Professional Documents
Culture Documents
T S NIELSEN
and others
Review
52 :3
R199R222
1,2
, Niels Jessen
2,3
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b
8000 Aarhus C, Denmark
3
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupga rdsvej 100, 8200 Aarhus N, Denmark
Abstract
Lipolysis is the process by which triglycerides (TGs) are hydrolyzed to free fatty acids (FFAs)
and glycerol. In adipocytes, this is achieved by sequential action of adipose TG lipase
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
Key Words
(ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase. The activity in the
"
lipolysis
lipolytic pathway is tightly regulated by hormonal and nutritional factors. Under conditions
"
adipose tissue
of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a
"
ATGL
to provide the organism with a sufficient supply of substrate for oxidative metabolism.
"
HSL
However, failure to efficiently suppress lipolysis when FFA demands are low can have
"
"
type 2 diabetes
profound increase in FFA release from adipose tissue (AT). This response is crucial in order
Introduction
The major energy reserve in mammals consists of fat
stored in adipose tissue (AT). In periods of excess energy
intake, dietary lipids are taken up by fat cells
(adipocytes) in AT and esterified into triglycerides (TGs),
which are stored in cytosolic lipid droplets (LDs). In
conditions like fasting and exercise, when mobilization
of endogenous energy stores is required, TG is
hydrolyzed through the process of lipolysis and released
to the circulation as free fatty acids
http://jme.endocrinology-journals.org
DOI: 10.1530/JME-13-0277
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R200
HSL
DG
FFA
MGL
MG
FFA
Glycerol
FFA
Figure 1
Schematic illustration of the lipolytic pathway. To fully hydrolyze TGs,
ATGL, HSL, and MGL act in sequence, with the release of one FFA in
each step. This successively converts TG to DG, then to MG, and finally
to glycerol and a total of tree FFA. TG, triglyceride; ATGL, adipose TG
lipase; DG, diacylglycerol; FFA, free fatty acid; HSL, hormone-sensitive
lipase; MG,
monoacylglycerol; MGL, monoglyceride lipase.
Review
T S NIELSEN
and others
G-proteins
contain
the
stimulating
Gs
subunit (Lafontan
& Berlan 1993). The activation of the receptors causes the
G-proteins to interact with adenylyl cyclase (AC), which
is inhibited by interaction with Gi and activated by
interaction with Gs (Lafontan & Berlan 1993). Upon
activation, AC converts ATP to cAMP, resulting in an
increase in intracellular cAMP levels, which activates
protein kinase A (PKA, also known as cAMP-dependent
protein kinase; Langin 2006). Activated PKA phosphorylates the LD-associated protein PLIN1 (Greenberg
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
Garton et al. 1988, Anthonsen et al. 1998). Phosphorylation of PLIN1 promotes the release of comparative gene
identification-58 (CGI-58), which is a potent co-activator
of ATGL (Lass et al. 2006, Granneman et al. 2009). This
facilitates the activation of ATGL, thus initiating the
stimulated lipolytic cascade. Furthermore, PKA-mediated
phosphorylation of HSL causes a rapid activation and
translocation of the lipase from the cytosol to the surface
of the LDs (Egan et al. 1992). Here, it docks on the
phosphorylated PLIN1 and thereby gains access to its DG
substrate, which is being generated by ATGL (Shen et al.
2009, Wang et al. 2009).
Natriuretic peptides
In addition to catecholamines, the cardiac hormones
atrial NP (ANP) and B-type NP (BNP) are important
positive regulators of AT lipolysis in humans. NPs, which
NPR-A
1/2-AR
AC
Gi
GC
Cytosol
Gs
ATP
PKB/Akt
GTP
cAMP
PIP3
PI3K
cGMP
PDE3B
PDE5
PKA
IR
PKG
5-AMP
PIP2
R201
2-AR
PDK
52 :3
5-GMP
IRS1/2
HSL
P
P
P P
HSL
Three FFA
+ glycerol
P
Figure 2
Primary signaling pathways in human lipolysis. Black and red lines
indicate pro-lipolytic and anti-lipolytic signaling events, respectively.
