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Apelin, a promising target for type 2 diabetes treatment?
Review
Apelin, a promising target for type 2 diabetes treatment? Isabelle Castan-laurell1,2, Ce´dric Dray1,2, Claude Knauf1,2, Oxana Kunduzova1,2 and Philippe Valet1,2* 1
Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), U1048, Toulouse, France Universite´ de Toulouse, Universite´ Paul Sabatier, Institut des Maladies Me´taboliques et Cardiovasculaires (I2MC), Toulouse, France
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Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. 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 improvement. 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 insulin, in an effort to maintain normal glycemia and to overcome 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 cardiovascular 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. ([email protected]). Current address: Institut de des Maladies Metaboliques et Cardiovasculaires, Inserm-Universite Paul Sabatier UMR 1048, BP 84225, 31432 Toulouse Cedex 4, France. *
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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 peripheral 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 predominant form is the Pyr(1)-apelin-13 [10]. Pyr(1)-apelin13, 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
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
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Disruption of energy metabolism •Lipotoxicity •Activation of inflammatory kinases in metabolic tissues •Mitochondrial dysfunction Fat cell hypertrophy immune cell infiltration
Insulinresistance
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 (55 amino acids)
22 - VPLMLPPDGTGLEEGSMRY LVKPRTSRTGPGAWQGGRR KFRR QRPRLSHKGPMPF- 77
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 posttranslationally 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
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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 concentrations, and are glucose intolerant. These mice also have increased abdominal and epididymal fat mass without differences 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. Apelin-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 insulin sensitivity by an overall rise in energy expenditure.
resistance [17]. Mitochondria can usually adapt to energy demand and the enzyme AMP-activated protein kinase (AMPK) plays a crucial role in activating metabolic processes 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 intramyofibrillar and subsarcolemmal mitochondria of soleus muscle (electron density of the matrix and loss of cristae), usually seen in T2DM [15,18]. These effects were associated with increased mitochondrial DNA, and an increase in the expression of peroxisome proliferator-activated receptor 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 oxidative 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 musclespecific inactive AMPK (AMPK-DN) mutant [15]. Apelin effects on AMPK are direct since apelin treatment increases both AMPK and acetyl CoA carboxylase phosphorylation in muscle of insulin-resistant mice [15]. The higher mitochondrial biogenesis observed in the skeletal muscle of apelin-treated mice is associated with an increase 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 catabolism substrates arising from incomplete FAO. Increased intracellular acylcarnitines levels have been associated
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
APJ GLUT4 G GLU UT4 U
Gluc lucose e Glucose
AMP AMPK MPK
PGC1α PGC1α
NRF-1
β-Oxidation
DNA Mt DNA Mitochondrial hondrial enesis biogenesis
OXPHOS proteins t i
TRENDS in Endocrinology & Metabolism
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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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 significantly 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 increased 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 metabolism of insulin-resistant muscles and, considering the important metabolic role of muscle mass in insulin sensitivity 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. Accumulation 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
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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 increased 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 glucagon-like peptide 1 (GLP-1) in INS-1 cells [25]. The intracellular 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 Gimediated 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 AMPKdependent signaling pathways and reduces the upregulation 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 hyperinsulinemia in order to improve insulin sensitivity. Hypothalamus The hypothalamus is the target of numerous factors including hormones, neurotransmitters and nutrients. The 237
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modification of hypothalamic neuronal activities induces large variations of peripheral glucose utilization. Apelin and apelin receptor mRNAs have been identified in different nuclei of the hypothalamus involved in the control of behavioral and endocrine processes and energy homeostasis [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 peripheral 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]. Intracerebroventricular (icv) apelin injection has been shown to either stimulate or inhibit food intake, depending of the nutritional 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 extent 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,
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, facilitating 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
?
Obese and insulin resistant mice
Pancreas ↓ insulin production
WAT
↓ fat mass
BAT
FFA
↑ thermogenesis
?
