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This Review is part of a thematic series on the Pathobiology of Obesity, which includes the following articles:

Adipose-Derived Stem Cells for Regenerative Medicine

Cardiac Energy Metabolism in Obesity

Leptin Signaling and Obesity: Cardiovascular Consequences

Lipid Disorders and the Metabolic Syndrome

Adiponectin As a Cardiovascular Protectant

Gary Lopaschuk, Guest Editor

Leptin Signaling and Obesity

Cardiovascular ConsequencesRonghua Yang, Lili A. Barouch

Abstract—Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ

systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal

transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of

leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its

contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism,

hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current

understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease. (Circ

Res. 2007;101:545-559.)

Key Words: leptin obesity cardiovascular disease

Over 60% of people in the United States are overweight orobese. Extensive evidence now supports the notion thatmaladaptation of the biological system for weight mainte-

nance makes it extremely difficult for people to maintain

weight loss.1 Several genes have been identified to disclose a

physiological system that maintains body weight within a

range of about twenty pounds.2 A key element of this system

is leptin, the 16-kDa hormonal product of the obesity ( ob)

gene.3 Leptin is primarily secreted by adipocytes and is a

classic member of the more than 50 identified adipocytokinesthat participate in adipose tissue hormonal signaling.4

Since its identification in 1994, leptin has attracted much

attention as one of the most important central and peripheral

signals for the maintenance of energy homeostasis.5–8 For

example, a 9-year-old girl with extreme obesity was found to

lack leptin.9 Leptin treatment reduced her weight to the

normal range for her age, and the same effects were observed

in her similarly affected cousin.10 Plasma leptin is generally

proportional to adipose mass.11,12 The primary physiological

role of leptin is to communicate to the central nervous system

(CNS) the abundance of available energy stores and to

restrain food intake and induce energy expenditure. The

absence of leptin therefore leads to increased appetite and

food intake that result in morbid obesity. Notably, only rare

cases of severe early childhood obesity have been associated

with leptin deficiency.9,13

The remainder of the obese popu-lation typically have elevated leptin levels.14 The failure of

leptin to induce weight loss in these cases is thought to be the

result of leptin resistance.

Hyperleptinemia, nearly universally observed in human

obesity and animal models, is accompanied by a disruption of

the usual activities of the hormone, possibly at different

Original received May 22, 2007; revision received July 20, 2007; accepted August 6, 2007.From the Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md.This manuscript was sent to Richard A. Walsh, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Correspondence to Lili A. Barouch, MD, Johns Hopkins University, 720 Rutland Ave, Ross 1050, Baltimore, MD 21205. E-mail [email protected]

© 2007 American Heart Association, Inc.Circulation Research is available at http:// circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.107.156596

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stages in the circulatory transport and/or in the signaling

cascade. Disruption of leptin signaling in the hypothalamus

results in obesity and confirms the central role of this

hormone in the maintenance of energy balance.7,15,16 Emerg-

ing evidence suggests that leptin resistance in the CNS may

be selective, namely that the effects of leptin on central

metabolic processes is disrupted, whereas its other effects,such as the sympathetic activation of blood pressure, is still

retained.17 In addition to its actions in the CNS, leptin

receptors (Ob-Rs) are found in multiple peripheral tissue

types and affect many systemic processes, such as reproduc-

tion, immunity, and cardiovascular functions.18–20

Obesity is also a part of the metabolic syndrome, which is

diagnosed by a set of criteria that include abdominal obesity,

insulin resistance, dyslipidemia, and hypertension. This pa-

tient population faces increased risk for type 2 diabetes and

cardiovascular diseases. The widely distributed Ob-Rs make

the hormone an attractive candidate for a molecular link in the

pathogenesis of obesity-related diseases. Although disruption

of leptin signaling can lead to altered phenotypic expressionand function of peripheral organs, the relative contributions

of central versus peripheral signal disruption are still contro-

versial. Increasing our understanding of how leptin and/or

leptin resistance affects the heart and vasculature will be

important for gaining comprehension of obesity-related

threats to cardiovascular health.

