedt J 2006 Human adipose triglyceride
lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro
triglyceride hydrolase activity. Diabetologia 49 1629–1636.
(doi:10.1007/s00125-006-0272-x)
Manolopoulos KN, Karpe F & Frayn KN 2010 Gluteofemoral body fat as a
determinant of metabolic health. International Journal of Obesity 34
949–959. (doi:10.1038/ijo.2009.286)
Manolopoulos KN, Karpe F & Frayn KN 2012 Marked resistance of femoral
adipose tissue blood flow and lipolysis to adrenaline in vivo. Diabetologia
55 3029–3037. (doi:10.1007/s00125-012-2676-0)
Marcus C, Bolme P, Micha-Johansson G, Margery V & Bronnegard M 1994
Growth hormone increases the lipolytic sensitivity for catecholamines
in adipocytes from healthy adults. Life Sciences 54 1335–1341.
(doi:10.1016/0024-3205(94)00512-5)
Marcus C, Ehren H, Bolme P & Arner P 1988 Regulation of lipolysis during
the neonatal period. Importance of thyrotropin. Journal of Clinical
Investigation 82 1793–1797. (doi:10.1172/JCI113793)
Martinez-Botas J, Anderson JB, Tessier D, Lapillonne A, Chang BH,
Quast MJ, Gorenstein D, Chen KH & Chan L 2000 Absence of perilipin
results in leanness and reverses obesity in Lepr(db/db) mice. Nature
Genetics 26 474–479. (doi:10.1038/82630)
Mason RR, Meex RC, Lee-Young R, Canny BJ & Watt MJ 2012
Phosphorylation of adipose triglyceride lipase Ser(404) is not related to
5 0-AMPK activation during moderate-intensity exercise in humans.
American Journal of Physiology. Endocrinology and Metabolism 303
E534–E541. (doi:10.1152/ajpendo.00082.2012)
Mauriege P, De PG, Berlan M & Lafontan M 1988 Human fat cell
b-adrenergic receptors: b-agonist-dependent lipolytic responses and
characterization of b-adrenergic binding sites on human fat cell
membranes with highly selective b1-antagonists. Journal of Lipid
Research 29 587–601.
Miyoshi H, Souza SC, Zhang HH, Strissel KJ, Christoffolete MA, Kovsan J,
Rudich A, Kraemer FB, Bianco AC, Obin MS et al. 2006 Perilipin
promotes hormone-sensitive lipase-mediated adipocyte lipolysis via
phosphorylation-dependent and -independent mechanisms. Journal of
Biological Chemistry 281 15837–15844. (doi:10.1074/jbc.M601097200)
Miyoshi H, Perfield JW, Souza SC, Shen WJ, Zhang HH, Stancheva ZS,
Kraemer FB, Obin MS & Greenberg AS 2007 Control of adipose
triglyceride lipase action by serine 517 of perilipin A globally regulates
protein kinase A-stimulated lipolysis in adipocytes. Journal of Biological
Chemistry 282 996–1002. (doi:10.1074/jbc.M605770200)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Montero-Moran G, Caviglia JM, McMahon D, Rothenberg A,
Subramanian V, Xu Z, Lara-Gonzalez S, Storch J, Carman GM &
Brasaemle DL 2010 CGI-58/ABHD5 is a coenzyme A-dependent
lysophosphatidic acid acyltransferase. Journal of Lipid Research 51
709–719. (doi:10.1194/jlr.M001917)
Moreno-Navarrete JM, Ortega F, Serrano M, Rodriguez-Hermosa JI,
Ricart W, Mingrone G & Fernandez-Real JM 2013 CIDEC/FSP27 and
PLIN1 gene expression run in parallel to mitochondrial genes in human
adipose tissue, both increasing after weight loss. International Journal of
Obesity [in press]. (doi:10.1038/ijo.2013.171)
Moro C, Galitzky J, Sengenes C, Crampes F, Lafontan M & Berlan M 2004a
Functional and pharmacological characterization of the natriuretic
peptide-dependent lipolytic pathway in human fat cells. Journal of
Pharmacological and Experimental Therapeutics 308 984–992.
(doi:10.1124/jpet.103.060913)
Moro C, Crampes F, Sengenes C, de GI, Galitzky J, Thalamas C, Lafontan M
& Berlan M 2004b Atrial natriuretic peptide contributes to physiologi-
cal control of lipid mobilization in humans. FASEB Journal 18 908–910.
(doi:10.1096/fj.03-1086fje)
Moro C, Polak J, Hejnova J, Klimcakova E, Crampes F, Stich V, Lafontan M
& Berlan M 2006 Atrial natriuretic peptide stimulates lipid mobilization
during repeated bouts of endurance exercise. American Journal of
Physiology. Endocrinology and Metabolism 290 E864–E869. (doi:10.1152/
ajpendo.00348.2005)
Moro C, Klimcakova E, Lafontan M, Berlan M & Galitzky J 2007a
Phosphodiesterase-5A and neutral endopeptidase activities in human
adipocytes do not control atrial natriuretic peptide-mediated lipolysis.
