Review
Apelin, a promising target for type 2
diabetes treatment?
Isabelle Castan-laurell1,2, Cédric Dray1,2, Claude Knauf1,2, Oxana Kunduzova1,2 and
Philippe Valet1,2*
1
Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Toulouse, France
2
Université de Toulouse, Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC),
Toulouse, France
Insulin resistance is a main feature of obesity and type 2
diabetes mellitus (T2DM). Several mechanisms linking
obesity to insulin resistance have been proposed. Adi-
pose tissue modulates metabolism by secreting a variety
of factors, which exhibit altered production during obe-
sity. Apelin, a small peptide present in a number of
tissues and also produced and secreted by adipocytes,
has emerged as a new player with potent functions in
energy metabolism, and in insulin sensitivity improve-
ment. In this review, we describe the various metabolic
functions that are affected by apelin and we present an
integrated overview of recent findings that collectively
propose apelin as a promising target for the treatment of
T2DM.
Insulin resistance and adipokines involvement
Insulin plays a crucial role in maintaining the homeostasis
of energy metabolism, by coordinating the storage and
utilization of fuel molecules in skeletal muscles, liver
and adipose tissue. Insulin resistance refers to a state in
which physiological concentrations of insulin are poorly
effective. During insulin resistance, pancreatic b cells
respond to excess plasma glucose by secreting more insu-
lin, in an effort to maintain normal glycemia and to over-
come the decreased ability of some tissues to respond to
insulin. Insulin resistance is a major characteristic of type
2 diabetes mellitus (T2DM) and is often linked to obesity
[1]. In combination, these events increase the risk of car-
diovascular diseases and obesity-associated morbidity, and
there is a plethora of evidence pointing to a causal role for
obesity in the initiation of insulin resistance [1]. Adipose
tissue releases a number of proteins called adipokines such
as leptin and adiponectin [2]. It also produces and secretes
non-esterified fatty acids and pro-inflammatory cytokines
such as interleukin-6 (IL-6), tumor necrosis factor-alpha
(TNFa), or the chemokine monocyte chemoattractant
protein-1 (MCP-1), usually regarded as adipokines when
produced by adipocytes (Figure 1). The production of these
adipokines could be altered with overweight and obesity
when plasma concentrations of some adipokines may
either be reduced or increased. Changes in concentrations
correlate with promoting or delaying obesity-associated
Corresponding author: Valet, P. (philippe.valet@inserm.fr).
*
Current address: Institut de des Maladies Metaboliques et Cardiovasculaires,
Inserm-Universite Paul Sabatier UMR 1048, BP 84225, 31432 Toulouse Cedex 4,
France.
234 1043-2760/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2012.02.005 Trends in Endocrinology and Metabolism, May 2012, Vol. 23, No. 5
pathologies. For example, leptin overproduction and a
defect in adiponectin secretion are observed during
obesity-associated insulin resistance. The role of these
factors in insulin resistance has been discussed extensively
in other reviews. In this review, we focus on a new player
called apelin, originally described as an adipokine in 2005
[3], and later shown to have novel and potent effects in the
regulation of energy metabolism.
Apelin and the apelin receptor
In 1998, Tatemoto and coworkers purified, from bovine
stomach extracts, a peptide binding to the ‘orphan’ APJ
receptor, a G protein-coupled receptor (GPCR), now known
as the apelin receptor (gene symbol APLNR [4]) [5]. The
identified gene encodes a 77-amino acid polypeptide with a
secretory signal sequence. The C-terminal part of this
polypeptide that contains the part of the molecule that
binds the apelin receptor was called ‘apelin’, for APJ
Endogenous Ligand [6]. The human apelin gene has been
localized on chromosome Xq25-q26.1 [6]. The receptor,
which was identified in humans in 1993, displays a
40–50% sequence homology and shares closest identity
to the type 1 angiotensin II receptor [7]; however, the
receptor does not bind angiotensin II. The gene encoding
the apelin receptor was mapped to chromosome 11 and
later sub-localized to the locus 11q12. RNA transcripts
were first detected in the brain, but it was subsequently
shown that apelin receptor is expressed in a wide range of
tissues [8]. In insulin-responsive tissues, apelin receptor is
expressed in the adipose tissue, skeletal muscles and heart
and at lower levels in the liver [9].
Apelin, like apelin receptor, is expressed in many periph-
eral tissues, and different brain regions, particularly the
hypothalamus [3,8]. To date, the main active forms of apelin
are apelin-13, -17 and -36 and the pyroglutaminated isoform
of apelin-13 (Pyr(1)-apelin-13) characterized by a higher
resistance to degradation [4]. In heart, the described pre-
dominant form is the Pyr(1)-apelin-13 [10]. Pyr(1)-apelin-
13, apelin-13 and apelin-36 have comparable efficacy and
potency in human cardiovascular tissues [10], whereas
apelin-17 appears to be the most efficient in promoting
apelin receptor internalization [11]. All isoforms originate
from a common 77-amino acid pre-propeptide precursor
(preproapelin) (Figure 2) consisting of a dimer which is
stabilized by disulfide bridges linking cysteine residues
[12]. The human, bovine and rat preproapelin peptides
 Review Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5