Leptin Signaling

Leptin and Leptin ReceptorLeptin is primarily secreted by adipocytes and circulates at a

level of 5 to 15 ng/mL in lean subjects.21 Its expression is

increased by overfeeding, insulin, glucocorticoids, endotoxin,and cytokines and is decreased by fasting, testosterone,

thyroid hormone, and exposure to cold temperature.22,23 In the

heart, increased leptin expression is seen following reperfu-

sion after ischemia,24,25 and leptin concentration in cardio-

myocyte culture serum is increased with endothelin (ET)-1

and angiotensin (Ang) II treatment,26 suggesting the heart as

a site of leptin production.

Six isoforms of the Ob-R (a to f) have been identified in themurine model, and they are closely related to the class I

cytokine receptor family. Ob-Ra and Ob-Rb represent the

dominant isoforms in the heart, whereas the others are

expressed at low levels27 and are not well conserved among

species.28,29 Ob-Re is the secreted form that binds circulating

leptin and regulates the concentration of free leptin.30

Janus-Activated Kinase/Signal Transducers andActivators of TranscriptionOb-Rs have been shown to activate Janus-activated kinase

(JAK), signal transducers and activators of transcription

(STAT), insulin receptor substrate, and the mitogen-activated

protein kinase (MAPK) pathways. The best-characterizedpathway in leptin signaling is the JAK/STAT pathway (Fig-

ure 1).31 Ligand binding causes Ob-R to undergo homooli-

gomerization32,33 and to bind to JAK, primarily JAK2.34 In

the case of overexpression of JAKs by transient transfection,

weak Ob-Rb/JAK1 and Ob-Ra/JAK2 association was ob-

served with leptin treatment.35 However, only Ob-Rb con-

tains the STAT-binding site.35

Studies in vivo have demonstrated that signaling occurs

mainly through STAT3.16 Ob-Rb binding to JAK2 leads to

JAK2 autophosphorylation and the phosphorylation of

Tyr985, Tyr1077, and Tyr1138 on Ob-Rb.32,34,36–38 Phos-

phorylation of Tyr1138 recruits STAT proteins to the Ob-Rb/ JAK2 complex. Tyrosine phosphorylated STAT3 molecules

Figure 1. Leptin receptor signaling. The binding of leptin to its receptor leads to formation of the Ob-R/JAK2 complex that results incross-phosphorylation. Tyr1138 on Ob-Rb is crucial for STAT3 activation, which stimulates SOCS3 expression that negatively inhibitsleptin signaling via Tyr985 and additional sites on JAK2. Protein tyrosine phosphatase 1B (PTP1B) is also capable of inhibition of leptinsignaling. JAK2 phosphorylation can lead to activation of MAPK and insulin receptor substrate/PI3K signaling pathways. See text.GRB2 indicates growth factor receptor–bound protein 2.

546 Circulation Research September 14, 2007


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Increasing evidence suggests that leptin signaling is prefer-

entially reduced in the arcuate nucleus of the hypothalamus

but not in other regions, such as the ventromedial, dorsome-dial, and/or premammillary nucleus of the hypothalamus that

also express Ob-Rs.68

Leptin Increases Sympathetic OutflowIn addition to reducing appetite and controlling weight gain,

leptin centrally activates the sympathetic nervous system. It

significantly increases plasma norepinephrine and epineph-

rine concentrations via the ventromedial hypothalamus.69

Whereas chronic leptin overstimulation in the hypothalamus

decreases the ability of leptin to regulate appetite, its sympa-

thetic excitatory effects are maintained as increased arterial

pressure and renal sympathetic nerve activity are presented in

obesity (Figure 2).70 This observation suggests that centralleptin resistance is selective.

The concept of selective resistance is suggested by a

comparison between ob/ob and Agouti yellow obese mice.

Lower arterial pressure is observed in ob/ob mice, which is

increased by leptin reconstitution despite the accompanying

weight loss.71 In contrast, Agouti yellow obese mice develop

obesity resulting from ubiquitous overexpression of agouti

protein, which blocks MC4R rather than directly affecting

leptin. They have elevated arterial pressure similarly to DIO

mice, despite the fact that they have milder obesity than ob/ob

mice.71,72 This preservation of sympathoactivation effects of

leptin despite disruption of its weight control effects has beenconfirmed in DIO mice, which is considered a more physio-

logic model of human obesity. In C57BL/6J mice fed a

10-week high-fat diet, intraperitoneal leptin administration

failed to decrease appetite and body weight, but increasedrenal sympathetic nerve activity. Sympathetic nerve activity

