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Cardiovascular Research Advance Access first published online on May 12, 2008
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Cardiovascular Research, doi:10.1093/cvr/cvn115
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Signalling mechanisms underlying the metabolic and other effects of adipokines on the heart

Morris Karmazyn*, Daniel M. Purdham, Venkatesh Rajapurohitam and Asad Zeidan

Department of Physiology and Pharmacology, University of Western Ontario, Schulich School of Medicine and Dentistry, Medical Sciences Building, London, Ontario, Canada N6A 5C1

* Corresponding author. Tel: +1 519 661 3872; fax: +1 519 661 3827. E-mail address: morris.karmazyn{at}schulich.uwo.ca

Received 26 January 2008; revised 18 April 2008; accepted 5 May 2008

Time for primary review: 20 days


   Abstract
Top
 Abstract
1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
Adipokines represent a family of proteins released by adipocytes that affect various biological processes including metabolism, satiety, inflammation, and cardiovascular function. The first adipokine to be identified is leptin, a product of the obesity gene whose primary function is to act as a satiety factor. However, it is now recognized that leptin and many of the newly discovered adipokines produce effects on numerous organ systems including the heart. Indeed, various adipokines including leptin, adiponectin, and apelin exert potent and diverse cardiovascular effects which are mediated by their specific receptors and involve complex and multifaceted cell-signalling pathways. Among these are effects on the heart as well as blood pressure where leptin has been proposed to potentially contribute to obesity-related hypertension. In this review, we focus primarily on the diverse effects of adipokines on the heart and discuss the potential cell-signalling mechanisms underlying their actions. The potential role of adipokines in the regulation of cardiac metabolism and function is discussed. Discussion is also presented on the emerging role, both deleterious and salutary, of various adipokines in heart disease with an examination of the possible underlying mechanisms which contribute to these effects.

KEYWORDS Leptin; Adiponectin; Apelin; Visfatin; Myocardial metabolism; Heart disease


   1. Introduction
Top
 Abstract
 1. Introduction
2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
The role of white adipose tissue as a source of biologically active products represents a very active area of research. Among the adipocyte-derived products include the cytokines and numerous other compounds possessing diverse biological properties.1 A number of adipokines exert potent cardiovascular effects involving direct actions on target tissues as well as secondary effects occurring as a consequence of central stimulation of the sympathetic nervous system. The identification of adipokines as potent biological molecules has made a major impact on the area of endocrinology as it is now generally recognized that adipocytes represent endocrine organs secreting molecules which modulate a wide array of functions.

The present review centres primarily on adipokines which have been shown to modify cardiac function and concentrates primarily on metabolic aspects of these agents. Although leptin was first identified 14 years ago, it would still be appropriate to refer to it as a novel adipokine in terms of its ability to modify cardiac function, a relatively recently identified phenomenon. Indeed, of the family of adipokines, primary attention regarding their cardiac effects is given to leptin and adiponectin since these compounds have been extensively studied, at least relative to other adipokines in terms of their cardiac effects. Some of the latter such as resistin, apelin, and visfatin are also mentioned in this review although their cardiac effects have been studied to a lesser degree or not at all relative to either leptin or adiponectin.


   2. Leptin
Top
 Abstract
 1. Introduction
 2. Leptin
3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
As noted above, among the adipokines, primary attention has been directed towards leptin, a 16 kDa protein secreted primarily by adipocytes but also produced by many tissues including the heart.2,3 The production of cardiomyocyte-derived leptin is increased by both endothelin-1 and angiotensin II suggesting a paracrine or autocrine role of leptin in the regulation of cardiac functions particularly under pathological conditions.3 Indeed, leptin mediates the prohypertrophic effect of both endothelin-1 and angiotensin II in cultured neonatal rat ventricular myocytes3 although whether this occurs under in vivo conditions is not currently known. The primary cardiac response to leptin in terms of physiological function appears to be a negative inotropic response which has been shown primarily in cardiomyocytes and which is mediated by endogenously produced nitric oxide (NO).4