↑ mitochondrial biogenesis ↑ complete fatty acid oxidation ↑ insulin-stimulated glucose uptake
Increased insulin sensitivity TRENDS in Endocrinology & Metabolism
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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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 activators [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 activated AMPK in adipose tissue skeletal muscle appears to be the main target tissue for apelin, by which fuel consumption 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 vasoconstrictor effects, involving endothelin [35]. Impaired vasodilatation and consequently reduced nitric oxide (NO) bioavailability in different vascular beds could affect peripheral 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 insulinmediated capillary recruitment [35]. Apelin, like insulin, can induce NO-dependent vasodilatation [36] and is involved 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 accompanied 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 metabolism, blood flow and more generally blood vessel physiology, 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 metabolic and cardiovascular diseases. Apelin has potent dosedependent positive inotropic, vasodilator actions and improves myocardial efficiency [41]. Apelin plays a protective role in ischemia/reperfusion by stimulating intracellular pathways such as PI3k-Akt or by reducing endoplasmic
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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 cardiac hypertrophic remodeling induced by pressure overload, by inhibiting reactive oxygen species production, and stimulating catalase activity. These results support the premise that apelin is a potent regulator of cardiomyocyte antioxidant 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 metabolism 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 concentrations of apelin, when compared with control subjects [48]. Recently, it was shown that increased plasma apelin concentration in obese and T2DM subjects is positively correlated not only with insulinemia but also with glycemia and the percentage of glycated hemoglobin [49]. Reduced plasma apelin levels were found in obese subjects with untreated 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 Obese and hyperinsulinemic Morbidly obese Obese and T2DM Untreated T2DM Non-obese T2DM Anti-diabetic treatment Bariatric surgery Caloric restriction
Changes in [apelin] Up Up Up Down Up Up Down Down
Refs [3] [46] [47,49] [50] [48] [51] [47] [52] 239
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 nondiabetic subjects, before and after euglycemic hyperinsulinemic 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 investigate the metabolic effects of apelin administration in both physiological and pathological situations. Concluding remarks All the effects of apelin depicted in obese and insulinresistant mice or by transgenic approaches clearly underline 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, angiogenesis and cell proliferation, but also on the central nervous system responses. In addition, the development of nonpeptidic ligands, highly selective for apelin receptor, longlasting and able to mimic the effects of apelin is warranted. Although a non-peptidic agonist has been identified recently [53] its effects on energy metabolism are still unknown. Finally, it is of importance to determine the optimal strategy 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 questions remain unanswered (Box 1), the apelin/apelin receptor 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 (Socie´te´ Francophone du Diabe`te) and SFN (Socie´te´ Franc¸aise 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
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3 Boucher, J. et al. (2005) Apelin, a newly identified adipokine upregulated 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 AMPKdependent 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 betacells 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 centrallyadministered 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-Dribofuranoside-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 ischemiareperfusion injury through inhibition of ER-dependent apoptotic
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pathways in a time-dependent fashion. Am. J. Physiol. Heart Circ. Physiol. 301, H1471–H1486 Kunduzova, O. et al. (2008) Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes. FASEB J. 22, 4146–4153 Foussal, C. et al. (2010) Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy. FEBS Lett. 584, 2363–2370 Pchejetski, D. et al. (2011) Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1. Eur. Heart J., in press 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 Soriguer, F. et al. (2009) Apelin levels are increased in morbidly obese subjects with type 2 diabetes mellitus. Obes. Surg. 19, 1574–1580 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 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 Erdem, G. et al. (2008) Low plasma apelin levels in newly diagnosed type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diab. 116, 289–292 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 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 Iturrioz, X. et al. (2010) Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J. 24, 1506–1517
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Apelin, a promising target for type 2 diabetes treatment? Isabelle Castan-laurell1,2, Ce´dric Dray1,2, Claude Knauf1,2, Oxana Kunduzova1,2 and Philippe Valet1,2* 1
Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), U1048, Toulouse, France Universite´ de Toulouse, Universite´ Paul Sabatier, Institut des Maladies Me´taboliques et Cardiovasculaires (I2MC), Toulouse, France
2
Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. 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 improvement. 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 insulin, in an effort to maintain normal glycemia and to overcome 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 cardiovascular 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. ([email protected]). Current address: Institut de des Maladies Metaboliques et Cardiovasculaires, Inserm-Universite Paul Sabatier UMR 1048, BP 84225, 31432 Toulouse Cedex 4, France. *
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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 peripheral 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 predominant form is the Pyr(1)-apelin-13 [10]. Pyr(1)-apelin13, 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
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
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Disruption of energy metabolism •Lipotoxicity •Activation of inflammatory kinases in metabolic tissues •Mitochondrial dysfunction Fat cell hypertrophy immune cell infiltration
Insulinresistance
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 (55 amino acids)
22 - VPLMLPPDGTGLEEGSMRY LVKPRTSRTGPGAWQGGRR KFRR QRPRLSHKGPMPF- 77
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 posttranslationally 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
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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 concentrations, and are glucose intolerant. These mice also have increased abdominal and epididymal fat mass without differences 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. Apelin-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 insulin sensitivity by an overall rise in energy expenditure.
resistance [17]. Mitochondria can usually adapt to energy demand and the enzyme AMP-activated protein kinase (AMPK) plays a crucial role in activating metabolic processes 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 intramyofibrillar and subsarcolemmal mitochondria of soleus muscle (electron density of the matrix and loss of cristae), usually seen in T2DM [15,18]. These effects were associated with increased mitochondrial DNA, and an increase in the expression of peroxisome proliferator-activated receptor 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 oxidative 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 musclespecific inactive AMPK (AMPK-DN) mutant [15]. Apelin effects on AMPK are direct since apelin treatment increases both AMPK and acetyl CoA carboxylase phosphorylation in muscle of insulin-resistant mice [15]. The higher mitochondrial biogenesis observed in the skeletal muscle of apelin-treated mice is associated with an increase 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 catabolism substrates arising from incomplete FAO. Increased intracellular acylcarnitines levels have been associated
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
APJ GLUT4 G GLU UT4 U
Gluc lucose e Glucose
AMP AMPK MPK
PGC1α PGC1α
NRF-1
β-Oxidation
DNA Mt DNA Mitochondrial hondrial enesis biogenesis
OXPHOS proteins t i
TRENDS in Endocrinology & Metabolism
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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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 significantly 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 increased 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 metabolism of insulin-resistant muscles and, considering the important metabolic role of muscle mass in insulin sensitivity 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. Accumulation 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
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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 increased 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 glucagon-like peptide 1 (GLP-1) in INS-1 cells [25]. The intracellular 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 Gimediated 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 AMPKdependent signaling pathways and reduces the upregulation 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 hyperinsulinemia in order to improve insulin sensitivity. Hypothalamus The hypothalamus is the target of numerous factors including hormones, neurotransmitters and nutrients. The 237
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modification of hypothalamic neuronal activities induces large variations of peripheral glucose utilization. Apelin and apelin receptor mRNAs have been identified in different nuclei of the hypothalamus involved in the control of behavioral and endocrine processes and energy homeostasis [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 peripheral 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]. Intracerebroventricular (icv) apelin injection has been shown to either stimulate or inhibit food intake, depending of the nutritional 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 extent 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,
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, facilitating 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
?