in brown adipose tissue and in hindlimb did not increase on

leptin administration, indicating region-specific preservation

of leptin sympathoactivation that serves to protect its circu-

latory effects.73

The sympathoactivation effect is completely abolished by

selective destruction of the arcuate nucleus.74 As the arcuate

nucleus is required for both metabolic and sympathetic

effects of leptin, these results seem to suggest that leptin

resistance occurs mainly through intracellular signaling dis-

ruption. Under resting conditions, it is estimated that only 5%

to 25% of Ob-R isoforms are located at the cell surface.75 The

ligand–receptor complex internalizes, and studies have shownthat leptin internalization was greater for the Ob-Rb iso-

form.75,76 Preferential downregulation of Ob-Rb in response

to prolonged leptin exposure may be important in regulating

different tissue sensitivity to leptin and another cause for

selective leptin resistance.

Leptin stimulation of adrenergic overdrive can lead to

numerous adverse effects on the cardiovascular system. Both

in vitro and in vivo studies have demonstrated adrenergic

influences on the growth of cardiomyocytes.77,78 Patients with

the metabolic syndrome have increased sympathetic activity,

hypertension, and higher occurrences of left ventricular

hypertrophy (LVH).79,80

Sympathetic influences also modu-lates the elastic properties of large and medium-size arteries

Figure 2. Systemic leptin function. Chronic hyperleptinemia impairs the centrally mediated metabolic actions of the hormone, alyhoughits activation of sympathetic outflow is preserved. Selective central leptin resistance results in obesity and adverse effects on the car-diovascular system including hypertension, atherosclerosis, and LVH. Although leptin can protect against ectopic lipid deposition innonadipose tissue, whether this effect is abolished because of (selective) peripheral leptin resistance requires further examination.




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Leptin Attenuates Cardiomyocyte Contractility

Possible Mechanisms Leading to Increased NO ProductionSimilar to its effects in endothelial cells, acute leptin infusion

in isolated rat ventricular myocytes increases NO activity,

which leads to attenuated cardiac contractility (Figure 3).108

Intracellular Ca2 transients were lowered and NO production

were increased with leptin. These effects were blocked by the

NO inhibitor N G-nitro-L-arginine methyl ester108 and by JAK2

or p38 MAPK inhibitors AG-490 and SB203580.109

The intermediate steps by which leptin signaling leads to

increase in NO production and the specific NOS isoforms that

mediate the effects of leptin have not been fully elucidated. In

rat VSMCs, leptin inhibits the contractile response induced

by Ang II through increased NO production. The upregula-

tion of inducible NO synthase through mechanisms involving

JAK2/STAT3 and PI3K/Akt pathways is responsible for the

increase of NO bioavailability in VSMCs.110

Elucidation of the NOS isoform(s) responsible for the

actions of leptin in the heart would lead to a better under-

standing of its role in myocardial contractility and hypertro-

phy responses. We have shown that spatial confinement of

different constitutive NOS isoforms within separate subcel-

lular compartments of the cardiac myocyte allows NO signals

to have independent, and even opposite, effects on cardiacphenotype and contractile response.111 Overexpression of

eNOS inhibits hypertrophy in the remote myocardium and

preserved cardiac function after myocardial infarction, pos-

sibly through attenuation of -adrenergic–stimulated com-

pensatory hypertrophy.112 Neuronal NO synthase and eNOS

independently contribute to the development of cardiac hy-

pertrophy, leading to marked age-related concentric hyper-

trophic remodeling in double-knockout mice lacking both

neuronal NO synthase and eNOS.113,114 Understanding the

leptin crosstalk with the -adrenergic signaling system in

cardiomyocytes would provide significant insight into the

understanding of myocardial dysfunction in obesity.

Whereas leptin-induced NO increase directly depresses

cardiomyocyte contractility, systemic actions such as in-creased sympathetic modulation may indirectly stimulate

contractility. Just as leptin-stimulated NO production in

endothelial cells may have a negligible role in blood pressure

in vivo, cardiac contractile depression may not manifest

under normal physiologic conditions. However, the depres-

sant effect may become important when considered in con-

juncture with alterations occurring in obese states.

