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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4087-4093
Copyright © 2005 by The Endocrine Society

Circulating Leptin Correlates with Left Ventricular Mass in Morbid (Grade III) Obesity before and after Weight Loss Induced by Bariatric Surgery: A Potential Role for Leptin in Mediating Human Left Ventricular Hypertrophy

Lucia Perego, Pierluigi Pizzocri, Domenico Corradi, Francesco Maisano, Michele Paganelli, Paolo Fiorina, Michelangela Barbieri, Alberto Morabito, Giuseppe Paolisso, Franco Folli and Antonio E. Pontiroli

Divisione di Medicina Interna (L.P., F.F., P.F.), Chirurgia Generale (M.P.), and Cardiochirurgia (F.M.), Istituto Scientifico San Raffaele, 20132 Milan, Italy; Cattedra di Medicina Interna, H. San Paolo, Università degli Studi di Milano (A.E.P., P.P.), 20142 Milan, Italy; Dipartimento di Patologia e Medicina di Laboratorio, Università degli Studi di Parma (D.C.), 43100 Parma, Italy; Istituto di Statistica Medica (A.M.), H San Paolo, Università degli Studi di Milano, Milan, Italy; and Dipartimento di Gerontologia, Geriatria e Malattie del Metabolismo, Seconda Università di Napoli (M.B., G.P.), 80138 Naples, Italy

Address all correspondence and requests for reprints to: Dr. Franco Folli, Department of Medicine, Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milan, Italy. E-mail: franco.folli{at}hsr.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Obesity is frequently associated with left ventricular hypertrophy, even when uncomplicated by hypertension or diabetes mellitus. Left ventricular hypertrophy is an important risk factor for congestive heart failure.

Objective: The objective of this study was to evaluate the relationship between leptin and left ventricular mass in uncomplicated, morbid (grade 3) obesity and the existence of leptin receptors and intracellular signaling proteins in the human heart.

Design: Left ventricular mass (LVM) was calculated through electrocardiogram reading in normotensive grade III obese patients (World Health Organization classification) undergoing bariatric surgery [laparoscopic adjustable gastric banding (LAGB)] at baseline and 1 yr later. The control group was composed of healthy lean normotensive subjects. Leptin receptors were detected by PCR and immunocytochemistry in human heart biopsies.

Setting: This study was performed at university hospitals.

Patients: Thirty-one grade 3 obese patients and 30 healthy nonobese normotensive, age- and sex-matched control subjects were studied.

Intervention: Obese subjects underwent LAGB to induce weight loss and were evaluated at baseline and after 1 yr.

Results: LVM, plasma leptin, glucose, insulin levels, and homeostasis model assessment index were higher in obese than in lean controls (P < 0.01); at univariate regression analysis, LVM correlated with body mass index, leptin, and homeostasis model assessment index; at multiple regression analysis, LVM only correlated with leptin levels (P = 0.001). Obese subjects were reevaluated 1 yr after LAGB, when their body mass index changed from 46.2 ± 1.24 to 36.6 ± 1.05 kg/m2 (P < 0.01); the decrease in LVM correlated only with the decrease in leptin levels (P < 0.01). We demonstrated that long and short isoforms of the leptin receptor and intracellular proteins mediating leptin signaling were expressed in human heart by RT-PCR, immunocytochemistry, or both methods.

Conclusions: These data suggest that leptin could contribute to the left ventricular hypertrophy in humans.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN IS PRODUCED in adipose tissue. Its plasma levels correlate with body mass index (BMI) and insulin resistance and are more elevated in women than in men (1, 2, 3, 4, 5). Leptin is an emerging risk factor for cardiovascular disease: in fact, leptin was an independent risk factor for ischemic heart disease in the West of Scotland Coronary Prevention Study (WOSCOPS) study, was increased in congestive heart failure, and was increased and correlated with left ventricular mass (LVM) in hypertensive subjects (6, 7, 8). Most of these interactions have been ascribed to an interaction between leptin and sympathetic overactivity, mediated at the hypothalamic level (9). In fact, leptin levels correlate with heart rate and with QTc, an electrocardiogram (ECG) index of sympathetic activity (10).