Arrows
indicate stimulation and/or translocation and blunt lines indicate inhibition. Stimulation of lipolysis is dependent on PKA- or PKG-mediated
phosphorylation of HSL and PLIN1. PKG is activated by cGMP, which
is
increased in response to activation of the GC-coupled NPR-A. Similarly,
stimulation of the Gs-protein-coupled b1/2-ARs activates AC, which
generates cAMP and activates PKA. Conversely, activation of Gi-protein-
MGL
MG
DG
TG
P
P
Lipid droplet
coupled a2-ARs inhibits AC and thereby reduces cAMP-dependent
signaling to lipolysis. Stimulation of the insulin signaling pathway through
the IR
increases the activity of PDE3B, which converts cAMP to 50 -AMP, thus
decreasing PKA activity and suppressing lipolysis. PKG activity is reduced by
diacylglycerol; FFA, free fatty acid; GC, guanylyl cyclase; HSL, hormonesensitive lipase; IR, insulin receptor; IRS1/2, IR substrates 1 and 2; MG,
monoacylglycerol; MGL, monoglyceride lipase; NPR-A, type-A natriuretic
peptide receptor; PDE3B, phosphodiesterase 3B; PDK, phosphoinositidedependent kinase; PI3K,
phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB/Akt, protein
kinase B; PLIN1, perilipin 1.
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R202
Review
T S NIELSEN
and others
Growth hormone
A1-R
HM74a GPR81
2-AR
MC
TSH-r
1/2-AR
Gi
TNFR1
AC
Gi
Gs
R203
ANGPTL4
NPY-Y 1
Glucocorticoids
52 :3
AC
ANGPTL4-r
Gs
ATP
ATP
cAMP
PKA
IR
HSL
Three FFA
+ glycerol
MGL
DG
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
TG
Figure 3
Alternative signaling pathways in lipolysis. Black and red lines indicate
pro- lipolytic and anti-lipolytic signaling events, respectively. Arrows
indicate
stimulation and blunt lines indicate inhibition. Dashed lines illustrate the
indirect lipolytic effects of growth hormone and glucocorticoids by
modulation of receptor sensitivities and ANGPTL4-mediated signaling.
Although the identity of the ANGPTL4 receptor is unknown, the
intracellular signaling has been shown to involve activation of AC.
Stimulation of the Gs-protein-coupled melanocortin (MC) receptor and TSH
receptor (TSH-r) also increases intracellular cAMP levels through activation
of AC. Conversely, the Gi-protein-coupled receptors for NPY/PYY (NPY-Y1),
adenosine (A1-R), b-hydroxybutyrate (HM74a), and lactate (GPR81)
MG
Lipid droplet
suppress lipolysis by inhibition of AC. Pro-inflammatory signaling through
the TNF-a receptor (TNFR-1) increases lipolysis by suppressing
antilipolytic signaling mediated by the insulin receptor (IR) and a2adrenergic receptors (a2-ARs). For clarity, the intermediate intracellular
steps in the different
signaling pathways have been omitted. AC, adenylyl cyclase;
ANGPTL4, angiopoietin-like protein 4; ATGL, adipose triglyceride
lipase; b1/2-ARs, b1- and b2-adrenergic receptors; CGI-58, comparative
gene
identification-58; DG, diacylglycerol; FFA, free fatty acid; Gi, inhibitory
G-protein; Gs, stimulating G-protein; HSL, hormone-sensitive lipase; MG,
monoacylglycerol; MGL, monoglyceride lipase; PKA, protein kinase A;
PLIN1, perilipin 1; TG, triglyceride; TSH, thyroid-stimulating hormone.
Review
T S NIELSEN
and others
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
52 :3
R204
Review
T S NIELSEN
and others
Physiological
lipolysis
regulation
of
human
AT
52 :3
R205
Exercise
Physical exercise is the other major situation in
which lipolysis is stimulated in humans and this is
believed to involve the concerted action of several
signaling pathways (Frayn 2010). Thus, circulating
levels of adrenaline, noradrenaline, ANP, GH, and
cortisol increase and insulin decreases in proportion to
exercise intensity, and these gradual changes are
reflected in the magnitude of the resulting lipolytic
response (Moro et al. 2007b). Further- more, the
adrenergic responsiveness of subcutaneous AT is
altered with a shift from predominant a-adrenergic
suppression during rest toward predominant badrenergic stimulation during exercise (Arner et al.
1990), and in the post-exercise recovery phase, b-AR
blockade has been shown to dramatically reduce
plasma levels of FFA and glycerol (Wijnen et al. 1993).
Similar to fasting conditions, GH and cortisol are likely
to be some of the hormonal mediators of these
exercise-induced
alterations
in
adrenergic
responsiveness (Kanaley et al. 2004). The primary
adrenergic stimulus of AT during exercise originates
from circulating catecholamines, with only a minor
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-
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
lipolysis further (Nellemann et al. 2012). Another important difference between upper- and lower-body subcutaneous AT is the primary way by which adipogenesis
occurs as obesity develops. Thus, AT can expand either
via an increase in the number of fat cells (i.e.
hyperplasia) or by enlargement of the existing
adipocytes (i.e. 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 lowerbody obesity, is associated with elevated systemic FFA
levels and metabolic dysfunction (Nielsen et al. 2004,
Piche et al. 2008, Lapointe et al. 2009, Amati et al. 2012).
