Review

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 Consequences
Ronghua 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
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understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease. (Circ
Res. 2007;101:545-559.)
Key Words: leptin 䡲 obesity 䡲 cardiovascular disease

O ver 60% of people in the United States are overweight or

obese. Extensive evidence now supports the notion that
maladaptation 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 adipocytokines
that 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 barouch@jhmi.edu
© 2007 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.107.156596

545
 546 Circulation Research September 14, 2007
Figure 1. Leptin receptor signaling. The binding of leptin to its receptor leads to formation of the Ob-R/JAK2 complex that results in
cross-phosphorylation. Tyr1138 on Ob-Rb is crucial for STAT3 activation, which stimulates SOCS3 expression that negatively inhibits
leptin signaling via Tyr985 and additional sites on JAK2. Protein tyrosine phosphatase 1B (PTP1B) is also capable of inhibition of leptin
signaling. 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.
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-
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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 expression
and 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 Receptor
Leptin 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 the
murine 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 and
Activators of Transcription
Ob-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-characterized
pathway 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
 Yang and Barouch
dimerize and translocate to the nucleus to activate transcrip-
tion of target genes, which includes the gene for a member of
the suppressors of the cytokine signaling family
(SOCS3).16,36,39 SOCS3 binding to Tyr985 and other sites
within the Ob-Rb/JAK2 complex mediates negative feedback
on leptin signaling.40,41 JAK2 phosphorylation of Tyr985 also
consequently leads to phosphorylation of the src homology 2
(SH2) domain of the tyrosine phosphatase SHP-2 (src homol-
ogy 2-containing tyrosine phosphatase), which activates the
extracellular signal-regulated kinase (ERK) signaling path-
way.36 Overexpression of SHP-2 has been shown to blunt
SOCS3-mediated inhibition, likely through competitive bind-
ing to Tyr985.40
JAK2 autophosphorylation is independent of tyrosine
phosphorylation sites on Ob-Rb and has many subsequent
effects. One of these effects is to phosphorylate insulin
receptor substrate proteins, which recruit the phosphatidyl-
inositol 3⬘-kinase (PI3K) to activate downstream signals.7,42
In the heart, the leptin-associated PI3K pathway, along with
ERK cascades, seems to be important in cardiomyocyte
proliferation and protecting cardiac tissue from ischemia/
reperfusion injury.24,43
Mitogen-Activated Protein Kinase
Phosphorylation of Tyr985 on Ob-Rb leads to SHP-2 and
Grb-2 activation of ERK1/2 of the MAPK family.36 ERK1/2
activation also occurs via a pathway independent of Tyr985.
In this case, JAK2 associates with the SH2 domain-
containing SHP-2.36,44 Therefore, both Ob-Ra and Ob-Rb can
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activate MAPK.35,36 Shc, another SH-2– containing protein
that is able to associate with Grb-2, has also been shown to
phosphorylate tyrosine after leptin treatment.45 Leptin-
induced phosphorylation of STAT3 and ERK1/2 have been
observed in isolated adult C57BL/6 mouse cardiomyocytes,
with maximal activation at 15 minutes after treatment. Four-
week leptin treatment also elevated STAT3 and ERK1/2
phosphorylation and abundance in cardiac tissue from leptin-
deficient ob/ob mice but not from Ob-Rb– deficient db/db
mice.46 Because Ob-Ra is intact in db/db mice and the distal
portion of Ob-Rb is not essential for MAPK signaling,35
ERK1/2 phosphorylation would be expected to increase even
if STAT3 phosphorylation were unaltered. Therefore, the
results suggest that either Ob-Rb is the predominant signaling
receptor in the mouse heart or that JAK2-induced ERK1/2
phosphorylation does not occurs at a significant level in
cardiomyocytes. ERK1/2 activation leads to the expression of
target genes, such as c-fos and egr-1, which participate in cell
proliferation and differentiation.
Phosphorylation of p38 MAPK in response to leptin has
also been demonstrated. The ␣ and ␤ isoforms of p38 MAPK
are broadly distributed, including at relatively high levels in
the heart.47 Although the specific mechanism leading to
leptin-induced p38 MAPK activation has not been elucidated,
it is associated with the onset of hypertrophy and pro-
grammed cell death in both rat vascular smooth muscle cells
(VSMCs) and cardiomyocytes.24,48,49
As with other cytokines, leptin has the ability to activate
the stress-activated protein kinase c-Jun N-terminal kinase
(JNK).50,51 However, we observed that phosphorylation of
Leptin Signaling and Obesity 547
JNK was unaltered in cultured adult cardiomyocytes from
C57BL/6, ob/ob, and db/db mouse strains with 15-minute
leptin treatment.46 The effects of long-term leptin treatment
on JNK activity in the heart remain to be investigated.