Obesity, even when uncomplicated by hypertension or diabetes, is frequently associated with left ventricular hypertrophy, as assessed through ECG criteria or echocardiography, and is a risk factor for congestive heart failure (11, 12, 13, 14). In recent years it has become clear that leptin appears to have a range of roles as a growth factor in many cell types, as a mediator of energy expenditure; as a permissive factor for puberty, as a signal of metabolic status and modulation between fetus and maternal metabolism, and as an important regulator of lipid metabolism (15). In particular, leptin may have a direct role in cardiac remodeling. Leptin has been shown to directly attenuate contraction or induce or prevent hypertrophy in isolated myocytes (16, 17, 18). Recently, additional evidence was reported for a potential direct link between leptin and cardiac remodeling by demonstrating a mitogenic effect of leptin on primary human pediatric cardiomyocytes and a stable murine cardiomyocyte cell line (19).

The aims of this study were to investigate the relationship between leptin and LVM in normotensive subjects, to prospectively assess changes in LVM and leptin in obese subjects undergoing durable weight loss, and to analyze the expression of leptin receptors and leptin receptor signaling apparatus in human heart.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All studies were approved by the local ethical committees. All patients gave informed consent for the studies and biopsies.

Clinical and laboratory characteristics of the subjects are detailed in Table 1Go. Thirty-one normotensive grade III obese patients (World Health Organization classification) underwent bariatric surgery [laparoscopic adjustable gastric banding (LAGB)] (20). Obese patients were evaluated under basal conditions and 1 yr after bariatric surgery associated with low calorie diet (900 kcal/d for women and 1100 kcal/d for men; 40% protein, 25% fat, and 35% carbohydrate). All subjects underwent a 75-g oral glucose tolerance test to detect diabetes mellitus under basal conditions and 1 yr later, with determination of insulin and blood glucose levels (20) and calculation of the homeostasis model assessment (HOMA), an index of insulin resistance (21). The control group was composed of 30 healthy control subjects (11 men and 19 women) with normal glucose tolerance (21); none of the subjects was affected by arterial hypertension. According to past history and clinical conditions, none of the patients or controls had experience of angina, ECG abnormalities, or admission to an emergency department for chest pain. There was no evidence of heart enlargement at chest x-ray. ECG in both groups was carried out after an overnight fast and rest.


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  		TABLE 1. Clinical, metabolic, and ECG data of obese subjects and lean controls

 
LVM

LVM was calculated, through ECG reading, as Cornell voltage-duration product [(RaVL + SV3). QRS (millimeters per milliseconds) was determined with adjustment of 6 mm in women. These composite ECG criteria detect left ventricular hypertrophy with about 95% specificity in healthy people and greater than 70% sensitivity in obese and hypertensive subjects (22, 23). In addition, this approach allows direct evaluation of LVM (24).

Laboratory assays

Blood glucose levels were measured by a glucose-oxidase method (YSI, Inc., Yellow Springs, OH). Insulin was assayed by a microparticle enzyme immunoassay (IMX, Abbott Laboratories, Chicago, IL) with a monoclonal antibody without cross-reactivity with human proinsulin (sensitivity, 6.0 pmol/liter; intraassay coefficient of variation, 3.0%; interassay coefficient of variation, 5.0%). The HOMA index was calculated as insulin (microunits per milliliter) x blood glucose (millimoles per liter)/22.5 (21). Leptin was assayed by RIA (Linco Research, Inc., St. Charles, MO) with inter- and intraassay coefficients of variation less than 10.0% and less than 7.0%, respectively.

Cardiac biopsy

Under general anesthesia, midline sternotomy, and cardiopulmonary bypass, the heart was arrested by cold cardioplegia, and the left atrium opened to carry on the mitral valve plastic procedure. The mitral valve leaflets were externalized, and the endomyocardial surface of the lateral wall of the left ventricle was exposed. The endomyocardial biopsy was obtained from a small muscular trabecula in the area in between the papillary muscles. The biopsy was immediately frozen and stored in liquid nitrogen or fixed in formalin.

