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(The FASEB Journal. 2006;20:1653-1659.)
© 2006 FASEB

Human adipocytes attenuate cardiomyocyte contraction: characterization of an adipocyte-derived negative inotropic activity

Valéria Lamounier-Zepter*,1, Monika Ehrhart-Bornstein*, Peter Karczewski{dagger}, Hannelore Haase{dagger}, Stefan R. Bornstein* and Ingo Morano{dagger}

* Medical Clinic III, University of Dresden, Dresden, Germany; and

{dagger} Max-Delbruck-Center for Molecular Medicine, Berlin-Buch, Germany

1Correspondence: Medical Clinic III, University of Dresden, Fetscherstr. 74, Dresden 01307, Germany. E-mail: Valeria.Zepter{at}uniklinikum-dresden.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The causal relationship between obesity and heart failure is broadly acknowledged; however, the pathophysiological mechanisms involved remain unclear. In this study we investigated whether human adipocytes secrete cardioactive substances that may affect cardiomyocyte contractility. We cultivated adipocytes obtained from human white adipose tissue and incubated isolated rat adult cardiomyocytes with adipocyte-conditioned or control medium. This is the first report to demonstrate that human adipocytes exhibit cardiodepressant activity with a direct and acute effect on cardiomyocyte contraction. This adipocyte-derived negative inotropic activity directly depresses shortening amplitude as well as intracellular systolic peak Ca2+ in cardiomyocytes within a few minutes. The adipocyte-derived cardiodepressant activity was dose-dependent and was completely blunted by heating or by trypsin digestion. Filtration of adipocyte-conditioned medium based on molecular mass characterized the cardiodepressant activity at between 10 and 30 kDa. In summary, adipose tissue exerts highly potent activity with an acute depressant effect directly on cardiomyocytes, which may well contribute to increased heart failure risk in overweight patients—Lamounier-Zepter, V., Ehrhart-Bornstein, M., Karczewski, P., Haase, H., Bornstein, S. R., Morano, I. Human adipocytes attenuate cardiomyocyte contraction: characterization of an adipocyte-derived negative inotropic activity.


Key Words: cardiodepressant activity • calcium transient • obesity • heart failure


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBESITY HAS LONG been recognized as an independent risk factor in heart failure (1 2 3 4) . Several mechanisms to explain this correlation have been discussed. Obesity is a well-known risk factor for systemic hypertension and diabetes mellitus; both have long been acknowledged as causes for heart failure (1 , 5) . Thus, the development of heart failure in obese patients may be explained by the cardiac effect of comorbidities secondary to obesity. However, the Framingham study also revealed a relationship between obesity and left ventricular mass and diastolic chamber size, independent of hypertension (6) . Similarly, the risk of developing heart failure was independent of diabetes mellitus in overweight and obese subjects (3) . Thus, hypertension and diabetes mellitus may have an additive deleterious effect on myocardial function, but they do not fully explain the mechanisms underlying obesity-associated heart failure.

Another proposed mechanism refers to the hemodynamic changes secondary to obesity. Obesity is associated with an increased hemodynamic load, which leads to left ventricular remodeling and systolic dysfunction; the latter is due to prolonged inadequate left ventricular stress (7) . Alternatively, increased lipid accumulation into cardiac myocytes, leading to cardiomyocyte apoptosis, is another proposed cause for cardiac dysfunction in obesity (8) .

