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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
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 population 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
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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.
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,
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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 cardiovascular 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.
Increasing evidence suggests that leptin signaling is preferentially reduced in the arcuate nucleus of the hypothalamus
but not in other regions, such as the ventromedial, dorsomedial, and/or premammillary nucleus of the hypothalamus that
also express Ob-Rs.68
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Pathways Involved
Development of hypertension
Development of atherosclerosis
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Figure 3. Leptin and myocardial contractility. Leptin directly depresses cardiomyocyte contractility. The signaling pathways implicated
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.
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coronary dilation, increased endothelium-derived hyperpolarizing 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 leptininteracting 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 concentrations of leptin stimulate expression of C-reactive protein 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 negative 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 antagonize 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 antiOb-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 effects and abolished increases in Ob-R gene expression elicited by leptin, Ang II, or ET-1.26 The hypertrophic effects of
leptin are also prevented by antibodies to Ob-Ra and ObRb.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 postinfarction 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 response. 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. Interaction with enhanced ROS production pathways in obesity, on
the other hand, can cause lipotoxicity and deleterious myo-
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
None.
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