Leptin Deficiency Leads to Decreased Responsiveness to-Adrenergic StimulationIn 10 week-old ob/ob isolated myocytes, attenuated sarco-

mere shortening and calcium transients and depressed sarco-

plasmic reticulum Ca2

stores were seen in response toisoproterenol stimulation of the -adrenergic receptor or to

Figure 3. Leptin and myocardial contractility. Leptin directly depresses cardiomyocyte contractility. The signaling pathways implicatedin this process include the NO-cGMP pathway and pathways that lead to increased ROS production. Changes that occur in a chronicleptin-deficient state are also illustrated. TG indicates triacylglycerol; iNOS, inducible NO synthase; nNOS, neuronal NO synthase; AC,adenylate cyclase; PKA, protein kinase A; XOR, xanthine oxidoreductase; SR, sarcoplasmic reticulum.




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post–receptor level stimulation with forskolin and dibutyryl–

cAMP. Leptin replenishment in ob/ob mice restored each of

these abnormalities toward normal without affecting gross

(wall thickness) or microscopic (cell size) measures of

cardiac architecture. Decreased Gs (52 kDa), increased

sarcoplasmic reticulum Ca2-ATPase, and depressed phos-

phorylated phospholamban abundance were detected in ob/ob

mice. In addition, protein kinase A activity in ob/ob mice was

depressed at baseline and corrected toward wild-type (WT)

level with leptin repletion.46 In the H9c2 cardiac cell line,

30-minute leptin treatment increased basal and catechol-

amine-stimulated adenylate cyclase activity, whereas 18-hour

treatment was associated with a reduced adenylate cyclase

activity and a different responsiveness to isoproterenol and

norepinephrine stimulation, likely attributable to differential

activation of Gs. Adenylate cyclase, Gs (52 kDa), Gi,

p21-ras, and phosphorylated ERK1/2 expressions were in-

creased with short-term leptin treatment and decreased at 18

hours, whereas Gs (45 kDa) continued to increase at 18

hours. Receptor level leptin resistance is conceivable inmyocytes, as Ob-R expression is seen to decrease at 18-hour

leptin treatment.115 Taken together, leptin deficiency or resis-

tance leads to decreased -adrenergic response, whereas

moderate leptin stimulation can improve the contractile

response.

Mechanisms Involving ROSMitochondrial formation of ROS is enhanced in obesity.

Xanthine oxidoreductase and nicotinamide adenine dinucle-

otide phosphate (NADPH) oxidase are 2 main sources of

superoxide (O2. ) production in the heart. O2

. is capable of

generating a large family of ROS by interacting with other

molecular compounds. In ob/ob hearts, impaired cardiaccontractile function is accompanied by elevated oxidative

stress, lipid peroxidation, protein carbonyl formation, redis-

tribution of myosin heavy chain isozymes from myosin heavy

chain- to -, and oxidative modification of SERCA2a.116

Neuronal NO synthase constrains xanthine oxidoreductase

activity.117,118 Reduced neuronal NO synthase expression is

observed in 2- to 6-month-old ob/ob mice, which leads to

increased xanthine oxidoreductase production of O2. , thereby

causing an imbalance between the production of ROS and

reactive nitrogen species.119 This nitroso–redox imbalance

may be partially responsible for the myocardial dysfunction

seen in ob/ob mice. Activation of NADPH oxidase is also

seen in the ob/ob heart.116 Treatment with apocynin, a

NADPH oxidase inhibitor, reversed cardiac contractile dys-

function in ob/ob myocytes but failed to reserve SERCA2a

oxidative modification.116 8-Bromo-cGMP, a membrane-

permeable cGMP analog, induced a greater negative effect in

ob/ob than lean C57BL/6J mice. However, the effect of

adding a NO donor was similar in the obese and lean models,

indicating that some cGMP-independent effect of NO pre-

vents the enhanced negative cGMP effects in ob/ob cardio-

myocytes.120 NAPDH-mediated reduction in NO bioavail-

ability could explain the failure of NO donor to elicit further

negative inotropic response in obese models.121,122 Addition-

ally, the interaction between NO and ROS produces per-oxynitrite, which can nitrosylate proteins and exert positive