Disruption of energy metabolism

•Lipotoxicity
•Activation of inflammatory kinases in metabolic tissues
•Mitochondrial dysfunction

Fat cell hypertrophy

immune cell infiltration

Insulin-
resistance
Obesity

↑ Fatty acids
↑ Pro-inflammatory cytokines
Adipokines :↓ adiponectin,↑ leptin
TRENDS in Endocrinology & Metabolism

Figure 1. Adipose tissue expansion promotes insulin-resistance. Increased fat mass during obesity is associated with: (i) adipocyte hypertrophy; (ii) low grade inflammation
due to macrophage infiltration; and (iii) increased levels of pro-inflammatory cytokines. The altered secretion of fatty acids and adipokines by adipose tissue promotes
lipotoxicity, and/or mitochondrial dysfunction, and insulin resistance in skeletal muscle.

Endopeptidases

1 -MNLRLCVQALLLLWLSLTAVCG VPLMLPPDGTGLEEGSMRY LVKPRTSRTGPGAWQGGRR KFRR QRPRLSHKGPMPF- 77

Preproapelin
(77 amino acids)

Proapelin 22 - VPLMLPPDGTGLEEGSMRY LVKPRTSRTGPGAWQGGRR KFRR QRPRLSHKGPMPF- 77

(55 amino acids)

Apelin 36 41 - LVKPRTSRTGPGAWQGGRRKFRR QRPRLSHKGPMPF- 77

Apelin 17 60 - KFRRQRPRLSHKGPMPF- 77
Apelin
active isoforms

Apelin 13 64 - QRPRLSHKGPMPF- 77

Pyr (1)-Apelin 13 64 Pyr - QRPRLSHKGPMPF- 77

TRENDS in Endocrinology & Metabolism

Figure 2. Apelin amino acid sequence and maturation. The preproapelin (77 amino acids) is cleaved into proapelin (55 amino acids) by endopeptidases (green arrows) in
rich basic amino-acids sites. The proapelin is then cleaved into various biologically active forms of apelin such as apelin-36, apelin-17 and apelin-13. Apelin-13 can be post-
translationally modified by the transformation of glutamine (Q) in the N-terminal position into pyroglutamine, forming the pyroglutamated apelin-13 (Pyr (1) apelin-13).