In fact, it has been suggested that the preference of
gluteofemoral fat for trapping lipids serves as a
metabolic sink providing metabolic and cardiovascular
protection from the deleterious effects of an excessive
daily influx of dietary lipids (Manolopoulos et al. 2010).
The regulation and implications of these gender- and
depot-specific differences in terms of AT metabolism
and signaling has been covered in great detail in a
recent review (White & Tchoukalova 2014).
52 :3
R206
428
430
(corresponding to Ser
and Ser
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
406
has
Review
T S NIELSEN
and others
52 :3
R207
A
TG
404
Lipid droplet
406
Acute stimulation
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
PKA
404
DG
TG
DG
Prolonged stimulation
Degradation
430
TG
DG
TG
DG
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.
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R208
2013). Furthermore, the normal fasting- or exerciseinduced rise in plasma FFA is absent in ATGL-KO animals
indicating a failure to increase lipolysis in WAT (Huijsman
et al. 2009, Schoiswohl et al. 2010). Without sufficient fuel
from lipid substrates, they rely primarily on carbohydrate
metabolism for energy conversion resulting in rapid
depletion of hepatic and SM glycogen stores (Huijsman
et al. 2009, Schoiswohl et al. 2010). Consequently, when
subjected to moderate exercise or short-term fasting, the
mice become hypoglycemic, and if fasting is extended
beyond a modest 812 h, they develop signs of severe
energy starvation like hypothermia, lethargy, reduced
oxygen consumption, and loss of lean mass (Haemmerle
et al. 2006, Schoiswohl et al. 2010, Wu et al. 2012).
Similarly, in spite of massively increased BAT mass,
ATGL- KO mice are unable to increase thermogenesis in
response to cold exposure, indicating that the
mobilization of lipid fuel in BAT is defective
(Haemmerle et al. 2006). In addition to the abnormal
substrate
metabolism,
ATGL deficiency causes
pancreatic steatosis leading to impaired insulin secretion
and hypoinsulinemia (Peyot et al. 2009). Interestingly,
however, despite the massive ectopic lipid accumulation
and b-cell dysfunction, the ATGL-deficient mice have
improved whole-body insulin sensitivity and glucose
tolerance compared with WT animals (Haemmerle et al.
2006, Peyot et al. 2009). Specifically, muscle and WAT
insulin signaling is improved, although in BAT and liver
it is reduced (Kienesberger et al. 2009).
The key role of defective TG catabolism in the
phenotype of ATGL-KO mice has recently been
supported with the generation of transgenic mice with
AT-specific overexpression of G0S2 (Heckmann et al.
2014). Like ATGL-deficient mice, WAT and BAT mass is
increased in these animals due to impaired basal and
stimulated lipolysis, but glucose and insulin tolerance is
improved. Moreover, thermogenesis is attenuated
leading to defec- tive cold adaptation, and the fastinginduced switch from carbohydrate to fatty acid
metabolism is severely impaired (Heckmann et al. 2014).
Conversely, mice with global G0S2 KO are lean and
resistant to high-fat diet-induced obesity and hepatic
steatosis (Zhang et al. 2013). Further- more, hepatic fatty
acid metabolism is enhanced as G0S2 ablation
accelerates ketogenesis and gluconeogenesis while
glycogen breakdown is impaired (Zhang et al. 2013).
Combined with the observations from Atgl-KO mice,
these results support a defining role for ATGL- mediated
lipolysis in whole-body substrate partitioning and
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R209
Hormone-sensitive lipase
HSL was discovered in rat AT in the early 1960s as a
lipolytic enzyme, which was inducible by fasting
and stimulation with ACTH or adrenaline and inhibited
by insulin (Hollenberg et al. 1961, Rizack 1964, Vaughan
et al. 1964).
Like ATGL, HSL is expressed in most tissues examined,
with the highest expression found in WAT and BAT
(Kraemer et al. 1993). The mRNA is generated from a
single gene controlled by a number of alternative
promoters that produce several different tissue-specific
isoforms of the HSL protein that range in size from
w85 kDa and up to 130 kDa (Langin et al. 1993, Mairal
et al. 2002). The HSL isoform found in human AT is a
786 aa protein with an apparent molecular weight of
w88 kDa (Langin et al. 1993).
