Dissecting adipose tissue lipolysis: molecular regulation

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

Email

[email protected]

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

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http://dx.doi.org/10.1530/JME-13-0277

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.

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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


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


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

subtypes exist (b1, b2, and b3), but in humans, only the

b1 and b2 isoforms are involved in lipolysis (Mauriege et al.

1988, Barbe et al. 1996, Tavernier et al. 1996). Both a2-AR

and b-AR belong to the G-protein-coupled receptor

(GPCR) family: the G-protein associated with a2-AR

contain the inhibitory Gi subunit, while b-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


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.





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are released from the atrial and ventricular walls of the

heart in response to myotube distension (Clerico et al.

2011), stimulate the guanylyl cyclase (GC)-linked type-A

NP receptor on the adipocytes (Sengenes et al. 2000)

(Fig. 2). Accordingly, upon stimulation of the receptor, GC

converts intracellular GTP into cGMP resulting in the

activation of PKG (also known as the cGMP-dependent

protein kinase), and, just like PKA, this kinase activates the

lipolytic cascade by phosphorylation of PLIN1 and HSL

(Sengenes et al. 2003). However, despite the similarities

between PKA- and PKG-mediated lipolysis, they are

distinct pathways and, unlike the 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


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).





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.

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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


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).





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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


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





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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).


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





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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


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





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

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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).


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





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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


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





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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


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





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)

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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).


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.





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.

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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.


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).





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)

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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


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





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expressed in the liver (Li et al. 2007), and CIDEC is

primarily found in WAT (Nishino et al. 2008), suggesting a

tissue-specific role of these proteins. Consistently, CIDEA-

deficient mice are characterized by elevations in body

temperature and overall metabolic rate due to accelerated

BAT lipolysis and thermogenesis (Zhou et al. 2003).

Consequently, these mice are lean and resistant to diet-

induce obesity and glucose intolerance. A 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.


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.





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)

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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


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





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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).

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Received in final form 14 February 2014Accepted 25 February 2014Accepted Preprint published online 27 February 2014



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Dissecting adipose tissue lipolysis: molecular regulation