share high sequence homology and 100% sequence identity
for the last 23 C-terminal amino acids [5,6].
Apelin and insulin sensitivity
It was recently shown that both short- and long-term apelin
treatment improves insulin sensitivity in insulin-resistant
obese mice. Indeed, acute Pyr(1)-apelin-13 treatment
(200 pmol/kg intravenously) of high-fat diet (HFD) fed
C57Bl6/J obese and insulin-resistant mice showed improved
glucose tolerance, during euglycemic–hyperinsulinemic
clamp [9]. Thus, apelin is efficient in improving altered
glucose metabolism, an effect that was found to be mediated
235
 Review
mainly by an increase in glucose uptake in skeletal muscle
[9]. The possible impact of apelin deficiency on adiposity and
insulin sensitivity has also been addressed. Apelin / mice
(8 weeks old) fed a chow diet exhibit significantly increased
insulin levels, decreased plasma adiponectin concentra-
tions, and are glucose intolerant. These mice also have
increased abdominal and epididymal fat mass without dif-
ferences in body weight [13]. Apelin / mice fed HFD and
high-sucrose drinking water were even more glucose and
insulin intolerant [14].
Long-term apelin treatment (from 2 to 4 weeks) of obese
and insulin-resistant mice has also been shown to improve
insulin sensitivity in different models [14,15]. HFD-fed
mice treated with apelin for 4 weeks have significant lower
blood glucose, are protected from hyperinsulinemia and
are less glucose and insulin intolerant, when compared to
control phosphate buffered saline (PBS)-treated mice. Ape-
lin-treated mice have also significantly reduced adiposity
and plasma triglycerides (TG), whereas plasma fatty acids
(FA) levels remain unchanged [15]. During the feeding
period, apelin-treated obese and insulin-resistant mice
exhibit lower respiratory exchange ratio values (RER),
measured by indirect calorimetry, characteristic of a
higher utilization of lipids. In line with these data, mice
with over-expression of apelin (apelin-Tg) possess a higher
energy expenditure and are protected against diet-induced
obesity (DIO) [16]. Thus, apelin treatment improves insu-
lin sensitivity by an overall rise in energy expenditure.
Apelin action in insulin responsive tissues
Skeletal muscle
Insulin resistance in muscle is characterized by impaired
glucose uptake, reduced glycogen synthesis, insufficient fat
oxidation, and, as a consequence, fat accumulation and
cellular stress. Recently, mitochondrial dysfunction has
been highlighted as a key factor contributing to insulin
Apelin
p
Glucose
Insulin-stimulated
glucose uptake GLUT4
G
GLU
UT4
U
Gluc
lucose
e
Glucose
NRF-1
DNA
Mt DNA
Mitochondrial
hondrial
enesis
biogenesis
Figure 3. Apelin effect in skeletal muscle metabolism. Apelin, via the activation of AMP-activated protein kinase (AMPK), increases peroxisome proliferator-activated
receptor g co-activator 1a expression in the muscle leading to fatty acid oxidation and nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM)
upregulation. Together, NFR-1 and TFAM promote mitochondrial biogenesis (Mt DNA) and mitochondrial oxidative phosphorylation capacity (OXPHOS proteins). AMPK
activation also increases insulin action on glucose uptake.
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Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5
resistance [17]. Mitochondria can usually adapt to energy
demand and the enzyme AMP-activated protein kinase
(AMPK) plays a crucial role in activating metabolic pro-
cesses such as glucose transport and FA oxidation, in order
to supply cellular ATP [18].
Chronic treatment of obese and insulin-resistant mice
with Pyr(1)-apelin-13 for 4 weeks, was shown to cause an
increase in mitochondrial biogenesis and a reduction in the
adverse alterations in the ultra-structure of both intra-
myofibrillar and subsarcolemmal mitochondria of soleus
muscle (electron density of the matrix and loss of cristae),
usually seen in T2DM [15,18]. These effects were associat-
ed with increased mitochondrial DNA, and an increase in
the expression of peroxisome proliferator-activated recep-
tor g co-activator 1a (PGC1a), nuclear respiratory factor-1
(NRF-1) and mitochondrial transcription factor A (TFAM),
factors that act in concert to increase mitochondrial oxida-
tive phosphorylation and mitochondrial biogenesis [19].
These apelin-mediated effects were shown to be AMPK
dependent, because they were completely blunted in the
muscle of HFD apelin-treated mice expressing a muscle-
specific inactive AMPK (AMPK-DN) mutant [15]. Apelin
effects on AMPK are direct since apelin treatment
increases both AMPK and acetyl CoA carboxylase phos-
phorylation in muscle of insulin-resistant mice [15]. The
higher mitochondrial biogenesis observed in the skeletal
muscle of apelin-treated mice is associated with an in-
crease in complete fatty acid oxidation (FAO), without
any modifications in incomplete FAO (Figure 3). These
effects were abrogated in the presence of a mutated apelin
receptor antagonist (apelin peptide F13A) indicating that
these effects are apelin receptor dependent [15]. The influx
of lipids in mitochondria is also associated with decreased
acylcarnitines levels that represent byproducts of catabo-
lism substrates arising from incomplete FAO. Increased
intracellular acylcarnitines levels have been associated
APJ
AMP
AMPK
MPK
PGC1α
PGC1α
β-Oxidation
OXPHOS proteins
t i
TRENDS in Endocrinology & Metabolism
Review
with obesity and insulin resistance [20]. The lower levels
of acylcarnitines observed in apelin-treated mice can be
associated with improved insulin sensitivity in skeletal
muscle, because insulin-stimulated glucose uptake is sig-
nificantly increased in the muscle of apelin-treated mice