Circulating total leptin levels are generally positively related with body mass index and the degree of adiposity with plasma levels ranging from 5 to 15 ng/mL in non-obese individuals and greater than 100 ng/mL in very obese subjects.5 Interestingly, circulating leptin exists primarily in the free form in obesity, whereas in lean individuals leptin circulates primarily bound to plasma proteins.5 This difference may be of biological importance since it suggests that, in obesity, substantially greater amounts of leptin are available to exert biological effects. The effects of leptin occur through leptin binding to its receptors, termed OBR, LEPR, or LR, although the former designation will be used in this review for consistency. OBRs are expressed as splice variants classified as short (OBRa, c, d, and f), secreted (OBRe), and long (OBRb) forms with OBRb generally considered as the primary functional isoform linked to full cell-signalling processes.6 These receptors are expressed abundantly in many different cells including cardiomyocytes and intact myocardium.2,3 The intracellular domain of OBRb belongs to the Janus kinase signal transduction and translation system (Jak2/STAT3). Moreover, it has been reported that leptin leads to the activation of various kinases in cardiomyocytes including RhoA/ROCK, ERK1/2, p38 MAPK, phosphoinositide 3-kinase (PI 3-kinase), Akt, and protein kinase C (reviewed by Karmazyn et al.7).

2.1 Leptin and cardiac pathology
Numerous studies have now been reported demonstrating an elevation in plasma leptin concentrations in patients with heart disease and leptin has been proposed as a predictor of poor outcome in patients with coronary heart disease or heart failure (reviewed by Karmazyn et al.7). In terms of experimental studies, one of the predominant observations is the ability of exogenous leptin to induce cardiac hypertrophy under both in vitro and in vivo conditions. The cell-signalling mechanisms underlying these effects appear to be very complex (reviewed by Karmazyn et al.7), although we have recently proposed that a key factor is the activation of the RhoA pathway resulting in alteration of actin dynamics exemplified by a reduction in the G/F actin ratio, the latter indicating increased actin polymerization.8 This phenomenon, which we have recently found to be dependent on the presence of intact caveolae,9 results in the selective translocation of p38 MAPK into nuclei and subsequent transcriptional modification producing the hypertrophic response.9 The nature of the transcriptional factors involved in leptin-induced hypertrophy is not known and requires further studies.

There are still numerous unresolved issues regarding the exact nature of leptin's effects on cardiac pathology. In the acutely ischaemic myocardium, leptin has been shown to exert protective effects against myocardial ischaemic and reperfusion injury possibly via the PI3K/Akt and ERK MAPK pathways.10 Moreover, it is interesting that increased sensitivity to 4 weeks of coronary artery ligation in leptin deficient ob/ob mice as manifested by increased mortality, left ventricular dysfunction, and hypertrophy, can be reversed by exogenous leptin administration through a STAT3 mechanism thereby demonstrating a salutary effect of the peptide.11 It is therefore evident that substantial future work is required in order to better delineate the role of leptin in cardiac pathology. It is possible, and indeed probable, that the nature of leptin's role in the cardiac response to insult may reflect the nature of the insult itself as well as other important issues such as animal species used. It is also possible that issues related to leptin concentration or dose may also strongly affect the nature of leptin-dependent responses. As such, leptin administration to animals may produce different conclusions regarding the role of leptin compared to results obtained by inhibiting the effect of endogenous leptin. The latter approach presents some difficulty at present due to the paucity of pharmacological tools currently available targeting the leptin receptor system. As specific OBR antagonists become commercially and more-readily available, it is anticipated that a much more clear and consistent consensus will emerge concerning the role of endogenous leptin, and indeed other adipokines, in the regulation of cardiac pathophysiology.

In addition to direct actions of leptin on the myocardium, its indirect effects may further contribute to cardiac hypertrophy particularly since leptin has been associated with the development of hypertension likely via sympathetic nervous system activation12 and leptin has been proposed to mediate obesity-related hypertension.13,14 Thus, the hypertensive effect of leptin and the resulting increased afterload should be considered as potentially further contributing to the development of heart disease particularly involving a hypertrophic phenotype.