RT-PCR

Total RNA was isolated from human heart, insulinomas, and adipose tissues using the RNAfast method (Molecular Systems, San Diego, CA). Two micrograms of total RNA were treated for 30 min at 37 C with 2 U RQ1 ribonuclease-free deoxyribonuclease in 40 mM Tris-HCl (pH 8.00) 10 mM MgSO4, and 1 mM CaCl2 in the presence of 25 U RNasin ribonuclease inhibitor (Promega Corp., Madison, WI). RT was performed as previously described (25).

The sequences of the oligonucleotides used in the RT-PCR analysis were: Ob-R short isoform (g1:1519389): forward, 5'-tccccattgagaagtaccagtt-3'; and reverse, 5'-agttggcacattgggttcat-3'; Ob-R isoform HuB219.1 (gi:1279900): forward, 5'-atggaaggagtgggaaaacc-3'; and reverse, 5'-caatagtggagggagggtca-3'; Ob-R long isoforms (gi:1519393): forward, 5'-aggacgaaagccagagacaa-3'; and reverse, 5'-aaatgcctgggcctctatct-3'; Janus kinase-2 (JAK2; gi:13325062): forward, 5'-gagcctatcggcatggaata-3'; and reverse, 5'-actgccatcccaagacattc-3'; Src homology protein tyrosine phosphatase-2 (SHP-2; gi:14250500): forward, 5'-cggtctggcaataccacttt-3'; and reverse, 5'-cctgcgctgtagtgtttcaa-3'; signal transducer and activator of transcription-3 (STAT3; gi:3850049): forward, 5'-tttcacttgggtggagaagga-3'; and reverse, 5'-gctacctgggtcagcttcag; suppressor of cytokine signaling-3 (SOCS3; gi:45439351): forward, 5'-ccacctgagtctccagcttct-3'; and reverse, 5'-gaggagcatgtcaccaggat-3'; phosphatidylinositol 3-kinase (PI3K) p85 {alpha}-isoform: forward (gi:32455247), 5'-tccagaagtacaaagctccga-3'; and reverse, 5'-aaaaggtcccgtctgctgtat3'; and Akt 1 (gi:33875493): forward, 5'-atggcaccttcattggctac-3': and reverse, 5'-cccagcagcttcaggtactc-3'.

The PCRs involved an initial incubation at 95 C for 2 min; denaturation at 95 C for 30 sec; annealing at 58 C for Ob-R (ob gene/leptin receptors) isoforms, SHP2, JAK2 for 30 sec; at 60 C for STAT3, SOCS3, and p85{alpha}-PI3K for 30 sec; and at 62 C for Akt1; and extension at 72 C for 30 sec.

For leptin receptor isoforms, a cycle titration between 33 and 48 cycles of RT-PCR products revealed that 39 cycles for short and HuB219.1 Ob-R isoforms and 42 cycles for long Ob-R isoforms were within the logarithmic phase of amplification. A cycle titration between 18 and 33 cycles of RT-PCR products revealed that 24 cycles for the housekeeping genes 18S were within the logarithmic phase of amplification. Therefore, these PCR conditions were used for subsequent quantification experiments. All PCR included one control tube with no RT step. PCR-amplified products were resolved in a 2% agarose gel, and DNA was visualized by ethidium bromide staining. Location of the products was determined using a GeneRuler 100-bp DNA ladder plus (MBI Fermentas, Hanover, MD) as standard size marker. All PCR products were controlled by automatic sequencing. Quantification of the PCR-amplified products was performed using the UVP BioImaging System (Upland, CA) and the ScionImage program (Scion Corp., Frederick, MD).