[15]. Finally, the mitochondrial respiratory capacity is also
increased in muscle of apelin-treated mice.
In apelin-Tg HFD-fed mice, increased mitochondrial
DNA was found in skeletal muscles, without modification
in PGC-1a expression [16], whereas the type I muscle fiber
ratio was found to be increased. It is still unknown whether
this increase is a result of a shift from type II to type I
muscle fiber, or an increase in type I fibers. Nevertheless,
these results corroborate with the high mitochondrial
content and the increased oxidative capacities observed
in skeletal muscle. Mitochondrial biogenesis was also in-
creased in rat triceps (in chow-fed conditions) after apelin
treatment [21]. This mechanism involves an increase in the
expression of PGC-1b but not PGC1a, and an enhanced
activity of the enzymes b-hydroxyacyl CoA dehydrogenase
(involved in the mitochondrial oxidative capacities), citrate
synthase (involved in the citric acid cycle) and cytochrome
C oxidase (involved in the respiratory chain). Increased
mitochondrial uncoupling protein 3 (UCP3) expression in
skeletal muscle has also been observed in different rodent
models treated with apelin or over-expressing apelin
[16,22]. Thus, apelin overexpression improves the metab-
olism of insulin-resistant muscles and, considering the
important metabolic role of muscle mass in insulin sensi-
tivity and glucose uptake, it might be sufficient to overcome
the overall insulin sensitivity although other tissues could
be involved.
Adipose tissue
Insulin resistance in white adipose tissue leads to an
increased release of free fatty acids (FFA), related to the
suppression of the antilipolytic action of insulin. Thus,
lipids partition away from adipose tissue and are stored
in other tissues such as liver and skeletal muscle. Accu-
mulation of excess FFA within these tissues reduces their
overall insulin sensitivity. In addition, changes in the
levels of adipose-secreted factors have also been associated
with the initiation of insulin resistance [1].
Apelin / mice have both increased abdominal adiposity
and circulating FFA levels [13]. After re-introduction of
apelin (apelin infusion for 2 weeks) in these mice, adiposity
and FFAs but also glycerol levels are decreased, suggesting
a role for apelin in the regulation of lipolysis. Indeed, in
both isolated mouse adipocytes and differentiated 3T3-L1
adipocytes, apelin was shown to inhibit isoproterenol-
(b-adrenergic agonist) induced lipolysis, through Gq, Gi
and AMPK dependent pathways [13]. However, in human
adipose tissue explants or human isolated adipocytes,
apelin had no effect on basal or isoproterenol-stimulated
lipolysis, even though acute apelin stimulation induces
AMPK phosphorylation [23]. In response to chronic apelin
treatment of obese and insulin-resistant mice, not only
isoproterenol-stimulated lipolysis but also glucose uptake
and FAO are not modified in epididymal adipose tissue,
when compared to PBS-treated mice [15]. In addition,
apelin-treated mice exhibit decreased fat accumulation
Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5
with a tendency to have reduced leptin expression and
increased adiponectin expression. However, plasma levels
of leptin and adiponectin were not found to be different in
apelin-treated HFD-fed mice. In HFD-fed apelin-Tg mice,
plasma levels of these adipokines were found to be similar
to those of control mice [16]. Thus, the beneficial effects of
apelin seem to be unrelated to the insulin-sensitizing
effects of adiponectin.
Brown adipose tissue (BAT) plays an important role in
rodents with regards to heat production and mitochondrial
oxidative phosphorylation. It has not been described
whether apelin receptors are present in BAT although
chronic apelin-13 treatment in chow-fed mice has been
shown to increase mitochondrial uncoupling protein 1
(UCP1) in BAT, body temperature and O2 consumption
[22]. In HFD conditions, apelin-Tg mice exhibit increased
expression of UCP1, higher rectal temperature and in-
creased oxygen consumption, compared with control
HFD-fed mice [16]. However, in obese and insulin-resistant
mice treated with apelin for 4 weeks, UCP1 expression and
FAO are not increased [15]. Thus, the contribution of BAT
to the action of apelin should not be neglected, although
diverging results have been obtained that were dependent
on the rodent model used.
Pancreas
The effects of apelin on the pancreas initially focused on
the regulation of insulin secretion. Sorhede Winzell et al.
showed that apelin inhibits insulin secretion stimulated by
glucose in vivo in mice, and in vitro in isolated Langerhans
islets [24]. Apelin-36 was used in this study and had no
glucose-lowering effect alone. More recently, apelin-13 was
also shown to inhibit insulin secretion stimulated by high
glucose concentrations (10 mM) or potentiated by gluca-
gon-like peptide 1 (GLP-1) in INS-1 cells [25]. The intra-
cellular pathway activated by apelin involves a decrease of
cAMP levels in the b cells, by a PI3-kinase-dependent
activation of phosphodiesterase 3B, rather than a Gi-
mediated inhibition of adenylyl cyclase.
Longer-term apelin treatment (10 weeks) improves
pancreatic islet morphology and insulin content in Akita
mice, a genetic model of type I diabetes. Moreover, apelin
treatment in this model activates Akt, Erk and AMPK-
dependent signaling pathways and reduces the upregula-
tion of IRE1a, and PERK-CHOP signaling, involved in
endoplasmic reticulum stress [26]. The effect of apelin
treatment on the morphology of the pancreas in obese
and insulin-resistant mice has not yet been studied. Apelin
not only acts on b cells in mice but is also present in b- as
well as a-cells of different species [27]. In addition, apelin
