Published online before print July 31, 2003, doi: 10.1161/01.RES.0000089255.37804.72
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© 2003 American Heart Association, Inc.
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The Obesity-Associated Peptide Leptin Induces Hypertrophy in Neonatal Rat Ventricular Myocytes
From the Department of Physiology and Pharmacology (V.R., X.T.G., M.K.), University of Western Ontario, London, Ontario, Canada, and the Institute of Cardiovascular Sciences (L.A.K), St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Correspondence to Dr M. Karmazyn, Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail Morris.Karmazyn{at}fmd.uwo.ca
Abstract
One of the major manifestations of obesity is increased production of the adipocyte-derived 16-kDa peptide leptin, which is also elevated in heart disease, including congestive heart failure. However, whether leptin can directly alter the cardiac phenotype is not known. We therefore studied the effect of leptin as a potential hypertrophic factor in cultured myocytes from 1- to 4-day-old neonatal rat heart ventricles. Using RT-PCR, we demonstrate that these cells express the short-form (OB-Ra) leptin receptor. Twenty-four hours of exposure to leptin (0.31 to 31.3 nmol/L) produces a significantly increased cell surface area that peaked at 0.63 nmol/L. Subsequent experiments were done with 3.1 nmol/L leptin, which significantly increased cell area by 42%, protein synthesis by 32%, and 
-skeletal actin and myosin light chain-2 expression by 250% and 300%, respectively. These events occurred in the absence of any increased cell death. Hypertrophy was preceded by rapid activation of the mitogen-activated protein kinase system including p38 and p44/42 as early as 5 minutes after leptin addition, whereas hypertrophy was inhibited by the p38 inhibitor SB203580 but not by the p44/42 inhibitor PD98059. Our results demonstrate a direct hypertrophic effect of leptin and may offer a biological link between hypertrophy and hyperleptinemic conditions such as obesity.
Key Words: leptin • cells • hypertrophy • mitogen-activated protein kinase • leptin receptor
Obesity is associated with increased production of leptin, a 16-kDa peptide that is a product of the obesity gene (ob) and produced primarily by adipocytes.1 The effects of leptin are mediated by distinct receptors (OB-R) belonging to the class I cytokine receptor family. It has been suggested that leptin may contribute to cardiovascular disease, independently of obesity such as in hypertension,2 where elevated levels of the peptide could be a contributing factor due to its ability to stimulate the sympathetic nervous system.3 Recent clinical evidence has implicated leptin as a potential independent risk factor for coronary heart disease,4 and increased plasma leptin levels have been found in patients with congestive heart failure.5 Heart failure is generally preceded by myocardial remodeling, involving cardiomyocyte hypertrophy and other maladaptive responses,6 although whether leptin contributes to these events has not been studied. Accordingly, we examined leptin’s effects in cultured cardiomyocytes and sought to identify potential mechanisms underlying these effects.
Materials and Methods
Experiments were done on primary cultures of rat neonatal cardiomyocytes exposed to leptin for 24 hours in the absence or presence of mitogen-activated protein kinase (MAPK) inhibitors. Hypertrophy was determined by measuring cell area, leucine incorporation, and gene expression of molecular markers. Cell viability was determined by vital staining and MAPK activation with Western blotting.
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
Results
The leptin receptors are generally classified into two groups, those with short intracellular domains of 40 or fewer amino acid residues (OB-Ra, -Rc, -Rd, -Re) and a family of receptors having a long intracellular domain (302 residues) termed OB-Rb.7 As shown in Figure 1A, only OB-Ra mRNA was identified in cardiomyocytes, while brain, as expected, expressed both forms of the receptor.
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As shown in Figure 1B, at the lowest concentration studied (0.31 nmol/L), leptin increased cell surface area by about 32% whereas peak effects (42% increase) were seen at 0.63 nmol/L and did not increase with higher concentrations. Subsequent experiments were done with a leptin concentration of 3.1 nmol/L (see Discussion). Figure 1C shows phase-contrast images whereas Figures 1D and 1E illustrate cells staining for sarcomeric myosin heavy chain and cell viability, respectively. Approximately 95% of cells demonstrated myosin staining, indicating relatively low nonmyocyte contamination. Leptin had no effect on cell death as determined with vital dye staining: the percentage of positive staining for dead cells was 5.46±0.52 and 5.40±0.8 for control and leptin-treated cells, respectively.