Nuclear factor ␬B has been proposed as an attractive down-
stream target for p38 and JNK MAPK pathways because this
transcription factor is essential in the transcriptional regula-
tion of proinflammatory cytokines such as tumor necrosis
factor (TNF)-␣ and interleukin (IL)-1␤.52 Additional leptin
signaling pathways are difficult to consolidate because of
tissue specificity. For a comprehensive review of leptin
signaling capabilities, see reviews by Fruhbeck52 or
Sweeney.53
Leptin Signaling in the CNS
Hypothalamic Leptin Decreases Food Intake
Most Ob-Rs in the CNS are located in the basomedial
hypothalamus.54,55 In neurons that synthesize proopiomelano-
cortin and express Ob-Rb, leptin stimulates the synthesis of
proopiomelanocortin, which is processed to produce ␣-mela-
nocyte–stimulating hormone and activate downstream
melanocortin-3 and -4 receptors to decrease appetite.56 Leptin
also inhibits the appetite-stimulating hormone neuropeptide
Y in the arcuate nucleus, and causes inhibition of agouti-
related peptide that restrain melanocortin-3 and -4 receptor
signaling.55,56
Ob-Rb–stimulated JAK2/STAT3 signaling is crucial in
leptin control of feeding and energy expenditure. Although
short forms of the leptin receptor may be capable of activating
JAK, insulin receptor substrate, and MAPK proteins, only
Ob-Rb is capable of activating STAT3.35,57,58 A homologous
replacement of Ob-Rb by a receptor mutant for Tyr1138
established that STAT3 is indispensable for the regulation of
expression of proopiomelanocortin and neuropeptide Y in the
hypothalamus.16
Mechanisms of Central Leptin Resistance
One theory of leptin resistance involves intracellular signal-
ing disruption. STAT3 and protein tyrosine phosphatase 1B
are 2 molecules known to attenuate leptin signaling.40,59 – 63
Hypothalamic protein tyrosine phosphatase 1B levels are not
known to be altered in obesity, although protein tyrosine
phosphatase 1B–null animals develop increased insulin sen-
sitivity and have a lean phenotype.64 As previously discussed,
leptin can induce its own negative feedback through STAT3-
induced SOCS3 accumulation during prolonged Ob-Rb stim-
ulation,36,40,61 which can occur via Tyr985 or additional sites
in the Ob-Rb/JAK2 complex.40,41 At low concentrations of
leptin, incremental changes in leptin would be almost fully
translated into increased Ob-Rb signaling, whereas, at high
levels, accumulated SOCS3 would counter most of the
increase in Ob-Rb signaling.39,65
Another possible mechanism of central leptin resistance
stems from the dependency of leptin on saturable transport
across the vascular barrier and, probably to a lesser extent,
across the choroid plexus to reach the arcuate nucleus.66 The
activity of this blood– brain barrier transport system seems to
decrease in diet-induced obese (DIO) rodents,67 resulting in
failure of circulating leptin to reach its targets in the brain.
 548 Circulation Research September 14, 2007

Figure 2. Systemic leptin function. Chronic hyperleptinemia impairs the centrally mediated metabolic actions of the hormone, alyhough
its 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 in
nonadipose tissue, whether this effect is abolished because of (selective) peripheral leptin resistance requires further examination.
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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 Outflow
In 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 central
leptin 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 been
confirmed 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 increased
renal 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 shown
that 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
 Yang and Barouch
Summary of Leptin Signaling in the Cardiovascular System
Leptin Action
Development of hypertension
Development of atherosclerosis
Impaired cardiomyocyte contractility
Liporegulation
Increase in size of cardiomyocyte
Deficiency leads to increased rate of
cardiomyocyte apoptosis
Enhanced cardiomyocyte mitosis and
proliferation
Protection from ischemia/reperfusion injury
and promote endothelial dysfunction, contributing to the
development of vascular structural alterations and the occur-
rence of atherosclerotic lesions.81
Leptin and the Cardiovascular System
Hyperleptinemia is associated with obesity-related hyperten-
sion and chronic congestive heart failure (HF) in humans, and
vascular endothelial and myocardial dysfunction in animal
models.82– 85 The role of leptin and leptin resistance in the
pathogenesis of LVH and HF in obesity remains controver-
sial. The Table provides a summary of the leptin signaling
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pathways involved in the cardiovascular system.