Efficient lipid hydrolysis by HSL requires the lipase
to form a complex with cytosolic fatty acid-binding
protein 4 (FABP4), which acts as a molecular chaperone
by shuttling the FFA generated by HSL out of the cell
(Fig. 5A; Furuhashi & Hotamisligil 2008). Upon
stimulation of lipolysis, HSL and FABP4 associate in the
cytosol and the complex translocate to LDs (JenkinsKruchten et al. 2003, Smith et al. 2007). Consistently, in
FABP4-KO mice, the lipolytic capacity is reduced, and
the intracellular FFA
Review
Table 1
and others
Affected
protein
Human
NLSDI
CGI-58
Human
NLSDI
CGI-58
Human
Human
NLSDI
NLSDM
CGI-58
ATGL
Human
NLSDM
ATGL
Human
NLSDM
ATGL
Human
NLSDM
ATGL
Mouse
and
KO
ATGL
Mouse
Mouse
Mouse
and
KO
KO
KO
HSL
ATGL
ATGL
ATGL
Mouse
Mouse
Mouse
specific
KO
KO
KO with cardio-
Mouse
Mouse
specific
Mouse
Mouse
52 :3
R210
Specie
s
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
Reference
Phenotyping of KO animals
Insulin sensitivity and glucose/lipid metabolism
Substrate partitioning and metabolism during
rest and exercise
HSL
ATGL
CGI-58
ATGL
expression
AT-specific KO
KO with cardio-
ATGL
ATGL
Wu et al. (2012)
Schrammel et al. (2013)
KOexpression
AT-specific overexpression
G0S2
G0S2
659
660
these sites are Ser , Ser , and Ser (Stralfors et al. 1984,
Garton et al. 1988, Anthonsen et al. 1998) corresponding
552
649
650
and
660
554
(Osuga et al. 2000, Harada et al. 2003, Park et al. 2005). This
Review
T S NIELSEN
and others
52 :3
R211
FFA
B
FFA- FABP4
cAMP
PDE3B
PKA
P
HSL
5-AMP
FABP4
HSL
P
P
P
P
P
P
DG
MG
Lipid droplet
Figure 5
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
AMPK
DG
HSL
HSL
PKA
MG
Lipid droplet
requires cAMP-dependent phosphorylation on Ser552 by PKA. Conversely,
AMPK is activated by 5 0 -AMP and phosphorylate HSL on the adjacent
Ser554. As phosphorylation on Ser552 and Ser554 is mutually exclusive, AMPK
reduces the LD association of HSL. AMPK, AMP-activated protein kinase;
DG, diacylglycerol; FABP4, fatty acid-binding protein 4; FFA, free fatty acid;
HSL, hormone-sensitive lipase; MG, monoacylglycerol; PDE3B, phosphodiesterase 3B; PKA, protein kinase A.
Monoglyceride lipase
MGL was identified in rats as an MG-specific lipase
with no affinity toward TG or DG (Tornqvist &
Belfrage 1976). The first MGL-KO mouse model has
recently been generated (Table 2), and these animals
accumulate MG in WAT, brain, and liver (Taschler
et al. 2011). Also, it was found that HSL partially
compensated for the absence of MGL in AT, as the
stimulated glycerol release was reduced by a modest
43% compared with WT mice. However, upon specifi
inhibition of HSL in cultured fat pads, the MGhydrolase activity was almost completely abolished
(Taschler et al. 2011). To date, no reports have been
Review
T S NIELSEN
and others
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
Specie
s
Geneti
c
model
Affecte
d
protein
Mouse
KO
FABP4
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
HSL
Mouse
KO
MGL
Coe et al.
(1999)
Osuga et al. (2000)
Highlights
of the study
Reference
Phenotyping of
KO animals
Phenotyping of
KO animals
Involvement of
HSL in
whole-body
DG catabolism
Lipid metabolism in
diet-induced
obesity
AT adaptations
to HSL
deficiency
Insulin sensitivity and
glucose/lipid
metabolism
Phenotyping of
KO animals
Haemmerle
et al. (2002)
Harada et al.
(2003)
Zimmermann
et al. (2003)
Park et al.
(2005)
Taschler et al.
(2011)
52 :3
R212
517
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R213
Review
T S NIELSEN
and others
52 :3
R214
Species
model
Diagnosis/genetic
Affected
protein
Human
Partial lipodystrophy
CIDEC
Human
truncations
Partial lipodystrophy
PLIN1
Human
Reference
Rubio-Cabezas et al.
(2009) Gandotra et al.