Since MAPK is an important mediator of cardiac hypertrophy,8 and because leptin can activate MAPK in noncardiac cell lines,9 we determined the role of MAPK as a potential mediator of leptin’s effects. As shown in Figure 2, both phospho-p38 (Figures 2A and 2B) and phospho-p44/p42 (Figures 2C and 2D) levels were rapidly increased with leptin with peak stimulation after 5 and 10 minutes of leptin treatment. The stimulation in MAPK completely reversed to control values after 24-hour leptin exposure (not shown).
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The p38 inhibitor SB203580 completely prevented the leptin-induced hypertrophy (Figure 3A), [3H]leucine incorporation (Figure 3B), and the increase in both -skeletal actin (Figure 3C) and myosin light chain-2 (MLC-2) expression (Figure 3D). The p44/42 inhibitor PD98059 was without effect on all indices, although it slightly reduced leucine incorporation such that values were not significantly greater from control (Figure 3). Neither drug exerted direct effects on its own on any parameter.
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Discussion
The basis for the increased incidence of cardiovascular-related diseases including cardiac hypertrophy in obese individuals is unknown,10 although increased plasma levels of leptin in obesity11 as well as cardiovascular disorders12–14 suggest that the peptide could be a contributing factor. Our findings demonstrate the presence of leptin receptors in neonatal rat ventricular myocytes. We also demonstrate that leptin can directly increase cell surface area and expression of -skeletal actin, a fetal gene, and MLC-2, a constitutive gene, which are upregulated in cardiac hypertrophy.15 We also show that leptin, at least at a concentration of 3.1 nmol/L, is devoid of a direct toxic influence as demonstrated by the lack of effect on cell death. Importantly, the hypertrophic effects of leptin occurred at concentrations well within plasma levels in obese individuals, which can exceed 100 ng/mL (6.1 nmol/L).11 Thus, the cardiac cell may be a target for circulating leptin: indeed leptin has been shown to inhibit myocyte shortening.16 Our novel observation that leptin produces cardiomyocyte hypertrophy may be important in providing a basis linking obesity and hypertrophy. Although hypertrophy can be a beneficial adaptive response to myocardial injury, it is generally perceived that progressive myocardial hypertrophy contributes to remodeling and development of heart failure.6 Hypertrophy involves numerous cell signaling processes including MAPK activation.17 Indeed, both p38 and p44/42 have been shown to be important in cell growth.18 Leptin activated both p38 and p44/42, although the effect on the former was more prolonged. Moreover, the hypertrophic effect of leptin was completely abrogated by a p38 inhibitor, but mostly unaffected by p44/42 inhibition except for a partial attenuation of leucine incorporation. As noted above, p38, along with other members of the MAPK family, has been implicated in the pathology of myocardial remodeling and heart failure. Although it is not known how p38 mediates these effects, they likely occur as a consequence of phosphorylation of a downstream transcriptional factor. We should add that the antibodies we used for Western blotting analysis do not permit us to distinguish between the various p38 isoforms, and thus at present it is not possible to comment on the nature or specificity of the p38 isoform mediating the effect of leptin.
Results using cultured myocytes should be interpreted cautiously. However, the ability of leptin to produce hypertrophy at concentrations well within plasma levels of obese individuals suggests a potential direct link between hyperleptinemia seen in obesity and some cardiovascular disorders and increased risk of cardiovascular disease, particularly associated with a hypertrophic phenotype. At present, a clear cause-and-effect relationship linking leptin to heart disease is difficult to demonstrate with certainty because of the unavailability of leptin receptor antagonists. A recent study has demonstrated an association between plasma leptin levels greater than 3.1 nmol/L and left ventricular hypertrophy.19 The prospect of leptin antagonism or inhibition of leptin synthesis as a therapeutic target for treating heart disease is potentially attractive and warrants further investigation aimed at determining the precise physiological or pathophysiological role of the peptide.
Acknowledgments
This study was supported by the Canadian Institutes of Health Research. Dr Karmazyn is a Career Investigator of the Heart and Stroke Foundation of Ontario. Dr Kirshenbaum is a Canada Research Chair in Molecular Cardiology.
Footnotes
Original received May 20, 2003; resubmission received June 25, 2003; revised resubmission received July 21, 2003; accepted July 21, 2003.
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