Immunohistochemistry

Myocardial samples from autoptic control subjects or endomyocardial biopsies were fixed in buffered 4% paraformaldehyde and paraffin-embedded, and 5-µm sections were obtained. Glass-mounted sections were cleared from paraffin with xylene and rehydrated by sequential washings with graded ethanol solutions (100–70%). After treatment with 0.3% H2O2 for 15 min at room temperature to inhibit endogenous peroxidase, the sections were treated for two cycles, 5 min each, in a microwave (700 watts) in citrate buffer and incubated for 72 h at 4 C with mouse or goat antibodies that recognized both long and short isoforms (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; sc-1834 and sc-8391) or goat antibodies that recognized only the long isoform (Santa Cruz Biotechnology, Inc.; sc-1832). To test the specificity of the antibody that recognized the long isoform, we performed staining by preincubating antibody with its specific blocking peptide (the blocking peptide is the peptide used to immunize the animal for preparation of antibody; Santa Cruz Biotechnology, Inc.; sc-1832 P) or a nonspecific peptide. After extensive washes, sections were incubated with a biotin-conjugated antimouse or antigoat secondary antibody (Chemicon International, Temecula, CA) for 1 h at room temperature (1:200) and then with peroxidase-conjugated streptavidin (Chemicon International) for 1 h at room temperature (1:200). In control experiments, primary antibodies were omitted. The reactions were developed with a solution of 0.03% 3,3-diaminobenzidine and stopped with water. The sections were counterstained with hematoxylin, dehydrated with graded ethanol solution (70–100%), and mounted.

Statistical analysis

Sample size. The sample size allowed detection of 20% difference or more between obese and control subjects in the mean level of leptin, with a type I error of 0.05 and a power of 0.8. Assuming a leptin mean level of 30 ± 6 ng/ml (mean ± SE) in obese subjects and 10 ± 4 ng/ml (mean ± SE) in lean subjects (2, 5), and a ratio of obese/control of 1:1 or 1:2, at least 15 subjects were required in obese and control groups, respectively. The formula used was: n1 = ({varsigma}12 + {varsigma}22/r) (z1 – {alpha} + z1 – ß)2/(µ1 – µ2)2, where n1 is the sample size of lean subjects, µ1 and {varsigma}1 are the mean and SD of the lean control group, µ2 and {varsigma}2 are the mean and SD of the obese group, r = n1/n2 is the ratio between the sample size of the lean control group and the n2 obese group, r = 1 shows the request of identical sample size for the two groups, and r = 1/2 is a double sample size for the control group (Rosner 2000; Stata Statistical software, release 8.0, Stata Corp., College Station, TX).

Calculations and statistical analysis. The difference among groups for clinical, endocrine, and metabolic variables and for ECG and echocardiography evaluation of LVM was assessed by ANOVA. Differences between groups were assessed using Student’s t test for unpaired samples. The significance of multiple comparisons was adjusted by the Bonferroni correction. Pairwise correlations between clinical and biochemical variables and LVM and between their changes at 1 yr were also calculated. Multiple regression analysis was carried out to estimate the independent contributions of selected variables (variables significant at linear regression plus age and sex) on LVM and its changes. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
To test the possibility of a correlation between plasma leptin levels and left ventricular hypertrophy in obese subjects, we analyzed a populations of 31 normotensive obese subjects and 30 healthy control subjects in whom LVM was measured by ECG (Table 1Go).

Obese subjects had significantly higher BMI, blood pressure, LVM, HOMA index, and fasting insulin and leptin levels than lean subjects. Significantly higher plasma glucose levels were also found, due to the presence among obese subjects of 13 with impaired glucose tolerance and one type 2 diabetic subject. In the entire study population (n = 61), both obese and lean women had significantly higher plasma leptin levels than men (data not shown). LVM was higher in men than in women (P = 0.0099).

At univariate regression analysis, LVM significantly correlated with BMI, leptin, insulin, and HOMA index (Fig. 1Go); this result did not change when data for insulin, HOMA, and leptin were log-transformed (data not shown); in addition, LVM evaluated by ECG correlated with blood glucose (r = 0.387; P = 0.0006), and LVM evaluated by echocardiography correlated with systolic (r = 0.426; P = 0.0012) and diastolic (r = 0.502; P = 0.0001) blood pressures (data not shown).