expression is upregulated in islets of db/db mouse and
Goto Kakizaki-rat (obese and non-obese T2DM models,
respectively) [27]. However, apelin secretion by b and a
cells has not yet been demonstrated. Since apelin receptor
exists in b cells, apelin could act as a paracrine or autocrine
regulator of insulin secretion and might prevent hyperin-
sulinemia in order to improve insulin sensitivity.
Hypothalamus
The hypothalamus is the target of numerous factors in-
cluding hormones, neurotransmitters and nutrients. The
237
 Review
modification of hypothalamic neuronal activities induces
large variations of peripheral glucose utilization. Apelin
and apelin receptor mRNAs have been identified in differ-
ent nuclei of the hypothalamus involved in the control of
behavioral and endocrine processes and energy homeosta-
sis [28]. The presence of apelin-positive nerve fibers in the
hypothalamus implies the existence of apelinergic neurons
and thus a dual action of apelin as a circulating peptide and
a neuropeptide. To date, it is not known whether periph-
eral plasma apelin can reach the hypothalamus and could
modulate apelin levels in the hypothalamus. However,
hypothalamic apelin levels were found to be higher in
HFD-fed C57Bl6/J and db/db mice [29]. Intracerebroven-
tricular (icv) apelin injection has been shown to either
stimulate or inhibit food intake, depending of the nutri-
tional status of the animals, and whether apelin was
injected during the feeding or fasting period. Clarke
et al. showed that icv apelin injection decreased food, water
intake and respiratory exchange ratio in control rats, but
had no effect in HFD-fed rats [30]. Recently, acute icv
apelin injection was shown to inhibit food intake in fed
and fasted mice, only during the dark period. The proposed
mechanism seems to involve the corticotrophin-releasing
factor system [31]. Reaux-Le Goazigo et al. have recently
demonstrated that apelin-immunoreactive neuronal cell
bodies were distributed throughout the rostrocaudal ex-
tent of the arcuate nucleus in rats, and that apelin was
weakly colocalized with NPY (an orexigen peptide) but
strongly colocalized with POMC, a neuropeptide known
to decrease food intake [29]. Thus, increased hypothalamic
apelin levels might be associated with reduced food
intake and limited weight gain. However, with obesity,
Obese and insulin
resistant mice
WAT
↓ fat mass
↑ insulin-stimulated glucose uptake
Figure 4. Effect of apelin treatment on energy metabolism in obese and insulin-resistant mice. In apelin-treated mice, the decreased fat mass of white adipose tissue (WAT)
leads to free fatty acids (FFA) release potentially taken up by the muscle, in order to be oxidized. Mitochondrial biogenesis is also increased as well as insulin-stimulated
glucose transport in skeletal muscle. FFA could also act on brown adipose tissue, in order to increase thermogenesis. The decreased insulinemia observed suggests an
action of apelin on the pancreas. However, the long-term effects of apelin of the central nervous system are still not known. These events combined increase the overall
insulin sensitivity in obese and insulin-resistant mice.
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Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5
the beneficial effect of apelin is probably counteracted by
the downregulation of brain apelin receptor by apelin
itself, as described by Clarke et al. in HFD-fed rats [30].
The role of central apelin on glucose metabolism has
recently been studied. Acute icv injection of apelin can have
a differential effect depending on the injected dose and the
nutritional status [32]. Acute low dose of icv administered
apelin can decrease peripheral glycemia in fed mice, and
increase glucose and insulin tolerance in mice. However,
an acute high dose apelin icv injection in chow-fed and
HFD-fed mice increases fasted hyperglycemia. Thus, a rise
in hypothalamic apelin levels, as described by Reaux-Le
Goazigo et al. [29], could be involved in the transition from
normal to diabetic status. Both the abolished circadian
plasma apelin regulation observed in HFD-treated mice
and the impact of chronic icv apelin treatment in normal
mice triggering insulin intolerance, are consistent with
this hypothesis [32].
Integrative view of apelin’s effects on peripheral
target organs
Collectively, the findings from the studies discussed above
suggest that apelin treatment during insulin resistance
triggers several coordinated beneficial effects, such as
reducing hyperinsulinemia, decreasing adiposity, facilitat-
ing glucose uptake and fuel consumption through FAO,
and increased skeletal muscle mitochondrial biogenesis
(Figure 4). The improvement in insulin sensitivity observed
after apelin treatment might be due to decreased adiposity
and optimized utilization of fatty acids by skeletal muscles. It
is likely that apelin treatment improves insulin-stimulated
glucose uptake in muscle, as a result of increased FAO
Apelin treatment
?
Pancreas
↓ insulin
production
FFA BAT
? ↑ thermogenesis
↑ mitochondrial biogenesis
↑ complete fatty acid oxidation
Increased insulin sensitivity
TRENDS in Endocrinology & Metabolism
Review
and limited accumulation of FA intermediates. The liver, due
to the weak expression of apelin receptor, does not seem to be
the main metabolic target of apelin’s actions. However, it
cannot be excluded that during pathological situations, as
reported in cirrhosis, apelin receptor expression could be
upregulated and thus, apelin might act in the liver [33].
Finally, as previously reported for other AMPK activa-
tors [34], it can be speculated that AMPK activation by
apelin regulates substrate flux and whole-body energy