2.2 Leptin and myocardial metabolism
Emerging evidence suggests that leptin may also be an important modulator of myocardial metabolism. In this review, we will concentrate on the effects of leptin on three aspects of myocardial metabolism including oxidation of fatty acids, glucose uptake, and anti-lipotoxic effects of leptin.

2.2.1 Leptin and fatty acid oxidation
Fatty acid oxidation is the preferred substrate in the healthy heart, accounting for approximately 70% of the ATP generated under normoxic conditions. There is emerging, albeit relatively limited evidence that leptin can modulate fatty acid metabolism in the heart, however discrepant results have been reported regarding the nature of these effects. It has been demonstrated that 1 h treatment with leptin significantly increases fatty acid oxidation in murine HL-1 cells, whereas 24 h exposure to leptin decreased fatty acid oxidation leading to intracellular lipid accumulation, and potential cardiac lipotoxicity.15 The potential enhanced lipotoxicity is interesting, particularly, as discussed below, since others have proposed an antilipotoxic effect of leptin. Of interest, the time course of leptin action was mirrored by the phosphorylation of AMP-activated protein kinase (AMPK) and its substrate acetyl-CoA carboxylase (ACC; a pivotal regulator of fatty acid oxidation), suggesting an important role for AMPK activation in leptin-induced fatty acid oxidation. However, using isolated working rat hearts, Atkinson et al.16 have showed that leptin increased myocardial fatty acid oxidation and triacylglycerol hydrolysis but produced no change in glucose oxidation. The increased fatty acid oxidation was associated with a decrease in cardiac efficiency and an increase in myocardial oxygen consumption. In addition, this study16 also reported that leptin-induced fatty acid oxidation was independent of AMPK/ACC activation, in contrast to the previously alluded-to report15 using the HL-1 cell line. Although the reasons for the differences between the two studies cannot be precisely explained, they may reflect differences between the response of the HL-1 cell line and the isolated working heart to the metabolic effects of leptin. The working heart can be considered as a more physiological model for determining energy metabolism in the intact myocardium compared to the HL-1 cell line and hence the results obtained in the former are likely of greater relevance in terms of understanding the effect of leptin on fatty acid oxidation in the heart and indeed the effect of other adipokines on myocardial metabolism in general.

2.2.2 Leptin and myocardial glucose uptake
Carbohydrates (such as glucose) become the major substrate during anaerobic periods and metabolic stress.17 Accumulating evidence suggests an important role for leptin in glucose homeostasis in different cell types18–21 although whether leptin affects glucose uptake in the heart is not certain. In this regard, leptin has been shown to stimulate glucose uptake in the isolated Langendorff perfused rat heart21 but was found to produce no effect on either basal or insulin-stimulated glucose uptake in the HL-1 cell line15 or, as noted above, in the working rat heart preparation.16 Such diversity of effects related to glucose homeostasis is difficult to explain at present. Further studies are therefore required to precisely determine the effect of leptin on glucose metabolism in the heart, both under physiological and pathophysiological conditions.

2.2.3 Leptin as an antilipotoxic and cardioprotective agent
Lipotoxicity occurs when fatty acid uptake exceeds oxidative capacity of a cell (reviewed by Unger et al.22). Lipid accumulation in cardiac muscle can mediate many detrimental effects on the heart including heart failure in obese individuals and in patients with diabetes mellitus,23 impaired cardiac contractile function,24 apoptosis, and changes in cell-signalling and membrane function (reviewed by Schaffer25). There is emerging evidence that leptin may exert beneficial effects on the myocardium via different mechanisms one of which involves limiting lipotoxicity. For instance, leptin appears to provide a signal that regulates lipotoxicity in peripheral tissues26–28 including the heart (reviewed by Unger29). It has been shown that when mice were fed a high-fat diet leptin plasma concentration increased within 24 h and was associated with a minimal amount of lipid accumulation in the heart suggesting a protective effect of leptin.26 Indeed, rodent models of leptin deficiency demonstrate impaired liporegulation in peripheral organs. Rodents that lack normal leptin action, whether due to a deficiency of leptin secretion (ob/ob) or due to a loss of function mutation of its receptors (db/db; fa/fa), have rapid ectopic deposition of lipids in non-adipose tissues leading to cellular dysfunction.24,28,30 Indeed, impairment in cardiac muscle contraction has been seen in Zucker Diabetic Fatty rats due to increased cardiac uptake of FA and a decrease in fatty acid oxidation.30 Moreover, cardiac contractile dysfunction due to increased lipotoxicity has been seen in obese ob/ob mice.24 While the majority of studies suggest an antilipotoxic effect of leptin, it should be mentioned that others have shown that chronic treatment with leptin increased fatty acid uptake, decreased FA oxidation, leading to lipotoxicity in HL-1 cells.15 As was already referred to previously, studies using HL-1 cells may not precisely reflect events occurring in the intact myocardium.