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  		FIG. 1. Relationship between LVM and BMI, serum insulin, HOMA index, and plasma leptin levels in obese and lean subjects in the Milan study.

 
When the independent contribution of the physical and metabolic variables on LVM was tested, only leptin resulted a significant determinant of LVM (P = 0.001), independently of sex, age, BMI, HOMA index, and 2 h-oral glucose tolerance test (Table 2Go); the results did not change when insulin was introduced into the model instead of HOMA index or when diastolic and systolic blood pressures were introduced into the model (data not shown).


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  		TABLE 2. Multivariate regression analysis with LVM as independent variable

 
We performed the same study in a different population in whom LVM was measured by echocardiography, and we obtained results that were almost completely overlapping (data not shown) (Paolisso, G., P. Giuseppe, and M. Barbieri, unpublished observations).

Obese subjects enrolled in Milan were re-evaluated 1 yr after LAGB, when their BMI decreased from 46.2 ± 1.24 to 36.6 ± 1.05 kg/m2 (P < 0.01); LVM decreased from 1731 ± 86 to 1530 ± 81 mm/msec (P < 0.05), leptin decreased from 39.2 ± 2.37 to 20.9 ± 2.17 ng/ml (P < 0.01), insulin decreased from 18.5 ± 2.72 to 9.5 ± 1.08 µU/ml (P < 0.01), and HOMA index decreased from 5.0 ± 0.87 to 2.2 ± 0.29 (P < 0.01); at simple regression analysis, the LVM decrease only correlated with the decrease in leptin levels (r = 0.509; P = 0.0034; Fig. 2Go).



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  		FIG. 2. Relationship between change in LVM ({Delta}LVM; millimeters per millisecond) and change in plasma leptin levels ({Delta}leptin; nanograms per milliliter) in 31 obese subjects undergoing weight loss through laparoscopic gastric banding.

 
Because studies with transgenic animals or cardiomyocytes in culture have suggested that leptin plays a direct role in cardiac remodeling interacting with specific receptors and leading to the activation of multiple signal-transducing pathways, we analyzed the expression of leptin receptor and leptin receptor signaling apparatus in the human heart (16, 17, 18, 19, 26, 27, 28, 29). We showed that the short, long, and HuB219.1 isoforms of the leptin receptor were expressed in two human heart biopsies. We then compared the expression levels of the three isoforms in insulinoma, adipose tissue, and heart. In all cases, the expressions of the three isoforms were higher in heart and adipose tissue (Fig. 3AGo). When we analyzed some proteins of the leptin receptor signaling apparatus, we showed that JAK2, SHP2, STAT3, SOCS3, p85{alpha} subunit of PI3K, and Akt mRNAs were also expressed in the human heart (Fig. 3BGo).



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  		FIG. 3. RT-PCR analysis of leptin receptor (Ob-R) isoforms and leptin receptor signaling proteins in human heart. A, Expression of leptin receptor isoforms mRNA was detected by RT-PCR using RNA extracted from ventricular biopsies from human heart (He), human insulinoma (In), and adipose tissue (Ad) as a positive control and a reaction in which Maloney murine leukemia virus reverse transcriptase was excluded in RT of human heart sample as a negative control (RT–He). Quantification was performed using a UVP BioImaging System. In each experiment, band densities were normalized against 18S. One representative gel is also shown. The mean ± SE of relative expressions of the genes are shown in the bar graph. Ld, MW ladder. B, Expression of some proteins of leptin receptor signaling apparatus in human insulinoma (In), adipose tissue (Ad), human heart (He), and RT-negative reaction of human heart (RT–He).