Recent studies have revealed the importance of human adipose tissue as a highly active endocrine organ. White adipose tissue produces and releases a wide variety of peptides and proteins, collectively referred to as adipokines, with important functions in the adipose metabolism itself, but also with effects on distant organs (9 , 10) . The first specific adipocyte-derived hormone identified was leptin in 1994, which has an important role in the central regulation of appetite and energy homeostasis (11) . To date, more than 100 different factors secreted by adipocytes have been identified, including cytokines/chemokines, fat-specific proteohormones, such as adiponectin and resistin, growth factors, members of the renin-angiotensin system and of the alternate complement pathway. Besides proteins and peptides, adipocytes secrete other nonprotein factors such as prostaglandins and steroid hormones (12 , 13) . The function of the secretory products of human adipocytes is not completely understood, but some of these factors may partly explain the pathogenesis of the metabolic syndrome, including type 2 diabetes mellitus, hypertension, and atherosclerosis (14) . Thus, we recently identified mineralocorticoid-stimulating factors secreted by human adipocytes, supposedly implicated in the pathophysiology of obesity-mediated hypertension (15) .

The involvement of adipokines in the development of heart failure is still unclear. Leptin has been suggested to play a role in cardiovascular system physiology and pathophysiology (16) . However, the effect of leptin on cardiac contraction is controversial. While high doses of leptin directly suppress cardiac contraction (17) , physiologically relevant concentrations (25 ng/ml) abolish the negative inotropic effect of interleukin-1 beta (IL-1ß) (18) . One possible hypothesis is that adipocyte secretory products other than leptin directly influence cardiomyocyte function, thus leading to heart failure. In this study, we tested whether human adipocytes produce cardioactive substances that directly and acutely affect cardiomyocyte contractility using rat adult cardiomyocytes. This is the first study to demonstrate that human adipocytes release a substance that depresses cardiac contraction by attenuating intracellular Ca2+ levels. This potent negative inotropic activity suggests a tight link between obesity and heart failure.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Human tissues
Human white adipose tissue was obtained from six overweight women (38 to 57 years old, BMI ranging between 27 and 35 kg/m2) undergoing surgical mammary reduction. All women were otherwise healthy and free of metabolic and endocrine diseases. Informed consent was obtained from all donors before the surgical procedure. The study was approved by the ethical committee of the Technical University of Dresden.

Isolation of human adipocytes and preparation of adipocyte-conditioned medium
Adipocyte-conditioned medium was prepared by individual samples of human adipose tissue. After surgical removal, adipose tissue samples were immediately transported to the laboratory in cell culture medium (Dulbecco’s modified Eagle’s medium/Nutrient Mix F12 (DMEM/F12, Life Technologies, Karlsruhe, Germany) containing 15 mmol/l HEPES and 4 mmol/l L-glutamine, supplemented with 1.2 g/l NaHCO3, 33 µmol/l biotin, 17 µmol/l pantothenic acid, 100 U/ml penicillin, and 100 µg/ml streptomycin). Adipose tissue was dissected free from fibrous material and visible blood vessels, minced into small pieces, and digested in Kreb’s ringer bicarbonate buffer (KRB) containing 120 U/ml collagenase type I from clostridium histolyticum (Sigma, Munich, Germany) in a shaking water bath for 60 min at 37°C. The digested tissue was filtered twice through nylon gauze (250 µm), washed with KRB, and separated by centrifugation for 10 min at 400 g. Two milliliters of isolated floating adipocytes were cultured in culture flasks (Becton Dickinson, Heidelberg, Germany) containing 2.5 ml of cell culture medium. Cells were kept at 37°C in a humidified atmosphere of 5% CO2 and cultured for 24 h. The adipocyte-conditioned medium (AM) containing all the factors released by the adipocytes was then collected and used for further experiments with isolated adult rat cardiomyocytes. Culture medium without adipocytes was incubated in the same way and used as control medium (CM).