There is also, as previously mentioned, evidence that leptin exerts a direct cardioprotective effect against ischaemic injury.10 This potential beneficial effect of leptin is of interest since it may contribute to the explanation for the clinically observed phenomenon termed the ‘obesity paradox’ in which a reduction in mortality and morbidity from cardiovascular disease has been observed in patients with elevated body mass index (reviewed in References31–33). The underlying mechanisms responsible for these observations are not known although they may reflect a beneficial effect of leptin as just alluded to. However, a more favourable outcome seen in obese individuals with cardiovascular disease may also be a consequence of increased production of other cardioprotective adopikines, some of which are discussed in greater detail below.


   3. Adiponectin
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
Adiponectin is a 30 kDa protein secreted by adipose tissue which plays a critical role in differentiation of adipocytes. The peptide belongs to the complement 1 family34 and can exist as a monomer or high molecular weight multimers. Adiponectin can function as a full-length protein of 245 amino acids or smaller globular fragment of 137 amino acids. The plasma adiponectin concentration in humans may range from 3 to 30 µg/mL35 and accounts for 0.01% of total plasma protein. Adiponectin expression and subsequent release from adipocytes are stimulated by activation of peroxisome proliferator-activated receptor (PPAR)-{gamma}, a key transcriptional factor involved in adipocyte differentiation.36

Two adiponectin receptors, termed as AdipoR1 (adiponectin receptor 1) having 375 amino acids and AdipoR2 (adiponectin receptor 2) with 311 amino acids, have been identified.37 Structural analysis revealed that these receptors are integral membrane proteins containing conserved seven transmembrane domains with internal N-terminus and external C-terminus.37 Scatchard plot analysis demonstrated that AdipoR1 binds to globular adiponectin whereas AdipoR2 to full-length adiponectin.37 AdipoR1 was shown to be expressed ubiquitously, whereas AdipoR2 expression is more restricted. In heart, AdipoR1 is expressed in substantially greater abundance compared to AdipoR2.37

3.1 Adiponectin and cardiovascular disease
Adiponectin is the most abundant adipokine secreted by adipose tissue and has been suggested to be involved in coupling regulation of insulin sensitivity with energy metabolism. Adiponectin levels are significantly reduced in obese subjects38 and patients with type 2 diabetes.39 The direct role of adiponectin in pathogenesis of cardiac disease still needs to be elucidated; however, it has been observed that increased plasma adiponectin levels are associated with a lower risk of myocardial infarction40 and coronary artery disease41 in men. Adiponectin levels were shown to be reduced significantly in patients with coronary artery disease42,43 as well as in patients with heart failure.44 In addition, an inverse correlation was reported between adiponectin levels and other cardiovascular risk factors such as hyperlipidaemia,35 hypertension,45 and C-reactive protein levels.46 Adiponectin levels may also be a predictor of mortality in patients with chronic heart failure47 and coronary artery disease.48 A recent study showed a particularly strong relationship between elevated plasma adiponectin levels and mortality in patients with heart failure but an association was also present in patients without cardiovascular disease.49 However, an association between plasma adiponectin levels and cardiovascular morbidity or mortality is not uniform as recent studies were unable to demonstrate any relationship between plasma adiponectin levels and the severity of coronary artery disease.50–52 Such discrepant findings clearly support further research into the clinical relevance of adiponectin in cardiovascular disease.