inotropic effects, thereby offsetting the cGMP-dependent

reduction in contractility.120 Peroxynitrite has shown both

negative and positive inotropy in isolated cardiomyo-

cytes,123,124 although it is generally accepted to trigger apo-

ptosis in cardiomyocytes in vitro and in vivo, possibly

through a pathway involving caspase-3 activation and the

cleavage of poly(ADP-ribose) polymerase.125

Another recent study proposes that ET-1 is upstream of

NADPH oxidase in leptin-induced myocardial contractile

response.126 There are at least 2 cardiac ET-1 receptors, ETAand ETB. Both are known to mediate cardiomyocyte inotropic

response, and ETA receptors also affect hypertrophy.127 Lep-

tin administration to rat neonatal cardiomyocytes induced

intracellular O2. generation and upregulated protein expres-

sion of p67 phox and p47 phox subunits of NAPDH, the effect

of which is attenuated by ETA and ETB receptor antagonists

and apocynin, suggesting that the ET-1 receptors are likely

upstream of NADPH oxidase in leptin-induced cardiac con-

tractile response.126

Additional Mechanisms Affecting ContractilityObesity is a lipotoxic disease featuring overtly elevated

ceramide levels (see section below, Leptin Shifts Myocardial

Metabolism Toward Fatty Acid Utilization). The de novo

ceramide pathway has been postulated to be key to the

lipoapoptosis of pancreatic cells and cardiomyocytes in

obese individuals.128,129 The ability of ceramide to amplify

leptin-induced depression of contractility in adult rat left

ventricular myocytes was recently demonstrated.130 Although

ceramide alone did not elicit any effect on cell mechanics and

intracellular Ca2 transients, it sensitized leptin-induced ef-

fects on myocyte shortening and intracellular Ca2 transients.

In vivo obese concentrations of plasma leptin lie in the lownanomolar range, which is seemingly disconnected from the

high in vitro leptin concentration (10 nmol/L) needed to

affect cardiac contractile function. The observation that

ceramide may augment the cardiac depressive effect of leptin

provides an additional explanation for hyperleptinemia-

associated cardiac dysfunction in obesity.

Elevated adipose mass in obesity also increases the secre-

tion of other proinflammatory factors, including TNF-, IL-6,

and Ang II. TNF- and leptin both depress contractility in

adult rat ventricular myocytes, although no additive response

by the 2 proinflammatory factors was observed. Inhibitory

effects were abolished by N G-monomethyl-L-arginine in both

cases and in the case of combined exposure.131 Thus, the

inhibitory effect on cardiac contraction by TNF- and leptin

may mask each other and share a common mechanism

dependent on NO.131

It is interesting, however, that hypertension seems to

attenuate leptin-induced cardiomyocyte contractile depres-

sion. Isolated rat ventricular myocytes from spontaneously

hypertensive rats (SHR) displayed decreased leptin-induced

depression of myocyte shortening and intracellular Ca2

transients, as well as blunted leptin-induced NOS activity

compared with the normotensive control mice. Additionally,

treatment of SHR myocytes with JAK or p38 inhibitor led to

further inhibition of myocyte shortening by leptin instead of abolishing such effects.109 The altered signal transduction of

Yang and Barouch Leptin Signaling and Obesity 551



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Cardiomyocyte HypertrophyLeptin-induced neonatal cardiomyocyte hypertrophy occurs

through a mechanism involving ET-1 and ROS generation.146

ET-1 has been shown to increase cardiomyocyte surface area

without increasing cell proliferation.148 In this study, blocking

the ETA receptor with the selective inhibitor ABT-627 par-

tially but significantly reduced leptin-induced hypertrophy.146

An interdependence of ET-1 and leptin signaling has been

proposed in the progression of myocardial dysfunction and

hypertrophy, suggesting that leptin may cause chronic oxida-

tive stress and inflammation in the myocardium, similar to

other agents such as TNF-, norepinephrine, and Ang II, all

of which induce hypertrophy via ROS upregulation.149,150

Leptin may indeed have an autocrine role in mediating

ET-1 and Ang II–induced cardiomyocyte hypertrophy. Treat-

ment of neonatal rat myocytes for 24 hours with leptin, Ang

II, or ET-1 significantly increased cell area by 37%, 36%, and

35%, respectively. In contrast to the study mentioned above

by Xu et al,146 Rajapurohitam et al26 have shown that

blocking the ETA receptor did not prevent leptin-inducedhypertrophy, neither did blocking the Ang receptor. Leptin