Vascular Effects of Leptin
Development of Hypertension
Both intravenous infusion and intracerebroventricular admin-
istration of leptin lead to increased arterial pressure and heart
rate in rodents.86,87 Blockade of the adrenergic system inhibits
the pressor response to leptin.88 In addition to increased
sympathetic activity in hyperleptinemia, other mechanisms
may also contribute to the development of obesity-related
hypertension. Leptin has been shown to increase the genera-
tion of reactive oxygen species (ROS) in endothelial cells50,89
and to stimulate secretion of proinflammatory cytokines such
as TNF-␣ and IL-6, both of which are promoters of hyper-
tension and atherosclerosis.90
While stimulating blood flow via increased sympathetic
output, leptin has also been shown to have direct vasodilatory
effects. In both intact rodents and in endothelial cells, leptin
induces NO production.83,91 Leptin administration in anesthe-
tized rats causes a dose-dependent increase in NO metabolite
concentrations, and inhibition of NO synthesis increases
arterial pressure.91 In vitro studies have shown that leptin
evokes an endothelium-dependent relaxation of arterial
rings.92,93 In endothelial cells, leptin activates a PI3K-
independent Akt-endothelial NO synthase (eNOS) phosphor-
ylation pathway to increase NO production, which can be
abolished by erbstatin A, a Ca2⫹-independent tyrosine kinase
inhibitor.94 However, the vasodilator action of leptin was not
found in conscious rats and the NOS inhibitor NG-nitro-L-
Leptin Signaling and Obesity 549
Pathways Involved
Increased catecholamine release, preserved renal
sympathetic nerve activity increase, NO
Endothelial cell NO and ROS production, VSMC
proliferation and hypertrophy, platelet
aggregation, proinflammatory cytokine production
JAK/STAT, NO-cGMP, G protein–coupled
receptor, adenylate cyclase, ET-1, NAPDH, ROS
Increased FA oxidation
ET-1, ROS
p38, caspase-3, DNA damage, Ang II
ERK1/2, p38, PI3K, peroxisome
proliferator-activated receptor-␣
PI3K, ERK1/2, NO, ROS
arginine methyl ester did not unmask any pressor effect.95 At
a concentration sufficient to increase sympathetic nerve
outflow, leptin did not change arterial pressure or blood flow
in mesenteric, lower aortic, and renal arteries.96 Blockade of
NO synthesis increased heart rate and renal vascular and
glomerular response but did not substantially augment the
pressor response to leptin,97 indicating a negligible role of
leptin-stimulated NO production on blood pressure in vivo.
Leptin has been shown to increases the release of ET-1, a
vasoconstrictor secreted primarily by endothelial cells but
also by macrophages, fibroblasts, and cardiomyocytes, pos-
sibly countering the effects of NO.98
Development of Atherosclerosis
The proatherogenic action of leptin is likely attributable to a
combination of its effects on various cell types. In endothelial
cells, leptin induces oxidative stress, increases production of
monocyte chemoattractant protein-1 and ET-1 and potentiates
proliferation.50,89,98,99 In VSMCs, leptin promotes migration,
proliferation, and hypertrophy.100 –102 Leptin also promotes
calcification of cells of the vascular wall and facilitates
thrombosis by increasing platelet aggregation.103,104
Hyperleptinemia has been associated with coronary athero-
sclerosis in type 2 diabetes, and this association has been
shown to be independent of insulin resistance.105 In apoli-
poprotein E– deficient (apoE⫺/⫺) mice that are atherosclerosis
prone, recombinant leptin treatment further promoted athero-
sclerosis and thrombosis, despite its metabolic benefits.106
This result indicates that elevation of leptin concentration in
obesity increases the risk for atherosclerotic damage.
Paradoxically, leptin resistance is also proatherogenic.
ApoE⫺/⫺ mice lacking Ob-Rb (apoE⫺/⫺ db/db) are character-
ized by a 5-fold higher area of spontaneous atherosclerotic
lesions in the aorta than apoE⫺/⫺ with intact Ob-R.107 Unlike
apoE⫺/⫺ mice, apoE⫺/⫺ db/db mice are also obese and insulin
resistant. Taken together, these data suggest either that a
supraphysiological level of exogenous leptin self-induces
resistance that is harmful or that the atherogenic effect seen in
apoE⫺/⫺ db/db is an effect more relevant to lipid profile
change, which is absent in apoE⫺/⫺ mice.