distribution to the tissues. Therefore, even if apelin acti-
vated AMPK in adipose tissue skeletal muscle appears to
be the main target tissue for apelin, by which fuel con-
sumption is achieved. Nevertheless, it cannot be excluded
that additional mechanisms within the tissues studied or
other target organs might be involved.
Other potential targets
Blood vessels
Both hyperinsulinemia and insulin resistance contribute
to vascular dysfunction due to an imbalance between
endothelium-dependent vasodilatation and vasoconstric-
tor effects, involving endothelin [35]. Impaired vasodilata-
tion and consequently reduced nitric oxide (NO)
bioavailability in different vascular beds could affect pe-
ripheral vascular resistance and substrate delivery to
metabolically active tissues. The physiological relevance
of insulin-stimulated vasodilatation in stimulating glucose
uptake remains controversial. However, it seems that in
the insulin-resistant muscle, decreased insulin-stimulated
glucose uptake could be partly due to impaired insulin-
mediated capillary recruitment [35]. Apelin, like insulin,
can induce NO-dependent vasodilatation [36] and is in-
volved in the caliber size regulation of blood vessels during
angiogenesis [37]. The apelin receptor is present in small
amounts in endothelial cells but also to a lesser extent, in
smooth muscle cells in vessels. This implies that apelin
might also have vasoconstrictor capacities [38]. Despite
this, the vasodilator effect of apelin seems to dominate in
the presence of a functional endothelium [39]. The effect of
apelin on blood flow during insulin resistance is poorly
documented. However, it has been shown that resistance to
diet-induced obesity of the apelin-Tg mice was accompa-
nied by an increase in vascular mass, within the skeletal
muscle [16]. It is not known whether this phenomenon was
due to increased blood vessel number or caliber size, but
angiopoietin-1 mRNA expression, a key factor in vascular
maturation, and its receptor Tie 2, were both significantly
increased [16]. The relationship between energy metabo-
lism, blood flow and more generally blood vessel physiolo-
gy, in response to apelin, deserves further investigation.
Heart
Myocardial energy metabolism plays a vital role in the
regulation of cardiac function, in both health and disease
[40]. Apelin may be an important and promising adipokine
that can help to understand better the link between meta-
bolic and cardiovascular diseases. Apelin has potent dose-
dependent positive inotropic, vasodilator actions and
improves myocardial efficiency [41]. Apelin plays a protec-
tive role in ischemia/reperfusion by stimulating intracellu-
lar pathways such as PI3k-Akt or by reducing endoplasmic
Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5
reticulum stress-induced apoptosis [42]. Previous studies
have also shown that apelin behaves as a potent angiogenic
inducer, contributing to the development of the functional
vascular network in hypoxic tissue [43]. It was recently
demonstrated that apelin prevents the progression of cardi-
ac hypertrophic remodeling induced by pressure overload,
by inhibiting reactive oxygen species production, and stim-
ulating catalase activity. These results support the premise
that apelin is a potent regulator of cardiomyocyte antioxi-
dant reserve against oxidative stress, in the failing heart
[44]. Additional evidence suggests that apelin blunts the
progression of fibrosis and preserves contractile function
during cardiac decompensation [45], highlighting the fact
that apelin behaves as a critical regulator of functional and
structural remodeling during chronic heart failure. In this
context, the role of the apelinergic system on metabolic
cardiac remodeling in the development and progression of
heart failure is of great interest, and of importance in
understanding the potential link between myocardial me-
tabolism and cardiac performance. Despite the metabolic
effects of apelin in adipose tissue and skeletal muscle,
the role of apelin in the regulation of myocardial fatty acid
and glucose metabolism in the failing heart remains to be
determined.
Relevance in humans
In humans, numerous studies have reported changes in
plasma apelin concentrations (Table 1) and variations of
apelin and its receptor expression in different tissues, in
physiological and pathological situations [8]. In obese and
hyperinsulinemic subjects, plasma apelin levels as well as
adipose tissue expression is increased [3]. Plasma apelin
levels are also raised in morbidly obese [46] and T2DM
subjects [47]. Non-obese patients with impaired glucose
tolerance or with T2DM also exhibited higher concentra-
tions of apelin, when compared with control subjects [48].
Recently, it was shown that increased plasma apelin con-
centration in obese and T2DM subjects is positively corre-
lated not only with insulinemia but also with glycemia and
the percentage of glycated hemoglobin [49]. Reduced plas-
ma apelin levels were found in obese subjects with untreat-
ed T2DM, compared to non-diabetic subjects [50]. These
results could be consistent with the fact that after 14 weeks
of anti-diabetic treatment (rosiglitazone and metformin),
plasma apelin levels were increased and the glycemic
profile improved [51]. A decline in apelin levels after
diet-induced weight loss [52] or bariatric surgery [47] in
obese individuals has also been described, showing that the
apelin upregulation can be reversed.
Table 1. Apelin action in humans
Phenotype Changes in [apelin] Refs
Obese and hyperinsulinemic Up [3]
Morbidly obese Up [46]
Obese and T2DM Up [47,49]
Untreated T2DM Down [50]
Non-obese T2DM Up [48]
Anti-diabetic treatment Up [51]
Bariatric surgery Down [47]