blockade attenuated the hypertrophic responses generated by

all 3 agents. Ang II and ET-1 significantly increased leptin

levels in the culture medium and increased the gene expres-

sion of both Ob-Ra and Ob-Rb. Additionally, Ang II and

ET-1 increased phosphorylation of ERK1/2, p38, JNK, and

nuclear factor B, but the ability of leptin blockade to

attenuate hypertrophic responses was generally dissociated

from these effects.26 The discrepancy between the studies by

Xu et al and Rajapurohitam et al in terms of blocking

leptin-induced hypertrophic response with ETA receptors

antagonists (ABT-627 versus BQ123) cautions against the

interpretation of results using pharmacological agents, as the

precise mechanisms of action is unclear in many cases.

Another study demonstrates that in 9-week-old mice fed a

high-fat diet, serum and myocardial ET-1, myocardial leptin,

and Ob-R mRNA are all elevated, whereas in ob/ob mice,

both serum and myocardial ET-1 levels are not higher than

WT mice, confirming a direct role of leptin in mediating

increased myocardial ET-1 signaling.151 Simvastatin, a cho-

lesterol-lowering drug decreases leptin-induced ROS-

mediated hypertrophy in rat neonatal cardiomyocytes.152

ApoptosisOne of the causes of HF is cardiomyocyte apoptosis and

necrosis.153 We recently found that leptin deficiency or

resistance results in increased cardiomyocyte apoptosis, as

assessed by TUNEL staining and caspase-3 levels.154 Aged

ob/ob and db/db mice showed increased DNA damage

compared with old WT mice. Leptin reconstitution ob/ob

animals reduced the rate of apoptosis, although not to WT

levels.154 This is consistent with earlier work demonstrating

increased apoptosis in islet cells and cardiomyocytes in fa/fa

rats.129,155 These results suggest that leptin signaling is

necessary to maintain normal low levels of cell death

and that leptin provides protection against lipotoxicity-

induced apoptosis.

On the other hand, JAK2 has been suggested as a mediatorof the apoptotic response in cardiomyocytes.156 It is promi-

nently involved in the upregulation of the renin–Ang system,

and Ang II–treated adult rat cardiomyocytes in culture exhibit

increased apoptosis. The somewhat paradoxical combination

of antiapoptotic roles of leptin and proapoptotic actions of

JAK2 merits further investigation. Leptin acutely increases

phosphorylation of ERK1/2 and p38 MAPK in rat neonatal

cardiomyocytes, but leptin-induced p38 activation in rat

neonatal cardiomyocytes sustains for a longer period than

ERK1/2 activation, suggesting that the downstream transcrip-

tion factors of p38 may be involved in the long-term

maladaptive cardiac remodeling in obese HF patients.48

Mitosis and ProliferationLeptin treatment at a level similar to plasma concentration in

obese individuals increased proliferation of both HL-1 car-

diac muscle cells and human pediatric ventricular myocytes.43

The proliferation was accompanied by increased DNA syn-

thesis associated with increased ERK1/2 phosphorylation and

increased association of the p85 regulatory subunit of PI3K

with phosphotyrosine immunoprecipitates.43 ERK1/2 inhibi-

tion significantly attenuated the leptin-induced proliferativeactivity and DNA replication in HL-1 and pediatric human

cardiomyocytes43 but failed to decrease [3H]-leucine incorpo-

ration in neonatal rat cardiomyocytes treated with leptin.48

Other pathways likely involved in leptin-induced hypertro-

phy include the activation of adenylate cyclase,115 peroxi-

some proliferator-activated receptor-,157 and the JAK/STAT

pathway associated with hsp56 and Ang II.109,158 Leptin

signaling is capable of activating other traditional pathways

for the development of hypertrophy, such as PI3K and protein

kinase C.159 Whether these pathways are activated in cardio-

myocytes in response to leptin and the specific isoforms

involved mandate further research.