 
Immunohistochemical analysis using an anti-leptin receptor antibody that recognizes both short and long isoforms of leptin demonstrated a strong positive immunostaining of myocytes in the left ventricular free wall (Fig. 4AGo), the septum (Fig. 4BGo), and the right ventricle (Fig. 4CGo). Also, the His bundle in the upper portion of the septum showed a strong positive signal, suggesting the expression of leptin receptors in the bundle of conduction. A strong positive signal was also observed using the antibodies that specifically recognized the long isoform of leptin receptor (Fig. 4EGo). To test the specificity of staining, we then performed immunostaining using the antibody directed against the long isoform of the receptor that had been preincubated with its specific blocking peptide or a nonspecific peptide. The staining was negative when the antibody were preincubated with its specific blocking peptide (Fig. 4FGo), whereas strong immunostaining was observed when the antibody was preincubated with a nonspecific peptide (Fig. 4GGo).



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  		FIG. 4. Immunohistochemical detection of leptin receptors (Ob-R) in myocardial sample from an autoptic control subject and in endomyocardial biopsies (A–G). Myocytes showed a strong expression of leptin receptors in the left ventricular free wall (A), the septum (B), and the right ventricle (C). Arrows in B outline the bundle of His in the upper portion of the septum. D, High magnification microphotograph confirming the localization of the immunolabeling in myocytes. E, Myocytes showed a strong expression of the leptin receptor long isoform. F, Staining was abolished when antibodies were preincubated with its specific blocking peptide. G, Staining was positive when antibodies were preincubated with a nonspecific peptide (G). Bars: A–C, 100 µm; D, 10 µm; E–G, 200 µm. Original magnifications: A–C, x100; D, x1000; E–G, x200.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, LVM, measured through different methods, ECG criteria, and echocardiography, was greater in obese than in lean normotensive subjects and correlated with BMI, insulin, HOMA index, and plasma leptin levels. With both methods at multiple regression analysis, LVM only correlated with leptin levels. Obese subjects experiencing a profound weight loss after LAGB had significant reductions of HOMA index, leptin and insulin levels, and LVM (ECG criteria); at simple linear regression, the only correlate of a decrease in LVM was a decrease in leptin levels.

Conflicting results have been obtained to date about the possible relationship between leptin and LVM, usually recorded through echocardiography; Paolisso et al. (8) reported a direct relationship in hypertensive subjects, whereas other researchers (24, 30) failed to confirm this association in population studies, because leptin was not associated with hypertension after adjusting for BMI. This discrepancy might be due to the confounding effect of hypertension, and this is why we have chosen to study only normotensive subjects; obesity and hypertension can coexist, and this leads to sympathetic overactivity greater than in either of the conditions considered separately (31). Recently, a relationship between insulin resistance and LVM has been detected in obese, normotensive subjects using echocardiographic assessment of LVM (32). Therefore, the fact that a direct relationship was found in this study between LVM and leptin, is apparently due to the choice of normotensive subjects, not to the method we used to determine LVM, because the result was the same with the two methods.

Our data are in agreement with previous reports indicating that weight loss is accompanied by reductions of HOMA, leptin levels, and LVM (33, 34, 35); the new finding is that a decrease in leptin correlates with a decrease in LVM, suggesting a role of leptin in left ventricular hypertrophy. In contrast, a potential role for leptin in human cardiac diseases and hypertrophy could be supported by the observations that elevated plasma leptin levels are found in patients with congestive heart failure, fasting plasma leptin concentrations in hypertensive men were significantly associated with myocardial wall thickness, independently of hypertension, and plasma leptin levels correlate with heart rate, independently of plasma insulin, BMI, waist/hip ratio, and percentage of body fat in men (7, 8, 36, 37). However little attempt has been made to understand possible molecular mechanisms involved in leptin action in the human heart.

It is well established that leptin is an important circulating satiety factor that regulates body weight and food intake via its actions on specific hypothalamic nuclei, where it interacts with a specific receptor, leading to the activation of multiple signal-transducing pathways, such as STAT, Ras-MAPK, and PI3K pathways and regulating the expressions of orexigenic and anorectic signals, but it has also become clear that leptin mediates many direct effects on peripheral tissues (38, 39, 40, 41, 42).