Caloric restriction Down [52]
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Review
Box 1. Outstanding questions
 Is the increasing plasma concentration of apelin observed during
obesity involved in the delay of the onset of diabetes?
 How does a single daily injection of such a short-lived peptide
promote long lasting effects?
 Which isoforms of apelin are increased and/or decreased in the
described diseases and do these changes in concentration have
distinct consequences?
 Is apelin able to interact with receptors other than APLNR (APJ)?
 Do the vascular effects of apelin contribute to the improvement of
metabolism in muscle?
Apelin receptor mRNA expression has been measured in
adipose tissue and skeletal muscle of T2DM and non-
diabetic subjects, before and after euglycemic hyperinsuli-
nemic clamp [9]. Although basal apelin receptor expression
in muscle of diabetic subjects was similar to controls [9], a
significant increase in expression was observed after the
clamp, in muscles of both control and diabetic subjects.
Thus, it can be hypothesized that this upregulation of apelin
receptor expression might be associated with increased
apelin metabolic functions in skeletal muscles.
Finally, in humans, studies of apelin and apelin receptor
are mostly descriptive and it is now of interest to investi-
gate the metabolic effects of apelin administration in both
physiological and pathological situations.
Concluding remarks
All the effects of apelin depicted in obese and insulin-
resistant mice or by transgenic approaches clearly under-
line a beneficial role of apelin on energy metabolism,
whereby increased insulin sensitivity and decreased fat
mass are observed. Skeletal muscle appears as the major
tissue target for apelin action, where it mediates increased
fuel consumption. However, many other aspects need to be
further addressed, such as the consequences of chronic
apelin treatment on cardiovascular functions, angiogene-
sis and cell proliferation, but also on the central nervous
system responses. In addition, the development of non-
peptidic ligands, highly selective for apelin receptor, long-
lasting and able to mimic the effects of apelin is warranted.
Although a non-peptidic agonist has been identified recent-
ly [53] its effects on energy metabolism are still unknown.
Finally, it is of importance to determine the optimal strat-
egy for apelin treatment, whether it is acute or chronic.
Indeed, acute apelin treatment improves mainly glucose
metabolism by inducing glucose-lowering effects, whereas
chronic apelin treatment increases lipid oxidation and
mitochondrial biogenesis. Thus, even though some ques-
tions remain unanswered (Box 1), the apelin/apelin recep-
tor system should be considered as a valuable target in the
treatment of type 2 diabetes.
Acknowledgments
The authors acknowledge Max Lafontan for fruitful discussions and
support from SFD (Société Francophone du Diabète) and SFN (Société
Française de Nutrition).
References
1 Kahn, S.E. et al. (2006) Mechanisms linking obesity to insulin
resistance and type 2 diabetes. Nature 444, 840–846
2 Ronti, T. et al. (2006) The endocrine function of adipose tissue: an
update. Clin. Endocrinol. (Oxf.) 64, 355–365
240
Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5
3 Boucher, J. et al. (2005) Apelin, a newly identified adipokine up-
regulated by insulin and obesity. Endocrinology 146, 1764–1771
4 Pitkin, S.L. et al. (2010) International Union of Basic and Clinical
Pharmacology. LXXIV. Apelin receptor nomenclature, distribution,
pharmacology, and function. Pharmacol. Rev. 62, 331–342
5 Tatemoto, K. et al. (1998) Isolation and characterization of a novel
endogenous peptide ligand for the human APJ receptor. Biochem.
Biophys. Res. Commun. 251, 471–476
6 Lee, D.K. et al. (2000) Characterization of apelin, the ligand for the APJ
receptor. J. Neurochem. 74, 34–41
7 O’Dowd, B.F. et al. (1993) A human gene that shows identity with the
gene encoding the angiotensin receptor is located on chromosome 11.
Gene 136, 355–360
8 Castan-Laurell, I. et al. (2011) Apelin, diabetes, and obesity. Endocrine
40, 1–9
9 Dray, C. et al. (2008) Apelin stimulates glucose utilization in normal
and obese insulin-resistant mice. Cell Metab. 8, 437–445
10 Maguire, J.J. et al. (2009) [Pyr1]apelin-13 identified as the
predominant apelin isoform in the human heart: vasoactive
mechanisms and inotropic action in disease. Hypertension 54, 598–604
11 El Messari, S. et al. (2004) Functional dissociation of apelin receptor
signaling and endocytosis: implications for the effects of apelin on
arterial blood pressure. J. Neurochem. 90, 1290–1301
12 Lee, D.K. et al. (2005) Modification of the terminal residue of apelin-13
antagonizes its hypotensive action. Endocrinology 146, 231–236
13 Yue, P. et al. (2011) Apelin decreases lipolysis via Gq, Gi, and AMPK-
dependent mechanisms. Endocrinology 152, 59–68
14 Yue, P. et al. (2010) Apelin is necessary for the maintenance of insulin
sensitivity. Am. J. Physiol. Endocrinol. Metab. 298, E59–E67
15 Attane, C. et al. (2012) Apelin treatment increases complete fatty acid
oxidation, mitochondrial oxidative capacity, and biogenesis in muscle
of insulin-resistant mice. Diabetes 61, 310–320
16 Yamamoto, T. et al. (2011) Apelin-transgenic mice exhibit a resistance
against diet-induced obesity by increasing vascular mass and
mitochondrial biogenesis in skeletal muscle. Biochim. Biophys. Acta
1810, 853–862
17 Kim, J.A. et al. (2008) Role of mitochondrial dysfunction in insulin
resistance. Circ. Res. 102, 401–414
18 Hegarty, B.D. et al. (2009) Insulin resistance and fuel homeostasis: the
role of AMP-activated protein kinase. Acta Physiol. (Oxf.) 196, 129–145