Extracellular Matrix RemodelingLeptin has been shown to increase the expression of matrix

metalloproteinase-2, and to increase collagen type III and IV

mRNA and decrease collagen type I mRNA without affecting

total collagen synthesis in human pediatric cardiomyo-

cytes.160 This suggests that leptin selectively regulates differ-

ent forms of collagen although further studies are required to

validate the regulation of collagen synthesis by leptin and to

confirm these effects on cardiac remodeling in obesity.

Protection in Ischemia/Reperfusion InjuryTimely reperfusion is necessary to salvage myocardium from

acute infarction, but reperfusion usually induces additional

injury. A recent report shows that exogenous leptin given at

early reperfusion in an isolated mouse heart model reduces

infarct size.24 This cardioprotective action of leptin is asso-

ciated with activation of the reperfusion injury salvage kinase

pathway that includes PI3K/Akt and ERK1/2, ultimately

leading to the inhibition of mitochondrial permeability tran-

sition pore opening.161 Infarct size in C57BL/6J mouse hearts

perfused with leptin was about half that of hearts perfused

without leptin. In a rat model, leptin and Ob-Ra expressions

were locally upregulated in scarred tissue following reperfu-

sion, whereas Ob-Rb expression was downregulated.24 PI3K

or ERK1/2 inhibition diminished the cardioprotective ef-fect.24 Interestingly, leptin did not increase phosphorylation




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of Akt or its downstream targets such as eNOS. Additionally,

there was increased phosphorylation of p38 MAPK and

reduced abundance and phosphorylation of STAT3 and

AMPK.24 Leptin-stimulated ROS production and NO synthe-

sis has been shown also to protect against ischemia reperfu-

sion injury in the gut and kidney.162,163 Clinically, it is

interesting to note that patients with a higher body mass index

have better outcomes following an acute coronary syndrome

or percutaneous coronary intervention.164,165

Leptin Resistance in theCardiovascular System?

The relative contributions of central and peripheral leptin

effects to disease pathogenesis are difficult to decipher.

Central leptin resistance disrupts hypothalamic control of

energy homeostasis, which results in obesity and increased

lipid production. This in turn may lead to ectopic lipid

deposition and lipotoxicity in peripheral organs. The attempt

to separate the effects of this pathological process from the

physiological effects of leptin in the cardiovascular systemhas proven to be challenging, complicated by different

isoform signaling capabilities and possible resistance in the

periphery. The question remains whether peripheral leptin

resistance occurs in the myocardium itself in obesity. Even

though chronic leptin stimulation has been seen to decrease

Ob-R expression in various studies,75,115 DIO mice show

increased Ob-R mRNA expression.151 On the other hand,

Ob-Rb expression in ob/ob left ventricular homogenate is

lower than WT.126 However, mRNA expression does not

necessarily correlate with receptor density at the membrane;

therefore, these results are not conclusive in determining

whether leptin resistance can occur at the myocyte receptorlevel. One recent study suggests that leptin resistance does

not occur in the myocardium in a model of early central

resistance. Eight-week DIO C57BL/6 mice showed attenu-

ated leptin phosphorylation of STAT3 in hypothalamic tissue,

whereas no such attenuation was shown in whole-heart

homogenate.136

Paradoxical results have been reported in almost all leptin-

related effects on the myocardium; that is, excessive exoge-

nous leptin and leptin deficiency often lead to the same end.

Whether these effects occur through entirely different mech-

anisms, are mediated through differential regulation of Ob-R

isoforms, or are attributable to peripheral resistance requires

further investigation. If peripheral myocardial resistance doesoccur, these differences could be resolved if we consider

leptin deficiency and leptin resistance both to be states of

dysfunctional downstream signaling.

Interestingly, obesity-induced leptin resistance, although

not reported in the myocardium, has been shown to extend to

affect platelets and the vascular wall.166 Obese concentrations

of leptin significantly attenuate coronary vasodilation to

intracoronarily administered acetylcholine and significantly

attenuate relaxation in left circumflex coronary rings in

control dogs. These effects were not seen when the same

concentrations of leptin were administered to dogs fed a

high-fat diet, suggesting that leptin resistance does occur inthe vasculature. This resistance is not attributable to altered