3.2 Adiponectin and experimental cardiac hypertrophy
Adiponectin knock out (ADN-KO) mice subjected to pressure overload by transverse aortic constriction (TAC) demonstrate elevated concentric hypertrophy evidenced by increased left ventricular wall thickness as well as increased mortality after 7 days compared to wild-type animals.53 The adenoviral transfection of adiponectin (Ad-ADN) to ADN-KO mice 3 days prior to subjecting them to TAC attenuated the development of cardiac hypertrophy.53 In obese db/db mice which lack the functional leptin receptor Ad-ADN treatment abolished the TAC-induced increase in interventricular septum and left ventricular posterior wall thickness.53 In the presence of Ad-ADN, angiotensin II-induced cardiac hypertrophy was attenuated in both ADN-KO and wild-type mice.53 These findings suggest that adiponectin overexpression can reverse the cardiac dysfunction induced by various pathological factors. For example, {alpha}-adrenergic receptor stimulation by norepinephrine increased cell surface area and protein synthesis in cardiomyocytes which was attenuated in the presence of adiponectin.53 Thus, adiponectin appears to be an endogenous antihypertrophic agent.

3.3 Cell-signalling underlying adiponectin-mediated cardioprotection
Adiponectin induces effects most likely via a multiplicity of cell-signalling mechanisms. For example, ERK1/2 MAPK activation was increased in ADN-KO mice subjected to TAC compared to wild-type.53 ERK1/2 activation induced by {alpha}-adrenergic agonist in cardiomyocytes was attenuated in presence of adiponectin or MEK inhibitor U0126.53 Taken together, these studies suggest that the protective effect of adiponectin is partly mediated through inhibition of ERK1/2 MAPK.

AMPK modulation may also mediate some of the actions of adiponectin. In ADN-KO hearts AMPK phosphorylation at Thr 172 on {alpha}-subunit was suppressed compared to wild-type hearts.53 Moreover, activation of AMPK has been proposed as a mechanism for the beneficial effects of adiponectin.53 ADN-KO mice exhibit enhanced myocardial remodelling following pressure overload which is associated with reduced AMPK levels.54 Hearts from ADN-KO mice also developed larger infarct area compared to wild-type after subjecting them to ischaemia/reperfusion (IR). In the presence of exogenous adiponectin, both ADN-KO and wild-type hearts had reduced infarct size after IR, an effect associated with AMPK activation and suppression of TNF-{alpha} production in myocardium.55 A role for AMPK has also been demonstrated in a study implicating adiponectin as the underlying factor in mediating cardioprotection in mice subjected to a calorie restricted diet.56

Adiponectin has also been shown to attenuate the increased gp91 protein in cardiac tissue subjected to IR and thus reduced oxidative stress-induced tissue injury.57 Studies on the regulation of NO production from eNOS and iNOS by adiponectin demonstrated that, in the hearts of ADN-KO mice subjected to IR eNOS phosphorylation was decreased and iNOS increased compared to wild-type.57 This may suggest that under physiological conditions adiponectin increases NO production from eNOS which may contribute to its protective effects whereas during cardiac pathology adiponectin inhibits iNOS activation and thus reduces the NO overproduction which can contribute to increased cardiac injury.

Another potential mechanism underlying the cardioprotective effect of adiponectin may involve a stimulation of prostaglandin (PG) synthesis via the inducible cyclooxygenase-2 (COX-2) dependent pathway. In this regard, it was shown that adiponectin stimulates PGE2 synthesis and increases COX-2 expression in neonatal rat ventricular myocytes whereas a COX-2 inhibitor abrogated the infarct size sparing the effect of adiponectin in mice subjected to 30 min coronary artery occlusion followed by 48 h of reperfusion.58