British Journal of Pharmacology 152 1102–1110. (doi:10.1038/sj.bjp.
0707485)
Moro C, Pillard F, de GI, Crampes F, Thalamas C, Harant I, Marques MA,
Lafontan M & Berlan M 2007b Sex differences in lipolysis-regulating
mechanisms in overweight subjects: effect of exercise intensity. Obesity
15 2245–2255. (doi:10.1038/oby.2007.267)
Nam SY, Kim KR, Cha BS, Song YD, Lim SK, Lee HC & Huh KB 2001 Low-dose
growth hormone treatment combined with diet restriction decreases
insulin resistance by reducing visceral fat and increasing muscle mass in
obese type 2 diabetic patients. International Journal of Obesity and Related
Metabolic Disorders 25 1101–1107. (doi:10.1038/sj.ijo.0801636)
Natali A, Gastaldelli A, Camastra S, Baldi S, Quagliarini F, Minicocci I, Bruno C,
Pennisi E & Arca M 2013 Metabolic consequences of adipose triglyceride
lipase deficiency in humans: an in vivo study in patients with neutral lipid
storage disease with myopathy. Journal of Clinical Endocrinology and
Metabolism 98 E1540–E1548. (doi:10.1210/jc.2013-1444)
Nellemann B, Gormsen LC, Sorensen LP, Christiansen JS & Nielsen S 2012
Impaired insulin-mediated antilipolysis and lactate release in adipose
tissue of upper-body obese women. Obesity 20 57–64. (doi:10.1038/oby.
2011.290)
Nellemann B, Vendelbo MH, Nielsen TS, Bak AM, Hogild M, Pedersen SB,
Bienso RS, Pilegaard H, Moller N, Jessen N et al. 2004 Growth hormone-
induced insulin resistance in human subjects involves reduced
pyruvate dehydrogenase activity. Acta Physiologica 210 392–402.
(doi:10.1111/apha.12183)
Ng TB 1990 Studies on hormonal regulation of lipolysis and lipogenesis in
fat cells of various mammalian species. Comparative Biochemistry and
Physiology. B, Comparative Biochemistry 97 441–446. (doi:10.1016/0305-
0491(90)90141-F)
Nielsen S, Moller N, Christiansen JS & Jorgensen JO 2001 Pharmacological
antilipolysis restores insulin sensitivity during growth hormone
exposure. Diabetes 50 2301–2308. (doi:10.2337/diabetes.50.10.2301)
Nielsen S, Jorgensen JO, Hartmund T, Norrelund H, Nair KS, Christiansen JS &
MollerN2002Effectsof loweringcirculatingfree fattyacid levelsonprotein
metabolisminadultgrowthhormonedeficientpatients.GrowthHormone&
IGF Research 12 425–433. (doi:10.1016/S1096-6374(02)00119-3)
Nielsen S, Guo Z, Johnson CM, Hensrud DD & Jensen MD 2004 Splanchnic
lipolysis in human obesity. Journal of Clinical Investigation 113
1582–1588. (doi:10.1172/JCI21047)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R220
Nielsen TS, Vend elbo MH, Jessen N, Pedersen SB, Jorgensen JO, Lund S &
Moller N 2011 Fasting, but not exercise, increases adipose triglyceride
lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein
and mRNA content in human adipose tissue. Journal ofClinical Endocrinology
and Metabolism 96 E1293–E1297. (doi:10.1210/jc.2011-0149)
Nielsen TS, Kampmann U, Nielsen RR, Jessen N, Orskov L, Pedersen SB,
Jorgensen JO, Lund S & Moller N 2012 Reduced mRNA and protein
expression of perilipin A and G0/G1 switch gene 2 (G0S2) in human
adipose tissue in poorly controlled type 2 diabetes. Journal of Clinical
Endocrinology andMetabolism97E1348–E1352. (doi:10.1210/jc.2012-1159)
Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W,
Inoue K, Kitazawa R, Kitazawa S, Matsuki Y et al. 2008 FSP27
contributes to efficient energy storage in murine white adipocytes by
promoting the formation of unilocular lipid droplets. Journal of Clinical
Investigation 118 2808–2821. (doi:10.1172/JCI34090)
Nordstrom EA, Ryden M, Backlund EC, Dahlman I, Kaaman M, Blomqvist L,
Cannon B, Nedergaard J & Arner P 2005 A human-specific role of cell
death-inducing DFFA (DNA fragmentation factor-a)-like effector A
(CIDEA) in adipocyte lipolysis and obesity. Diabetes 54 1726–1734.