In particular, recent evidence in animal models and isolated cardiomyocytes suggests that multiple signal-transducing pathways activated by leptin are also involved in cardiac hypertrophy and survival. leptin has been shown to directly attenuate contraction and induce or prevent hypertrophy in isolated myocytes (16, 17, 18, 19). Inhibitors of ERK1/2 activation and PI3K action reduced leptin-stimulated cardiomyocyte proliferation (17, 19). Transgenic mice expressing constitutively active or dominant-negative mutants of PI3K in the heart showed, respectively, larger hearts and smaller hearts than controls (27). Rapamycin, a specific inhibitor of mammalian target of rapamycin, a protein involved in PI3K pathways, is able to attenuate cardiac hypertrophy (28). Heart size is increased in transgenic mice that express constitutively active forms of Akt from a cardiac specific promoter (29). Our data demonstrated directly the expression of leptin receptors (by both RT-PCR and immunohistochemistry) and leptin receptor signaling proteins (by RT-PCR) in human heart, suggesting a possible role for leptin in mediating heart hypertrophy in obese patients.

Leptin regulates many intracellular signaling pathways that are common to insulin signaling. It is known that at the hypothalamic level, insulin and leptin have overlapping effects in the control of energy homeostasis. Insulin modulates the leptin signal transduction pathway and may provide a molecular basis for the coordinated effects of insulin and leptin in feeding behavior and weight control (43, 44). Recently, it has been hypothesized that positive cross talk between insulin and leptin could play an important role in peripheral tissues and in hyperinsulinemia-associated cardiac hypertrophy (45, 46, 47).

Obesity is a complex syndrome associated with both hyperinsulinemia and hyperleptinemia as well as to insulin and leptin resistance. A recent study showed that insulin resistance contributes to hyperleptinemia associated with cardiac contractile dysfunctions; however, it may not necessarily lead to cardiac leptin resistance (48). In fact, it is possible that selective hypothalamic leptin resistance may occur in obesity, such that centrally mediated effects of leptin are blunted while its peripheral effects are more prominent in the presence of high circulating levels of the hormone.

We did not evaluate IGF-I levels in our patients; however, IGF-I levels are not increased in obesity, and do not decrease after weight loss (49).

In conclusion, studies in transgenic animals and in cell cultures and our findings suggest that leptin may play a role in determining left ventricular hypertrophy (16, 17, 18, 19, 27, 28, 29). Nevertheless, the pathogenesis of left ventricular hypertrophy is multifactorial, and it has been hypothesized that the action of leptin on the sympathetic nervous system could also contribute to the progression of cardiovascular structural alterations (9). Additional studies are warranted to establish a direct effect of leptin on cardiac hypertrophy. In contrast, it is also tempting to hypothesize a therapeutic role for leptin as a growth factor for the myocardium in some forms of heart failure.


   Acknowledgments
 
We thank Francesca Sanvito for generous help with photography.


   Footnotes
 
This work was supported by Grant FIRST 2002 from Università degli Studi di Milano, Ministero dell’Università e della Ricerca Scientifica e Tecnologica 2002 (Grant 2002064582-003), and Ministero della Salute (Grant 199/02; to A.E.P.); and Ministero della Salute (RF02-224; to F.F.). L.P. was supported by a postdoctoral fellowship from the Università degli Studi di Milano and Ministero della Salute. P.P. was supported by a postdoctoral fellowship from the Università degli Studi di Milano.

First Published Online April 26, 2005

Abbreviations: BMI, Body mass index; ECG, electrocardiogram; HOMA, homeostasis model assessment; JAK, Janus kinase; LAGB, laparoscopic adjustable gastric banding; LVM, left ventricular mass; Ob-R, ob gene/leptin receptors; PI3K, phosphatidylinositol 3-kinase; SHP, Src homology protein tyrosine phosphatase; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription.

Received October 6, 2004.

Accepted April 19, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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