19 Scarpulla, R.C. (2008) Transcriptional paradigms in mammalian
mitochondrial biogenesis and function. Physiol. Rev. 88, 611–638
20 Mihalik, S.J. et al. (2010) Increased levels of plasma acylcarnitines in
obesity and type 2 diabetes and identification of a marker of
glucolipotoxicity. Obesity (Silver Spring) 18, 1695–1700
21 Frier, B.C. et al. (2009) The effects of apelin treatment on skeletal
muscle mitochondrial content. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 297, R1761–R1768
22 Higuchi, K. et al. (2007) Apelin, an APJ receptor ligand, regulates body
adiposity and favors the messenger ribonucleic acid expression of
uncoupling proteins in mice. Endocrinology 148, 2690–2697
23 Attane, C. et al. (2011) Apelin stimulates glucose uptake but not
lipolysis in human adipose tissue ex vivo. J. Mol. Endocrinol. 46,
21–28
24 Sorhede Winzell, M. et al. (2005) The apj receptor is expressed in
pancreatic islets and its ligand, apelin, inhibits insulin secretion in
mice. Regul. Pept. 131, 12–17
25 Guo, L. et al. (2009) Apelin inhibits insulin secretion in pancreatic beta-
cells by activation of PI3-kinase-phosphodiesterase 3B. Endocr. Res.
34, 142–154
26 Chen, H. et al. (2011) Apelin alleviates diabetes-associated
endoplasmic reticulum stress in the pancreas of Akita mice.
Peptides 32, 1634–1639
27 Ringstrom, C. et al. (2010) Apelin is a novel islet peptide. Regul. Pept.
162, 44–51
28 Reaux, A. et al. (2001) Physiological role of a novel neuropeptide,
apelin, and its receptor in the rat brain. J. Neurochem. 77, 1085–1096
29 Reaux-Le Goazigo, A. et al. (2011) Apelin and the proopiomelanocortin
system: a new regulatory pathway of hypothalamic alpha-MSH
release. Am. J. Physiol. Endocrinol. Metab. 301, E955–E966
30 Clarke, K.J. et al. (2009) Diminished metabolic responses to centrally-
administered apelin-13 in diet-induced obese rats fed a high-fat diet.
J. Neuroendocrinol. 21, 83–89
Review
31 Lv, S.Y. et al. (2012) Central apelin-13 inhibits food intake via the CRF
receptor in mice. Peptides 33, 132–138
32 Duparc, T. et al. (2011) Central apelin controls glucose homeostasis via
a nitric oxide-dependent pathway in mice. Antioxid. Redox Signal. 15,
1477–1496
33 Principe, A. et al. (2008) The hepatic apelin system: a new therapeutic
target for liver disease. Hepatology 48, 1193–1201
34 Gaidhu, M.P. et al. (2006) 5-Aminoimidazole-4-carboxamide-1-beta-D-
ribofuranoside-induced AMP-activated protein kinase phosphorylation
inhibits basal and insulin-stimulated glucose uptake, lipid synthesis,
and fatty acid oxidation in isolated rat adipocytes. J. Biol. Chem. 281,
25956–25964
35 Clark, M.G. et al. (2003) Blood flow and muscle metabolism: a focus on
insulin action. Am. J. Physiol. Endocrinol. Metab. 284, E241–E258
36 Japp, A.G. et al. (2010) Acute cardiovascular effects of apelin in
humans: potential role in patients with chronic heart failure.
Circulation 121, 1818–1827
37 Kidoya, H. et al. (2008) Spatial and temporal role of the apelin/APJ
system in the caliber size regulation of blood vessels during
angiogenesis. EMBO J. 27, 522–534
38 Barnes, G. et al. (2010) Translational promise of the apelin – APJ
system. Heart 96, 1011–1016
39 Japp, A.G. and Newby, D.E. (2008) The apelin-APJ system in heart
failure: pathophysiologic relevance and therapeutic potential.
Biochem. Pharmacol. 75, 1882–1892
40 Gray, S. and Kim, J.K. (2011) New insights into insulin resistance in
the diabetic heart. Trends Endocrinol. Metab. 22, 394–403
41 Szokodi, I. et al. (2002) Apelin, the novel endogenous ligand of the
orphan receptor APJ, regulates cardiac contractility. Circ. Res. 91,
434–440
42 Tao, J. et al. (2011) Apelin-13 protects the heart against ischemia-
reperfusion injury through inhibition of ER-dependent apoptotic
Trends in Endocrinology and Metabolism May 2012, Vol. 23, No. 5
pathways in a time-dependent fashion. Am. J. Physiol. Heart Circ.
Physiol. 301, H1471–H1486
43 Kunduzova, O. et al. (2008) Apelin/APJ signaling system: a potential
link between adipose tissue and endothelial angiogenic processes.
FASEB J. 22, 4146–4153
44 Foussal, C. et al. (2010) Activation of catalase by apelin prevents
oxidative stress-linked cardiac hypertrophy. FEBS Lett. 584,
2363–2370
45 Pchejetski, D. et al. (2011) Apelin prevents cardiac fibroblast activation
and collagen production through inhibition of sphingosine kinase 1.
Eur. Heart J., in press
46 Heinonen, M.V. et al. (2005) Apelin, orexin-A and leptin plasma levels
in morbid obesity and effect of gastric banding. Regul. Pept. 130, 7–13
47 Soriguer, F. et al. (2009) Apelin levels are increased in morbidly obese
subjects with type 2 diabetes mellitus. Obes. Surg. 19, 1574–1580
48 Li, L. et al. (2006) Changes and relations of circulating visfatin, apelin,
and resistin levels in normal, impaired glucose tolerance, and type 2
diabetic subjects. Exp. Clin. Endocrinol. Diab. 114, 544–548
49 Dray, C. et al. (2010) Apelin and APJ regulation in adipose tissue and
skeletal muscle of type 2 diabetic mice and humans. Am. J. Physiol.
Endocrinol. Metab. 298, E1161–E1169
50 Erdem, G. et al. (2008) Low plasma apelin levels in newly diagnosed
type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diab. 116, 289–292
51 Kadoglou, N.P. et al. (2010) Effects of rosiglitazone and metformin
treatment on apelin, visfatin, and ghrelin levels in patients with type 2
diabetes mellitus. Metabolism 59, 373–379
52 Castan-Laurell, I. et al. (2008) Effect of hypocaloric diet-induced weight
loss in obese women on plasma apelin and adipose tissue expression of
apelin and APJ. Eur. J. Endocrinol. 158, 905–910
53 Iturrioz, X. et al. (2010) Identification and pharmacological properties
of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J.
24, 1506–1517
241