(doi:10.2337/diabetes.54.6.1726)
Norrelund H, Moller N, Nair KS, Christiansen JS & Jorgensen JO 2001
Continuation of growth hormone (GH) substitution during fasting in
GH-deficient patients decreases urea excretion and conserves protein
synthesis. Journal of Clinical Endocrinology andMetabolism 86 3120–3129.
(doi:10.1210/jcem.86.7.7618)
Norrelund H, Nair KS, Nielsen S, Frystyk J, Ivarsen P, Jorgensen JO,
Christiansen JS & Moller N 2003 The decisive role of free fatty acids for
protein conservation during fasting in humans with and without
growth hormone. Journal of Clinical Endocrinology and Metabolism 88
4371–4378. (doi:10.1210/jc.2003-030267)
Oh SA, Suh Y, Pang MG & Lee K 2011 Cloning of avian G(0)/G(1) switch
gene 2 genes and developmental and nutritional regulation of
G(0)/G(1) switch gene 2 in chicken adipose tissue. Journal of Animal
Science 89 367–375. (doi:10.2527/jas.2010-3339)
Ong KT, Mashek MT, Bu SY, Greenberg AS & Mashek DG 2011 Adipose
triglyceride lipase is a major hepatic lipase that regulates triacylglycerol
turnover and fatty acid signaling and partitioning. Hepatology 53
116–126. (doi:10.1002/hep.24006)
Osuga J, Ishibashi S, Oka T, Yagyu H, Tozawa R, Fujimoto A, Shionoiri F,
Yahagi N, Kraemer FB, Tsutsumi O et al. 2000 Targeted disruption of
hormone-sensitive lipase results in male sterility and adipocyte hyper-
trophy,butnot in obesity.PNAS97787–792. (doi:10.1073/pnas.97.2.787)
Pagnon J, Matzaris M, Stark R, Meex RC, Macaulay SL, Brown W, O’Brien PE,
Tiganis T & Watt MJ 2012 Identification and functional characterization
of protein kinase A phosphorylation sites in the major lipolytic protein,
adipose triglyceride lipase. Endocrinology 153 4278–4289. (doi:10.1210/
en.2012-1127)
Park SY, Kim HJ, Wang S, Higashimori T, Dong J, Kim YJ, Cline G, Li H,
Prentki M, Shulman GI et al. 2005 Hormone-sensitive lipase knockout
mice have increased hepatic insulin sensitivity and are protected from
short-term diet-induced insulin resistance in skeletal muscle and heart.
American Journal of Physiology. Endocrinology and Metabolism 289
E30–E39. (doi:10.1152/ajpendo.00251.2004)
Pasarica M, Zachwieja JJ, Dejonge L, Redman S & Smith SR 2007 Effect of
growth hormone on body composition and visceral adiposity in
middle-aged men with visceral obesity. Journal of Clinical Endocrinology
and Metabolism 92 4265–4270. (doi:10.1210/jc.2007-0786)
Peyot ML, Guay C, Latour MG, Lamontagne J, Lussier R, Pineda M,
Ruderman NB, Haemmerle G, Zechner R, Joly E et al. 2009 Adipose
triglyceride lipase is implicated in fuel- and non-fuel-stimulated insulin
secretion. Journal of Biological Chemistry 284 16848–16859.
(doi:10.1074/jbc.M109.006650)
Piche ME, Lapointe A, Weisnagel SJ, Corneau L, Nadeau A, Bergeron J &
Lemieux S 2008 Regional body fat distribution and metabolic profile in
postmenopausal women. Metabolism 57 1101–1107. (doi:10.1016/
j.metabol.2008.03.015)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Plockinger U & Reuter T 2008 Pegvisomant increases intra-abdominal fat
in patients with acromegaly: a pilot study. European Journal of
Endocrinology 158 467–471. (doi:10.1530/EJE-07-0637)
Pulinilkunnil T, Kienesberger PC, Nagendran J, Waller TJ, Young ME,
Kershaw EE, Korbutt G, Haemmerle G, Zechner R & Dyck JR 2013
Myocardial adipose triglyceride lipase overexpression protects diabetic
mice from the development of lipotoxic cardiomyopathy. Diabetes 62
1464–1477. (doi:10.2337/db12-0927)
Puri V, Ranjit S, Konda S, Nicoloro SM, Straubhaar J, Chawla A,
Chouinard M, Lin C, Burkart A, Corvera S et al. 2008 Cidea is associated
with lipid droplets and insulin sensitivity in humans. PNAS 105
7833–7838. (doi:10.1073/pnas.0802063105)
Radner FP, Streith IE, Schoiswohl G, Schweiger M, Kumari M, Eichmann TO,
Rechberger G, Koefeler HC, Eder S, Schauer S et al. 2009 Growth
retardation, impaired triacylglycerol catabolism, hepatic steatosis, and
lethal skin barrier defect in mice lacking comparative gene identifi-
cation-58 (CGI-58). Journal of Biological Chemistry 285 7300–7311.