Partial lipodystrophy
PLIN1
Mouse
(2000) Mouse
Mouse
Mouse
Mouse
Mouse
KO
KO
KO
KO
KO
KO
PLIN1
PLIN1
CIDEA
CIDEB
CIDEC
CIDEC
Mouse
KO
CIDEA
as causative mutations
Characterization of PLIN1 mutants in
regulation of lipolysis in cell
culture
Phenotyping of KO animals
Phenotyping of KO animals
Phenotyping of KO animals
Phenotyping of KO animals
Phenotyping of KO animals
Analysis of WAT browning in KO
animals
Characterization of the role of
CIDEA in hepatic metabolism
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the review.
Funding
This work was supported by grants from: i) The FOOD Study
Group/Ministry of Food, Agriculture and Fisheries & Ministry of Family
and Consumer
Review
T S NIELSEN
and others
Affairs, Denmark, ii) The Lundbeck Foundation, Denmark, iii) The Novo
Nordisk Foundation, Denmark, iv) Augustinus Fonden, Denmark, and
v) Aase og Ejnar Danielsens Fond, Denmark.
Acknowledgements
The Novo Nordisk Foundation Center for Basic Metabolic Research is an
independent Research Center at the University of Copenhagen partially
funded by an unrestricted donation from the Novo Nordisk Foundation
(www.metabol.ku.dk).
References
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
52 :3
R215
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
32563265. (doi:10.1021/pr070158j)
Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria
R, DeFronzo RA & Cusi K 2005 Doseresponse 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 203210. (doi:10.1055/s-2007993148)
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 309318.
(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 28012808. (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 419440. (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 50695075.
(doi:10.1210/endo.142.12.8518)
Boura-Halfon S & Zick Y 2009 Phosphorylation of IRS proteins, insulin
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R216
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 E488E494. (doi:10.1152/ajpendo.
00199.2003)
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R217
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
6473. (doi:10.2337/db10-0698)
Hollenberg CH, Raben MS & Astwood EB 1961 The lipolytic response to
corticotropin. Endocrinology 68 589598. (doi:10.1210/endo-68-4589) 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 E505E513.
(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
1664416651.
(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 541547. (doi:10.1097/00005176-19971100000011)
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
16761684. (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 17121716.
(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 4896848975. (doi:10.1074/jbc.
M407841200)
Jenkins-Kruchten AE, Bennaars-Eiden A, Ross JR, Shen WJ, Kraemer FB &
Bernlohr DA 2003 Fatty acid-binding proteinhormone-sensitive
lipase interaction. Fatty acid dependence on binding. Journal of
Biological Chemistry 278 4763647643. (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 22972303. (doi:10.1172/JCI118285)
Jensen MD 2003 Fate of fatty acids at rest and during exercise: regulatory
mechanisms. Acta Physiologica Scandinavica 178 385390.
(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 6876.
(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 207213.
(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 of Clinical
Endocrinology and Metabolism 95 54495453. (doi:10.1210/jc.20100776)
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)
Review
M
ol
ec
ul
ar
E
n
d
oc
ri
n
ol
o
g
y
T S NIELSEN
and others
52 :3
R218
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R219
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
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 of Clinical
Endocrinology and Metabolism 96 E1293E1297. (doi:10.1210/jc.20110149)
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 and Metabolism 97 E1348E1352. (doi:10.1210/jc.20121159)
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 efcient energy storage in murine white adipocytes by
promoting the formation of unilocular lipid droplets. Journal of
Clinical Investigation 118 28082821. (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 17261734.
(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 and Metabolism 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
43714378. (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 367375. (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
116126. (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 hypertrophy, but not in obesity. PNAS 97 787792.
(doi:10.1073/pnas.97.2.787)
Pagnon J, Matzaris M, Stark R, Meex RC, Macaulay SL, Brown W, OBrien
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
42784289. (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
E30E39. (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 42654270. (doi:10.1210/jc.20070786)
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 1684816859.
52 :3
R220
(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 11011107. (doi:10.1016/
j.metabol.2008.03.015)
Review
M
ol
ec
ul
ar
E
n
d
oc
ri
n
ol
o
g
y
T S NIELSEN
and others
52 :3
R221
PNAS 98
64946499. (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 1746717477.
(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
8797.
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 1822618231.
(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 resistancerelated changes in the expression of lipogenic and lipolytic genes in
morbidly obese subjects. Obesity Surgery 20 15591567.
(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 813819.
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 352355.
(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 146156. (doi:10.1007/s00125-010-1895-5)
Review
Jo
ur
n
al
of
M
ol
ec
ul
ar
E
n
d
oc
ri
n
T S NIELSEN
and others
52 :3
R222
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
11611170. (doi:10.1210/me.2008-0464)