   4. Resistin
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
A relatively new adipokine, resistin (for ‘resistance to insulin’), was first identified in 2001 as a gene target of the insulin-sensitizing drugs thiazolidinediones. Resistin is an adipose derived secreted factor, produced almost exclusively in white adipose tissue. Resistin is a 12 kDa protein that circulates as either a trimer (monomeric form of the peptide hormone) or hexamer (dimeric form of resistin). However, controversy remains as to which form, monomeric or dimeric, is responsible for the physiologic properties of the peptide.1 The monomeric form was shown to impair hepatic insulin action more potently than the dimerized form.59 In contrast, the dimerized form of resistin was shown to be more effective in antagonizing insulin-stimulated glucose uptake in adult murine cardiomyocytes.60 Interestingly, the notion of differential regulation of hormone signalling based on oligerimization state is shared by another adipokine, adiponectin.61,62

4.1 Resistin and cardiovascular disease
Emerging evidence suggests that cardiovascular disease is accompanied by changes in resistin levels, for example, in women, plasma resistin levels are elevated in patients with coronary heart disease.63 What role resistin plays in the disease process is not known although in patients with atherothrombotic strokes, plasma resistin levels are associated with elevated risk of 5-year mortality.64 Serum resistin concentrations have also been shown to be elevated in patients with heart failure with levels positively related to the severity of heart failure according to New York Heart Association functional classification.65 Although these studies do not indicate cause and effect relationships, nonetheless increasing plasma resistin concentrations appear to be a predictor of poor prognosis in patients with cardiovascular disease.

4.2 Experimental studies on cardiac actions of resistin
Although resistin cell receptors have yet to be identified, direct action of resistin in the heart and specifically on cardiomyocytes has been described. Mouse adult cardiomyocytes treated with resistin show a reduction in insulin-stimulated glucose uptake.60 Furthermore, in contrast to liver, cardiomyocyte resistin signalling requires oligomerization of the ligand prior to receptor binding.60 The precise mechanisms by which resistin exerts its effects on glucose transport is not completely understood but this appears to occur by impeding vesicular transport.60

The potential role of resistin in cardiac pathobiology has not been extensively studied although it is interesting that mechanical stretch of neonatal rat cardiomyocytes induced resistin gene and protein expression, via TNF-{alpha}-dependent ERK activation.66 This finding would indicate that resistin is a response gene to hypertrophic stimuli although whether resistin plays a role in the hypertrophic response is currently not known. Further studies would also be important to determine if resistin expression is altered by classical G-protein-coupled hormonal hypertrophic stimuli such as phenylephrine, endothelin-1, or angiotensin II.

Studies have also been carried out to assess the effect of resistin on the ischaemic and reperfused heart with contradictory results. In one report, resistin depressed functional recovery from ischaemia in isolated perfused rat hearts, an effect which appeared to be dependent on NF-{kappa}B activity.67 In contrast, resistin reduced infarct size in mice subjected to coronary artery occlusion and reperfusion.68 These authors also demonstrated that resistin improved functional recovery of isolated mouse hearts and reduced infarct size and proposed that the salutary effect of resistin occurs via a PI3K/Akt/PKC pathway.68 The obvious discrepancy between the two studies is difficult to explain at present but may reflect different concentrations of resistin, differences in experimental model or species diversity.


   5. Apelin
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
Apelin is an adipokine which was found to be the endogenous ligand for the G protein-coupled APJ receptor. Apelin has been shown to exert potent positive inotropic effects on both normal and failing myocardium.69–73 These effects likely occur through multifaceted cell-signalling mechanisms which involve multiple kinases including protein kinases C as well as Na-H exchange activity.69 The exact nature of these intracellular messengers especially how they contribute to the effects of apelin is uncertain but activation of Na-H exchange activity is likely of importance in mediating the ability of apelin to increase myofilamental sensitivity to calcium thus producing a positive inotropic response.69

5.1 Apelin and heart disease
Apelin's role in heart disease is not well established. In experimental heart failure models, myocardial apelin expression has been reported to be decreased (Dahl sensitive rat)74 or increased (ischaemic heart failure)75 whereas plasma apelin levels are decreased in patients with heart failure.76,77 Interestingly, but adding to the complexity, myocardial unloading in patients with heart failure with the use of a left ventricular assist device results in the upregulation of left ventricular apelin expression.78 Thus, it appears the apelin response in heart failure is multifaceted and complex.