(doi:10.1074/jbc.M109.081877)
RayH, PinteurC,FreringV, Beylot M & LargeV 2009 Depot-specificdifferences
in perilipin and hormone-sensitive lipase expression in lean and obese.
Lipids in Health and Disease 8 58. (doi:10.1186/1476-511X-8-58)
Reid BN, Ables GP, Otlivanchik OA, Schoiswohl G, Zechner R, Blaner WS,
Goldberg IJ, Schwabe RF, Chua SC Jr & Huang LS 2008 Hepatic
overexpression of hormone-sensitive lipase and adipose triglyceride
lipase promotes fatty acid oxidation, stimulates direct release of free
fatty acids, and ameliorates steatosis. Journal of Biological Chemistry 283
13087–13099. (doi:10.1074/jbc.M800533200)
Richter WO & Schwandt P 1983 In vitro lipolysis of proopiocortin peptides.
Life Sciences 33 (Suppl 1) 747–750. (doi:10.1016/0024-3205(83)90610-0)
Rizack MA 1964 Activation of an epinephrine-sensitive lipolytic activity
from adipose tissue by adenosine 3 0,5 0-phosphate. Journal of Biological
Chemistry 239 392–395.
Robidoux J, Martin TL & Collins S 2004 b-Adrenergic receptors and
regulation of energy expenditure: a family affair. Annual Review of
Pharmacology and Toxicology 44 297–323. (doi:10.1146/annurev.
pharmtox.44.101802.121659)
Roden M, Stingl H, Chandramouli V, Schumann WC, Hofer A, Landau BR,
Nowotny P, Waldhausl W & Shulman GI 2000 Effects of free fatty acid
elevation on postabsorptive endogenous glucose production and
gluconeogenesis in humans. Diabetes 49 701–707. (doi:10.2337/
diabetes.49.5.701)
Rodrigues AR, Almeida H & Gouveia AM 2013 a-MSH signalling
via melanocortin 5 receptor promotes lipolysis and impairs
re-esterification in adipocytes. Biochimica et Biophysica Acta 1831
1267–1275. (doi:10.1016/j.bbalip.2013.04.008)
RoustLR&JensenMD1993Postprandial free fattyacidkineticsareabnormal in
upper body obesity.Diabetes421567–1573. (doi:10.2337/diab.42.11.1567)
Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S,
Hyden CS, Bottomley W, Vigouroux C, Magre J et al. 2009 Partial
lipodystrophy and insulin resistant diabetes in a patient with a
homozygous nonsense mutation in CIDEC. EMBO Molecular Medicine 1
280–287. (doi:10.1002/emmm.200900037)
Ryden M, Dicker A, van HV, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F
& Arner P 2002 Mapping of early signaling events in tumor necrosis
factor-a-mediated lipolysis in human fat cells. Journal of Biological
Chemistry 277 1085–1091. (doi:10.1074/jbc.M109498200)
Ryden M, Jocken J, van HV, Dicker A, Hoffstedt J, Wiren M, Blomqvist L,
Mairal A, Langin D, Blaak E et al. 2007 Comparative studies of the role
of hormone-sensitive lipase and adipose triglyceride lipase in human
fat cell lipolysis. American Journal of Physiology. Endocrinology and
Metabolism 292 E1847–E1855. (doi:10.1152/ajpendo.00040.2007)
Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ,
Strassmann PG & Wajchenberg BL 1999 Overnight lowering of free
fatty acids with Acipimox improves insulin resistance and glucose
tolerance in obese diabetic and nondiabetic subjects. Diabetes 48
1836–1841. (doi:10.2337/diabetes.48.9.1836)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R221
Scherer T, O’Hare J, Diggs-Andrews K, Schweiger M, Cheng B, Lindtner C,
Zielinski E, Vempati P, Su K, Dighe S et al. 2011 Brain insulin controls
adipose tissue lipolysis and lipogenesis. Cell Metabolism 13 183–194.
(doi:10.1016/j.cmet.2011.01.008)
Schoiswohl G, Schweiger M, Schreiber R, Gorkiewicz G, Preiss-Landl K,
Taschler U, Zierler KA, Radner FP, Eichmann TO, Kienesberger PC et al.
2010 Adipose triglyceride lipase plays a key role in the supply of the
working muscle with fattyacids. Journal of Lipid Research 51 490–499.