Obese and insulin resistant mice
Pancreas ↓ insulin production
WAT
↓ fat mass
BAT
FFA
↑ thermogenesis
?
↑ mitochondrial biogenesis ↑ complete fatty acid oxidation ↑ insulin-stimulated glucose uptake
Increased insulin sensitivity TRENDS in Endocrinology & Metabolism
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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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 activators [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 activated AMPK in adipose tissue skeletal muscle appears to be the main target tissue for apelin, by which fuel consumption 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 vasoconstrictor effects, involving endothelin [35]. Impaired vasodilatation and consequently reduced nitric oxide (NO) bioavailability in different vascular beds could affect peripheral 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 insulinmediated capillary recruitment [35]. Apelin, like insulin, can induce NO-dependent vasodilatation [36] and is involved 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 accompanied 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 metabolism, blood flow and more generally blood vessel physiology, 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 metabolic and cardiovascular diseases. Apelin has potent dosedependent positive inotropic, vasodilator actions and improves myocardial efficiency [41]. Apelin plays a protective role in ischemia/reperfusion by stimulating intracellular pathways such as PI3k-Akt or by reducing endoplasmic
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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 cardiac hypertrophic remodeling induced by pressure overload, by inhibiting reactive oxygen species production, and stimulating catalase activity. These results support the premise that apelin is a potent regulator of cardiomyocyte antioxidant 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 metabolism 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 concentrations of apelin, when compared with control subjects [48]. Recently, it was shown that increased plasma apelin concentration in obese and T2DM subjects is positively correlated not only with insulinemia but also with glycemia and the percentage of glycated hemoglobin [49]. Reduced plasma apelin levels were found in obese subjects with untreated 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 Obese and hyperinsulinemic Morbidly obese Obese and T2DM Untreated T2DM Non-obese T2DM Anti-diabetic treatment Bariatric surgery Caloric restriction
Changes in [apelin] Up Up Up Down Up Up Down Down
Refs [3] [46] [47,49] [50] [48] [51] [47] [52] 239
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 nondiabetic subjects, before and after euglycemic hyperinsulinemic 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 investigate the metabolic effects of apelin administration in both physiological and pathological situations. Concluding remarks All the effects of apelin depicted in obese and insulinresistant mice or by transgenic approaches clearly underline 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, angiogenesis and cell proliferation, but also on the central nervous system responses. In addition, the development of nonpeptidic ligands, highly selective for apelin receptor, longlasting and able to mimic the effects of apelin is warranted. Although a non-peptidic agonist has been identified recently [53] its effects on energy metabolism are still unknown. Finally, it is of importance to determine the optimal strategy 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 questions remain unanswered (Box 1), the apelin/apelin receptor 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 (Socie´te´ Francophone du Diabe`te) and SFN (Socie´te´ Franc¸aise 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 upregulated 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 AMPKdependent 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 betacells 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 centrallyadministered 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-Dribofuranoside-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 ischemiareperfusion injury through inhibition of ER-dependent apoptotic
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43
44
45
46 47 48
49
50 51
52
53
pathways in a time-dependent fashion. Am. J. Physiol. Heart Circ. Physiol. 301, H1471–H1486 Kunduzova, O. et al. (2008) Apelin/APJ signaling system: a potential link between adipose tissue and endothelial angiogenic processes. FASEB J. 22, 4146–4153 Foussal, C. et al. (2010) Activation of catalase by apelin prevents oxidative stress-linked cardiac hypertrophy. FEBS Lett. 584, 2363–2370 Pchejetski, D. et al. (2011) Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1. Eur. Heart J., in press 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 Soriguer, F. et al. (2009) Apelin levels are increased in morbidly obese subjects with type 2 diabetes mellitus. Obes. Surg. 19, 1574–1580 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 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 Erdem, G. et al. (2008) Low plasma apelin levels in newly diagnosed type 2 diabetes mellitus. Exp. Clin. Endocrinol. Diab. 116, 289–292 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 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 Iturrioz, X. et al. (2010) Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J. 24, 1506–1517
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