Overall, from experimental studies apelin appears to exert beneficial effects. For example, apelin has been shown to exert cardioprotective effects as demonstrated against both ischaemia and reperfusion injury as well isoproterenol-induced cardiotoxicity.79,80 The mechanisms for the cardioprotective effects of apelin are not known although pharmacological inhibitors of PI3K/Akt or P70S6 kinase were found to produce no effect on apelin-induced cardioprotection.79 Animal knockout mice demonstrate enhanced cardiac dysfunction and enhanced myocardial remodelling in aging and in response to pressure overload, thus suggesting an important role for endogenous apelin in regulating cardiac function in response to insult.81


   6. Visfatin
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 
Visfatin is an adipokine which exerts insulin-like effects by binding to the insulin receptor thus exerting a hypoglycemic effect.82 At present cardiac actions of visfatin are not known nor its role if any in heart disease. Adipose tissue visfatin levels, along with various other adipokines including leptin, were found to be elevated in patients with coronary artery disease although adiponectin levels were reduced.83 In that study, the effect was greater in abdominal adipose tissues suggesting that changes in abdominal adiposity and the resultant influence on adipokine production exert a relatively greater influence on the aetiology of coronary artery disease.


   7. Other novel adipokines
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
8. Summary, conclusions, and...
 Funding
 References
 
A large number of other adipocyte-derived factors have also been recently identified, among these including vaspin, omentin, and chemerin; however, these have as yet not been studied in terms of their ability to modulate cardiac function in either health or disease.


   8. Summary, conclusions, and future directions
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
Funding
 References
 
The discovery of leptin nearly 15 years ago heralded a new era in research as it was eventually demonstrated that this adipocyte-derived peptide not only regulates energy production but exerts peripheral effects on a large number of tissues including the heart. Since the initial identification of leptin, numerous adipocyte-derived peptides have been discovered which have been assigned the collective name of adipokines. It is now clear that adipokines exert a myriad of effects on diverse organs, including the heart, as is summarized in Figure 1. The importance of adipokines to cardiac function in either physiology or pathology is still emerging and studies addressing this question represent an exciting area of research not only with respect to obesity, since adipokine production is generally related to adiposity, but also with respect to the central issue of the potential role of adipose tissue as an endocrine organ regulating cardiac function in health and disease. Of the adipokines currently identified, our primary understanding as related to cardiac actions and cellular mechanisms underlying these effects relate primarily to leptin and adiponectin. These adipokines appear to exert opposite effects and an emerging concept is that a leptin/adiponectin ratio may influence the predisposition to heart disease, at least with respect to myocardial remodelling and heart failure. There are numerous challenges facing investigators in this field. Important among these is the fundamental question of precisely how leptin, adiponectin, and other adipokines affect cardiac pathology. This task will undoubtedly be facilitated and expedited with the eventual development of new pharmacological tools targeting specific adipokine systems.


Figure 1
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  		Figure 1 Summary depicting the multiplicity of cell-signalling responses to adipokines and their cardiac effects. See text for discussion.

 
A second major challenge is to understand how the various adipokines interact with each other since numerous adipokines with diverse biological properties can be released simultaneously and, as such, the net effect of increased adipokine production may not reflect the actions of a single individual substance. This remains a challenge for future investigations which are important not only to fully understand the role of adipokines in cardiac regulation but in terms of potential for the development of novel cardiac therapeutic targets.


   Funding
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
References
 
Studies from the authors' laboratory were supported by the Canadian Institutes of Health Research.


   Acknowledgements
 
D. Purdham was a recipient of a Heart and Stroke Foundation of Canada Doctoral Scholarship. M. Karmazyn holds a Canada Research Chair in Experimental Cardiology.

Conflict of interest: none declared.


   References
Top
 Abstract
 1. Introduction
 2. Leptin
 3. Adiponectin
 4. Resistin
 5. Apelin
 6. Visfatin
 7. Other novel adipokines
 8. Summary, conclusions, and...
 Funding
 References
 

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  3. Rajapurohitam V, Javadov S, Purdham DM, Kirshenbaum LA, Karmazyn M. An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. J Mol Cell Cardiol (2006) 41:265–274.[CrossRef][Web of Science][Medline]
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