(doi:10.1194/jlr.M001073)
Schrammel A, Mussbacher M, Winkler S, Haemmerle G, Stessel H,
Wolkart G, Zechner R & Mayer B 2013 Cardiac oxidative stress in a
mouse model of neutral lipid storage disease. Biochimica et Biophysica
Acta 1831 1600–1608. (doi:10.1016/j.bbalip.2013.07.004)
Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P,
Tornqvist H, Zechner R & Zimmermann R 2006 Adipose triglyceride
lipase and hormone-sensitive lipase are the major enzymes in adipose
tissue triacylglycerol catabolism. Journal of Biological Chemistry 281
40236–40241. (doi:10.1074/jbc.M608048200)
Schweiger M, Schoiswohl G, Lass A, Radner FP, Haemmerle G, Malli R,
Graier W, Cornaciu I, Oberer M, Salvayre R et al. 2008 The C-terminal
region of human adipose triglyceride lipase affects enzyme activity and
lipid droplet binding. Journal of Biological Chemistry 283 17211–17220.
(doi:10.1074/jbc.M710566200)
Schweiger M, Lass A, Zimmermann R, Eichmann TO & Zechner R 2009
Neutral lipid storage disease: genetic disorders caused by mutations in
adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. American
Journal of Physiology. Endocrinology and Metabolism 297 E289–E296.
(doi:10.1152/ajpendo.00099.2009)
Schweiger M, Paar M, Eder C, Brandis J, Moser E, Gorkiewicz G, Grond S,
Radner FP, Cerk I, Cornaciu I et al. 2012 G0/G1 switch gene-2 regulates
human adipocyte lipolysis by affecting activity and localization of
adipose triglyceride lipase. Journal of Lipid Research 53 2307–2317.
(doi:10.1194/jlr.M027409)
Sengenes C, Berlan M, de GI, Lafontan M & Galitzky J 2000 Natriuretic
peptides: a new lipolytic pathway in human adipocytes. FASEB Journal
14 1345–1351. (doi:10.1096/fj.14.10.1345)
Sengenes C, Stich V, Berlan M, Hejnova J, Lafontan M, Pariskova Z &
Galitzky J 2002 Increased lipolysis in adipose tissue and lipid
mobilization to natriuretic peptides during low-calorie diet in obese
women. International Journal of Obesity and Related Metabolic Disorders
26 24–32. (doi:10.1038/sj.ijo.0801845)
Sengenes C, Bouloumie A, Hauner H, Berlan M, Busse R, Lafontan M &
Galitzky J 2003 Involvement of a cGMP-dependent pathway in the
natriuretic peptide-mediated hormone-sensitive lipase phosphoryl-
ation in human adipocytes. Journal of Biological Chemistry 278
48617–48626. (doi:10.1074/jbc.M303713200)
Serradeil-Le GC, Lafontan M, Raufaste D, Marchand J, Pouzet B, Casellas P,
Pascal M, Maffrand JP & Le FG 2000 Characterization of NPY receptors
controlling lipolysis and leptin secretion in human adipocytes. FEBS
Letters 475 150–156. (doi:10.1016/S0014-5793(00)01649-5)
Sethi JK, Xu H, Uysal KT, Wiesbrock SM, Scheja L & Hotamisligil GS 2000
Characterisation of receptor-specific TNFa functions in adipocyte cell
lines lacking type 1 and 2 TNF receptors. FEBS Letters 469 77–82.
(doi:10.1016/S0014-5793(00)01250-3)
Shan T, Ren Y & Wang Y 2013 Sirtuin 1 affects the transcriptional
expression of adipose triglyceride lipase in porcine adipocytes.
Journal of Animal Science 91 1247–1254. (doi:10.2527/jas.2011-5030)
Shen WJ, Patel S, Miyoshi H, Greenberg AS & Kraemer FB 2009 Functional
interactionofhormone-sensitive lipaseandperilipin in lipolysis. Journal of
Lipid Research 50 2306–2313. (doi:10.1194/jlr.M900176-JLR200)
Smith AJ, Thompson BR, Sanders MA & Bernlohr DA 2007 Interaction of
the adipocyte fatty acid-binding protein with the hormone-sensitive
lipase: regulation by fatty acids and phosphorylation. Journal of
Biological Chemistry 282 32424–32432. (doi:10.1074/jbc.M703730200)
Souza SC, de Vargas LM, Yamamoto MT, Lien P, Franciosa MD, Moss LG &
Greenberg AS 1998 Overexpression of perilipin A and B blocks the
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
ability of tumor necrosis factor a to increase lipolysis in 3T3-L1
adipocytes. Journal of Biological Chemistry 273 24665–24669.