coronary dilation, increased endothelium-derived hyperpolar-

izing factor, nor changes in coronary Ob-R mRNA levels.166

A recent hypothesis relevant to both central and peripheral

leptin resistance involves leptin interaction with circulating

factors in the blood.167 Five serum leptin–interacting proteins

have been isolated, one of which is C-reactive protein. It

directly inhibits the binding of leptin to Ob-Rs and blocks its

ability to signal in cultured cells. Infusion of human

C-reactive protein into ob/ob mice blocked leptin treatment

effects on satiety and weight reduction. Physiological con-

centrations of leptin stimulate expression of C-reactive pro-

tein in human primary hepatocytes,167 and human C-reactive

protein has been correlated with increased adiposity and

plasma leptin,168 suggesting an systemic self-induced nega-

tive feedback that may cause leptin resistance in the obese

state.167

Leptin AntagonistsLeptin antagonists used in animal models have been shown to

block central leptin effects and increase appetite and foodintake.169,170 Three approaches have been employed to antag-

onize leptin activity: (1) binding free leptin in the circulation,

(2) competitive Ob-R binding by mutants that do not cause

signaling activation, and (3) specific anti–Ob-R monoclonal

antibodies. An example of the first approach is a recombinant

human and mouse Ob-R/Fc chimeric glycoprotein.171,172 Only

the latter 2 approaches have been employed in cardiac-related

research. In neonatal rat ventricular cardiomyocytes, rat

L39A/D40A/F41A leptin mutein blocked hypertrophic ef-

fects and abolished increases in Ob-R gene expression elic-

ited by leptin, Ang II, or ET-1.26 The hypertrophic effects of

leptin are also prevented by antibodies to Ob-Ra and Ob-

Rb.26 Cardiac dysfunction did not develop in rats treated withOb-R antibodies after coronary artery ligation compared with

sham, indicating that blocking Ob-R can improve postinfarc-

tion HF in rats.173 The recent proposal of nanobodies (a

unique form of antibodies that is characterized by a single

antigen-binding domain and generally does not cross the

blood– brain barrier) may lead to an antagonist that could

selectively inhibit peripheral activities of leptin.174 This form

of leptin antagonist might be clinically useful, as they can

target peripheral adverse effect of leptin without inducing

central weight gain.

SummaryObesity leads to cardiac hypertrophy, ventricular dysfunction,

reduced diastolic compliance, and hypertension, as well as

type 2 diabetes and hyperlipidemia.175 The high risk of

developing cardiovascular diseases in obesity has drawn

much effort to study the neurohormone effects of leptin on

cardiac function and remodeling. Hyperleptinemia, central

leptin resistance, and leptin deficiency are all associated with

impaired postreceptor leptin signaling and contractile re-

sponse. Short-term administration of leptin seems to have

beneficial effects on the myocardium, including antisteatotic

actions, protection against ischemia/reperfusion injury, and

participation in compensatory myocyte hypertrophy. Interac-

tion with enhanced ROS production pathways in obesity, onthe other hand, can cause lipotoxicity and deleterious myo-




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cardial effects such as cell death and maladaptive hypertro-

phy. Perturbations of leptin signaling and other signal trans-

duction pathways regulated by leptin in cardiomyocytes

likely underlie the pathology of cardiomyocyte hypertrophy

in obesity. In particular, alterations in JAK/STAT, MAPK,

NO, and -adrenergic pathways have been implicated in the

negative inotropic and hypertrophic responses. Additional

studies investigating the integrated effects of leptin on car-

diomyocytes via SOCS3, PI3K/Akt, protein kinase C, and

other signaling pathways could provide a more comprehen-

sive understanding of leptin action on the cardiovascular

system.

The unresolved debate about selective preservation of

peripheral leptin signaling in the setting of hyperleptinemia

and central resistance complicates the interpretation of exper-

imental results involving the myocardium. Despite such

challenges, a picture is emerging in which the risk of obesity

is not merely attributable to the physical burden of extra

weight but is, rather, a complex condition of hormonal

dysregulation. Improved understanding of the actions of leptin within the cardiovascular system will greatly improve

our understanding of obesity-associated heart disease.

Sources of FundingThis work was supported in part by the Donald W. ReynoldsFoundation, NIH grant K08-HL076220, the W.W. Smith CharitableTrust, and the Irvin Talles Endowed Fund for CardiomyopathyResearch.

DisclosuresNone.

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Ronghua Yang and Lili A. BarouchLeptin Signaling and Obesity: Cardiovascular Consequences

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