 550 Circulation Research September 14, 2007

Figure 3. Leptin and myocardial contractility. Leptin directly depresses cardiomyocyte contractility. The signaling pathways implicated
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in this process include the NO-cGMP pathway and pathways that lead to increased ROS production. Changes that occur in a chronic
leptin-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.

Leptin Attenuates Cardiomyocyte Contractility
Possible Mechanisms Leading to Increased
NO Production
Similar 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 NG-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 cardiac
phenotype 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 Stimulation
In 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 to
isoproterenol stimulation of the ␤-adrenergic receptor or to
 Yang and Barouch
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 G␣s (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 G␣s. Adenylate cyclase, G␣s (52 kDa), G␣i,
p21-ras, and phosphorylated ERK1/2 expressions were in-
creased with short-term leptin treatment and decreased at 18
hours, whereas G␣s (45 kDa) continued to increase at 18
hours. Receptor level leptin resistance is conceivable in
myocytes, 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 ROS
Mitochondrial formation of ROS is enhanced in obesity.
Xanthine oxidoreductase and nicotinamide adenine dinucle-
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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 cardiac
contractile 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
Leptin Signaling and Obesity 551
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, ETA
and 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 p67phox and p47phox 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 Contractility
Obesity 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 low
nanomolar 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 NG-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
 552 Circulation Research September 14, 2007
JAK/STAT and p38 pathways to attenuate leptin-induced
cardiomyocyte dysfunction possibly serves as a compensa-
tory mechanism to prevent further impairment of ventricular
function in sustained hypertension or hyperleptinemia.109
Leptin Shifts Myocardial Metabolism Toward
Fatty Acid Utilization
Accumulating evidence suggests that leptin regulates energy
homeostasis through direct actions on peripheral lipid and
glucose metabolism.132 Fatty acid (FA) oxidation produces
the major source of ATP to sustain contractile function of the
heart. AMP-activated protein kinase (AMPK) has a key role
as a fuel gauge in the heart and regulates cardiac FA oxidation
by phosphorylation and inhibition of acetyl– coenzyme A
(CoA) carboxylase, which then lowers malonyl-CoA levels
and stimulates carnitine palmitoyltransferase-1–induced FA
oxidation.133 AMPK activation is also known to reduce FA
incorporation into triacylglycerol.134
Examination of leptin effects on cardiac FA oxidation
confirmed that leptin infusion increases FA oxidation and
triacylglycerol lipolysis in isolated working rat hearts, al-
though this effect was independent of changes in the AMPK/
acetyl-CoA carboxylase/malonyl/CoA axis. Neither did leptin
affect glucose oxidation rates.135 Myocardial oxygen con-
sumption was increased, possibly because of increased mito-
chondrial uncoupling protein activity.135 In DIO mice, plasma
leptin concentration increase was associated with an induc-
tion of uncoupling protein 2 and an increase in phosphoryla-
tion of AMPK that led to increased FA oxidation.136 At this
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stage, leptin signaling in the heart as assessed by STAT3
phosphorylation remained unaltered from WT, suggesting
that the shift to FA oxidation is at least mediated, in part, by
leptin. Increased FA oxidation may confer antisteatosis pro-
tection to the myocardium during hyperleptinemia in early
stages of obesity. This is consistent with the observation that
DIO rodents exhibit minimal rise in myocardial triacylglyc-
erol content, whereas ob/ob, db/db, and fa/fa animals show
significantly greater accumulation.137 Leptin deficiency per-
turbs liporegulation in peripheral organs and results in lipo-
toxicity, lipoapoptosis, and generalized steatosis, manifesting
in clinical conditions such as nonalcoholic steatohepatitis,
type 2 diabetes, and lipotoxic cardiomyopathy.128 Lipotoxic
cardiomyopathy has been identified in fa/fa rats and has been
transgenically induced in acyl–CoA synthase transgenic
mice.138 Overexpression of acyl–CoA synthase, which actives
and esterifies FAs, led to severe cardiomyopathy that was
attenuated by injection of recombinant adenovirus containing
the leptin cDNA.138
Increased de novo lipogenesis and decreased compensatory
oxidation of FAs are two possible mechanisms for intracel-
lular accumulation of lipids in nonadipose tissue. Enzymes
involved in FA oxidation such as acyl-CoA oxidase and
carnitine palmitoyltransferase-1 are observed at attenuated
levels in fa/fa rats. Hydrolysis of the increased stores of
triacylglycerol to fatty acyl-CoA in fa/fa rats also increased
the substrate for de novo ceramide synthesis and activated the
expression of inducible NO synthase in the myocardium,
which led to acceleration of apoptosis.129 Ceramide also