(doi:10.1074/jbc.273.38.24665)
Stallknecht B, Lorentsen J, Enevoldsen LH, Bulow J, Biering-Sorensen F,
Galbo H & Kjaer M 2001 Role of the sympathoadrenergic system in
adipose tissue metabolism during exercise in humans. Journal of
Physiology 536 283–294. (doi:10.1111/j.1469-7793.2001.00283.x)
Steinberg GR, Kemp BE & Watt MJ 2007 Adipocyte triglyceride lipase
expression in human obesity. American Journal of Physiology. Endocrinology
and Metabolism 293 E958–E964. (doi:10.1152/ajpendo.00235.2007)
Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF,
Holmes AB, McCormick F & Hawkins PT 1997 Dual role of
phosphatidylinositol-3,4,5-trisphosphate in the activation of protein
kinase B. Science 277 567–570. (doi:10.1126/science.277.5325.567)
Stralfors P, Bjorgell P & Belfrage P 1984 Hormonal regulation of hormone-
sensitive lipase in intact adipocytes: identification of phosphorylated
sites and effects on the phosphorylation by lipolytic hormones and
insulin. PNAS 81 3317–3321. (doi:10.1073/pnas.81.11.3317)
Sukonina V, Lookene A, Olivecrona T & Olivecrona G 2006 Angiopoietin-
like protein 4 converts lipoprotein lipase to inactive monomers and
modulates lipase activity in adipose tissue. PNAS 103 17450–17455.
(doi:10.1073/pnas.0604026103)
Sun Z, Gong J, Wu H, Xu W, Wu L, Xu D, Gao J, Wu JW, Yang H, Yang M
et al. 2013 Perilipin1 promotes unilocular lipid droplet formation
through the activation of Fsp27 in adipocytes. Nature Communications 4
1594. (doi:10.1038/ncomms2581)
Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R,
Wu K, Wu TJ et al. 2005 (D)-b-hydroxybutyrate inhibits adipocyte
lipolysis via the nicotinic acid receptor PUMA-G. Journal of Biological
Chemistry 280 26649–26652. (doi:10.1074/jbc.C500213200)
Tansey JT, Sztalryd C, Gruia-Gray J, Roush DL, Zee JV, Gavrilova O,
Reitman ML, Deng CX, Li C, Kimmel AR et al. 2001 Perilipin ablation
results in a lean mouse with aberrant adipocyte lipolysis, enhanced
leptin production, and resistance to diet-induced obesity. PNAS 98
6494–6499. (doi:10.1073/pnas.101042998)
Taschler U, Radner FP, Heier C, Schreiber R, Schweiger M, Schoiswohl G,
Preiss-Landl K, Jaeger D, Reiter B, Koefeler HC et al. 2011 Monoglyceride
lipase deficiency in mice impairs lipolysis and attenuates diet-induced
insulin resistance. Journal of Biological Chemistry 286 17467–17477.
(doi:10.1074/jbc.M110.215434)
Tavernier G, Barbe P, Galitzky J, Berlan M, Caput D, Lafontan M & Langin D
1996 Expression of b3-adrenoceptors with low lipolytic action in human
subcutaneous white adipocytes. Journal of Lipid Research 37 87–97.
Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL &
Jensen MD 2010 Regional differences in cellular mechanisms of adipose
tissue gain with overfeeding. PNAS 107 18226–18231. (doi:10.1073/
pnas.1005259107)
Tinahones FJ, Garrido-Sanchez L, Miranda M, Garcia-Almeida JM,
Macias-Gonzalez M, Ceperuelo V, Gluckmann E, Rivas-Marin J, Vendrell
J & Garcia-Fuentes E 2010 Obesity and insulin resistance-related changes
in the expression of lipogenic and lipolytic genes in morbidly obese
subjects. Obesity Surgery 20 1559–1567. (doi:10.1007/s11695-010-0194-z)
Toh SY, Gong J, Du G, Li JZ, Yang S, Ye J, Yao H, Zhang Y, Xue B, Li Q et al.
2008 Up-regulation of mitochondrial activity and acquirement of
brown adipose tissue-like property in the white adipose tissue of fsp27
deficient mice. PLoS ONE 3 e2890. (doi:10.1371/journal.pone.0002890)
Tornqvist H & Belfrage P 1976 Purification and some properties of a
monoacylglycerol-hydrolyzing enzyme of rat adipose tissue. Journal of
Biological Chemistry 251 813–819.
Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K & Offermanns S
2003 PUMA-G and HM74 are receptors for nicotinic acid and mediate its
anti-lipolytic effect. Nature Medicine 9 352–355. (doi:10.1038/nm824)
Turpin SM, Hoy AJ, Brown RD, Rudaz CG, Honeyman J, Matzaris M &
Watt MJ 2011 Adipose triacylglycerol lipase is a major regulator of
hepatic lipid metabolism but not insulin sensitivity in mice.
Diabetologia 54 146–156. (doi:10.1007/s00125-010-1895-5)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access
JournalofMolecu
larEndocrinology
Review T S NIELSEN and others Dissecting adipose tissuelipolysis
52 :3 R222
Vaughan M, Berger JE & Steinberg D 1964 Hormone-sensitive lipase and
monoglyceride lipase activities in adipose tissue. Journal of Biological
Chemistry 239 401–409.
Vendelbo MH, Jorgensen JO, Pedersen SB, Gormsen LC, Lund S, Schmitz O,
Jessen N & Moller N 2010 Exercise and fasting activate growth
hormone-dependent myocellular signal transducer and activator of
transcription-5b phosphorylation and insulin-like growth factor-I
messenger ribonucleic acid expression in humans. Journal of Clinical
Endocrinology and Metabolism 95 E64–E68. (doi:10.1210/jc.2010-0689)
Villena JA, Roy S, Sarkadi-Nagy E, Kim KH & Sul HS 2004 Desnutrin, an
adipocyte gene encoding a novel patatin domain-containing protein, is
induced by fasting and glucocorticoids: ectopic expression of desnutrin
increases triglyceride hydrolysis. Journal of Biological Chemistry 279
47066–47075. (doi:10.1074/jbc.M403855200)
Virtue S & Vidal-Puig A 2010 Adipose tissue expandability, lipotoxicity and
the metabolic syndrome – an allostatic perspective. Biochimica et
Biophysica Acta 1801 338–349. (doi:10.1016/j.bbalip.2009.12.006)
Wang H, Hu L, Dalen K, Dorward H, Marcinkiewicz A, Russell D, Gong D,
Londos C, Yamaguchi T, Holm C et al. 2009 Activation of hormone-
sensitive lipase requires two steps, protein phosphorylation and
binding to the PAT-1 domain of lipid droplet coat proteins. Journal of
Biological Chemistry 284 32116–32125. (doi:10.1074/jbc.M109.006726)
Watt MJ, Holmes AG, Pinnamaneni SK, Garnham AP, Steinberg GR,
Kemp BE & Febbraio MA 2006 Regulation of HSL serine phosphoryl-
ation in skeletal muscle and adipose tissue. American Journal of
Physiology. Endocrinology and Metabolism 290 E500–E508. (doi:10.1152/
ajpendo.00361.2005)
Wei S, Lai K, Patel S, Piantedosi R, Shen H, Colantuoni V, Kraemer FB &
Blaner WS 1997 Retinyl ester hydrolysis and retinol efflux from BFC-1b
adipocytes. Journal of Biological Chemistry 272 14159–14165.
(doi:10.1074/jbc.272.22.14159)
Weyer C, Foley JE, Bogardus C, Tataranni PA & Pratley RE 2000 Enlarged
subcutaneous abdominal adipocyte size, but not obesity itself, predicts
type II diabetes independent of insulin resistance. Diabetologia 43
1498–1506. (doi:10.1007/s001250051560)
White MF 1998 The IRS-signalling system: a network of docking proteins
that mediate insulin action. Molecular and Cellular Biochemistry 182
3–11. (doi:10.1023/A:1006806722619)
White UA & Tchoukalova YD 2014 Sex dimorphism and depot differences
in adipose tissue function. Biochimica et Biophysica Acta 1842 377–392.
(doi:10.1016/j.bbadis.2013.05.006)
Whitman M, Downes CP, Keeler M, Keller T & Cantley L 1988 Type I
phosphatidylinositol kinase makes a novel inositol phospholipid,
phosphatidylinositol-3-phosphate. Nature 332 644–646. (doi:10.1038/
332644a0)
Wijnen JA, van Baak MA, de HC, Boudier HA, Tan FS & Van Bortel LM 1993
b-Blockade and lipolysis during endurance exercise. European Journal of
Clinical Pharmacology 45 101–105. (doi:10.1007/BF00315488)
Wilson PA, Gardner SD, Lambie NM, Commans SA & Crowther DJ 2006
Characterization of the human patatin-like phospholipase family.
Journal of Lipid Research 47 1940–1949. (doi:10.1194/jlr.M600185-JLR200)
Wu JW, Wang SP, Alvarez F, Casavant S, Gauthier N, Abed L, Soni KG,
Yang G & Mitchell GA 2011 Deficiency of liver adipose triglyceride
lipase in mice causes progressive hepatic steatosis. Hepatology 54
122–132. (doi:10.1002/hep.24338)
Wu JW, Wang SP, Casavant S, Moreau A, Yang GS & Mitchell GA 2012
Fasting energy homeostasis in mice with adipose deficiency of
desnutrin/adipose triglyceride lipase. Endocrinology 153 2198–2207.