activated protein kinase C isoforms, which can induce gene
transcription through MAPK and nuclear factor ␬B and are
implicated in the development of cardiomyocyte hypertro-
phy.139 It seems paradoxical that enhanced expression of ␤
oxidation enzymes such as long-chain acyl-CoA dehydroge-
nase and carnitine palmitoyltransferase-1 are seen in ob/ob
mice,140 as leptin-deficient hearts are also characterized by
increased FA utilization.141 This is likely attributable to
long-term adaptation to the changes in the lipid profile in
these animals. Genes for lipoprotein lipase, which generates
free FAs, and FA transport proteins are seen at an greatly
elevated level in ob/ob myocytes, which causes accumulation
of free FAs that promote ceramide, inducible NO synthase,
and NO production in the cardiomyocyte.140 When increased
FA delivery and hyperinsulinemia are imposed in ob/ob
hearts, myocardial function is maintained, albeit with de-
creased efficiency, whereas WT hearts are unable to adapt
acutely.141
Increased FA uptake accompanied by decreased oxidation
leads to lipotoxicity in long-term leptin-treated cardiomyo-
cytes. The antisteatotic effects of leptin in early obesity might
be lost with the progression of leptin resistance occurring in
late stage obesity, leading to lipotoxicity that promotes
cardiomyocyte contractile dysfunction and apoptosis129 or
acts in a maladaptive fashion because of increased ceramide
synthesis.
Leptin Effects on Cardiac Hypertrophy
and Remodeling
Postmortem clinical studies of obesity-associated hypertro-
phy have demonstrated excessive heart weight but low
heart/body weight ratios.142 Fatty infiltration of the myocar-
dium, presence of metabolic inclusions, excessive fibrosis, or
increases in extracellular matrix do not appear to play a direct
role in augmenting wall thickness in obesity-related hyper-
trophy.143 The findings on endomyocardial biopsy in the
majority of obese patients with cardiomyopathy appear to be
primarily myocyte hypertrophy.144 Hyperleptinemia is ob-
served in patients with LVH.145 Leptin effects on cardiomyo-
cyte hypertrophy is not entirely clear. We had previously
shown leptin repletion to be antihypertrophic in ob/ob hearts.
Four- to 6-week leptin infusion reduced weight and reversed
LVH, whereas caloric restriction reduced weight but did not
effectively reduce wall thickness and myocyte size.113 Recon-
stitution to normal levels may provide the antisteatotic effect
of leptin that can reverse lipotoxic effects of FA deposition in
the myocardium. On the other hand, leptin has been shown to
induce hypertrophy in a concentration-dependent manner in
cultured neonatal rat ventricular myocytes.48,146 Fasting
plasma leptin levels are associated with increased myocardial
wall thickness in hypertensive humans, although this may be
related to leptin resistance.147 The different types of cardio-
myocytes used in experiments could also contribute to the
observed paradoxical effects of leptin on cardiomyocyte
hypertrophy. Direct effects of leptin on cardiomyocyte hy-
pertrophy, apoptosis, proliferation, and extracellular matrix
remodeling could all contribute to maladaptive hypertrophy
and HF in obesity.
 Yang and Barouch
Cardiomyocyte Hypertrophy
Leptin-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-induced
hypertrophy, 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
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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
Apoptosis
One 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 mediator
of the apoptotic response in cardiomyocytes.156 It is promi-
Leptin Signaling and Obesity 553
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 Proliferation
Leptin 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 proliferative
activity 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 Remodeling
Leptin 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 Injury
Timely 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
 554 Circulation Research September 14, 2007
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 the
Cardiovascular 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 system
has 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
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necessarily correlate with receptor density at the membrane;
therefore, these results are not conclusive in determining
whether leptin resistance can occur at the myocyte receptor
level. 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 does
occur, 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 in
the 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 Antagonists
Leptin antagonists used in animal models have been shown to
block central leptin effects and increase appetite and food
intake.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 with
Ob-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.
Summary
Obesity 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, on
the other hand, can cause lipotoxicity and deleterious myo-
 Yang and Barouch
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 Funding
This work was supported in part by the Donald W. Reynolds
Foundation, NIH grant K08-HL076220, the W.W. Smith Charitable
Trust, and the Irvin Talles Endowed Fund for Cardiomyopathy
Research.
Disclosures
Downloaded from http://ahajournals.org by on April 15, 2022
None.
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