(doi:10.1210/en.2011-1518)
Xu C, He J, Jiang H, Zu L, Zhai W, Pu S & Xu G 2009 Direct effect of
glucocorticoids on lipolysis in adipocytes. Molecular Endocrinology 23
1161–1170. (doi:10.1210/me.2008-0464)
http://jme.endocrinology-journals.org � 2014 Society for EndocrinologyDOI: 10.1530/JME-13-0277 Printed in Great Britain
Yang S, Mulder H, Holm C & Eden S 2004 Effects of growth hormone on the
function of b-adrenoceptor subtypes in rat adipocytes. Obesity Research
12 330–339. (doi:10.1038/oby.2004.41)
Yang X, Lu X, Lombes M, Rha GB, Chi YI, Guerin TM, Smart EJ & Liu J 2010
The G(0)/G(1) switch gene 2 regulates adipose lipolysis through
association with adipose triglyceride lipase. Cell Metabolism 11
194–205. (doi:10.1016/j.cmet.2010.02.003)
Yang X, Zhang X, Heckmann BL, Lu X & Liu J 2011 Relative contribution of
adipose triglyceride lipase and hormone-sensitive lipase to tumor
necrosis factor-a (TNF-a)-induced lipolysis in adipocytes. Journal of
Biological Chemistry 286 40477–40485. (doi:10.1074/jbc.M111.257923)
Yang X, Heckmann BL, Zhang X, Smas CM & Liu J 2013 Distinct
mechanisms regulate ATGL-mediated adipocyte lipolysis by lipid
droplet coat proteins. Molecular Endocrinology 27 116–126.
(doi:10.1210/me.2012-1178)
Yao-Borengasser A, Varma V, Coker RH, Ranganathan G, Phanavanh B,
Rasouli N & Kern PA 2011 Adipose triglyceride lipase expression in
human adipose tissue and muscle. Role in insulin resistance and
response to training and pioglitazone. Metabolism 60 1012–1020.
(doi:10.1016/j.metabol.2010.10.005)
Yonezawa T, Kurata R, Kimura M & Inoko H 2011 Which CIDE are you on?
Apoptosis and energy metabolism Molecular BioSystems 7 91–100.
(doi:10.1039/c0mb00099j)
Zandbergen F, Mandard S, Escher P, Tan NS, Patsouris D, Jatkoe T,
Rojas-Caro S, Madore S, Wahli W, Tafuri S et al. 2005 The G0/G1 switch
gene 2 is a novel PPAR target gene. Biochemical Journal 392 313–324.
(doi:10.1042/BJ20050636)
Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G,
Lass A & Madeo F 2012 FAT SIGNALS – lipases and lipolysis in lipid
metabolism and signaling. Cell Metabolism 15 279–291. (doi:10.1016/
j.cmet.2011.12.018)
Zhang HH, Halbleib M, Ahmad F, Manganiello VC & Greenberg AS 2002
Tumor necrosis factor-a stimulates lipolysis in differentiated human
adipocytes through activation of extracellular signal-related kinase and
elevation of intracellular cAMP. Diabetes 51 2929–2935. (doi:10.2337/
diabetes.51.10.2929)
Zhang X, Xie X, Heckmann BL, Saarinen AM, Czyzyk TA & Liu J 2013
Target disruption of G0/G1 switch gene 2 enhances adipose lipolysis,
alters hepatic energy balance, and alleviates high fat diet-induced liver
steatosis. Diabetes 63 934–946. (doi:10.2337/db13-1422)
Zhou Z, Yon TS, Chen Z, Guo K, Ng CP, Ponniah S, Lin SC, Hong W & Li P
2003 Cidea-deficient mice have lean phenotype and are resistant to
obesity. Nature Genetics 35 49–56. (doi:10.1038/ng1225)
Zhou L, Xu L, Ye J, Li D, Wang W, Li X, Wu L, Wang H, Guan F & Li P 2012
Cidea promotes hepatic steatosis by sensing dietary fatty acids.
Hepatology 56 95–107. (doi:10.1002/hep.25611)
Zierler KA, Jaeger D, Pollak NM, Eder S, Rechberger GN, Radner FP,
Woelkart G, Kolb D, Schmidt A, Kumari M et al. 2013 Functional cardiac
lipolysis in mice critically depends on comparative gene identification-
58. Journal of Biological Chemistry 288 9892–9904. (doi:10.1074/jbc.
M112.420620)
Zimmermann R, Haemmerle G, Wagner EM, Strauss JG, Kratky D &
Zechner R 2003 Decreased fatty acid esterification compensates for the
reduced lipolytic activity in hormone-sensitive lipase-deficient white
adipose tissue. Journal of Lipid Research 44 2089–2099. (doi:10.1194/jlr.
M300190-JLR200)
Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-
Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F,
Hermetter A et al. 2004 Fat mobilization in adipose tissue is promoted
by adipose triglyceride lipase. Science 306 1383–1386. (doi:10.1126/
science.1100747)
Received in final form 14 February 2014Accepted 25 February 2014Accepted Preprint published online 27 February 2014
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 11/17/2021 04:45:55AMvia free access