Isolation of adult rat cardiomyocytes
Male Wistar rats aged 3 months were anesthetized with isoflurane, followed by intraperitoneal injection of 8 µg xylazine and 35 µg ketamine. Hearts were rapidly removed, transferred into isotonic NaCl solution containing heparin (1000 U), and connected to a canula in a Langendorff perfusion system. Hearts were perfused at 37°C for 5 min with Ca2+-free Krebs Henseleit buffer (KHB) gassed with carbogen. After that, perfusion was switched to recirculation with KHB containing 0.04% collagenase (Worthington Biochemical Corp, Lakewood, NJ, USA), 0.2% BSA, 10 mmol/l butanedione monoxime, and 22.5 µmol/l CaCl2. After 30 min, the hearts were pale and soft. The ventricles were minced and incubated in the digestion medium for another 10 min at 37°C. After filtration through a nylon mesh (200 µm pore size) and centrifugation, cells were resuspended in Ca2+-free medium. Ca2+ concentration was increased stepwise to 500 µmol/l to obtain Ca2+-tolerant cardiomyocytes. After final washes, cardiomyocytes were resuspended in M199 medium completed with 0.2% BSA, 5% fetal calf serum, 5 mmol/l creatine, 5 mmol/l taurine, 2 mmol/l carnitine, 10 µmol/l cytosine-D-arabinofuranoside, and antibiotics. Cardiomyocytes were seeded in laminin-coated 4-well chamber slides (Nunc, Wiesbaden-Schierstein, Germany) specialized for fluorescence microscopy for contractility and fluorescence measurement. Experiments were approved by the institutional animal care body in Berlin, Germany.

Measurement of cell shortening and Ca2+ transients
Attached cardiomyocytes were washed with Hank’s balanced salts solution buffered with 10 mM HEPES at pH 7.4 (HBSS). Cells were loaded with Fura-2-acetoxymethyl ester for 30 min at room temperature in the dark. Dye solution was removed, and cells were left on HBSS for another 15 min. Only cardiomyocytes of optically intact rod-shaped morphology with clear cross striation were analyzed. Cell shortening and fura-signals were simultaneously measured at 30°C on an Ionoptix Contractility and Fluorescence System (Ionoptix, Milton, MA, USA). Cardiomyocytes were electrically field-stimulated with bipolar pulses of 5 ms duration at 1 Hz. Cell shortening, expressed as percentage of resting cell length, was measured using the video-edge technique at a sampling rate of 240/s. Ca2+ transients were monitored as a ratio of fluorescence emission at 510 nm obtained by alternate excitation at 340 and 380 nm (340/380 ratio). Data files from 15 consecutive beats recorded at intervals were averaged for analysis.

Characterization of adipocyte-conditioned medium
Leptin concentrations in the AM were determined by RIA for human leptin (Lincon Research, St. Charles, MO, USA); interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF{alpha}) concentrations by chemiluminescence immunoassay for human IL-6 and TNF{alpha}, respectively (DPC Biermann, Bad Nauheim, Germany); and IL-1ß and interleukin-2 (IL-2) concentrations by ELISA for human IL-1ß and IL-2, respectively (R & D Systems, Wiesbaden-Nordenstadt, Germany).

Incubation of adult rat cardiomyocytes
Adult cardiomyocytes were electrically stimulated at 1 Hz until both shortening and Fura-2-acetoxymethyl ester signals reached a steady-state level after 10–15 min. Electrical pacing was then switched off, and different volumes of the adipocyte-conditioned medium or the appropriate volume of control medium were added directly to the cardiomyocyte chamber for 5 min. Subsequently, the cardiomyocytes were electrically paced at 1 Hz for 7 min, and mechanical and fluorescence signals were collected. To analyze the heat stability of the cardiodepressant activity, AM was heated to 99°C for 15 min, the denaturized protein was pelleted by centrifugation at 12,000 g for 5 min, and the supernatant was collected and kept frozen at –20°C. We selectively fractionated AM using filtration devices with a cutoff of 10 or 30 kDa (Centricon YM-10 and YM-30, Millipore, Bedford, MA, USA) at 5000 g for 20 min. Protein digestion was performed by incubating AM with trypsin (Invitrogen, Karlsruhe, Germany) in the ratio of 1:50 to total protein content for 4 h at 37°C. Trypsin was inactivated with trypsin inhibitor soybean (Sigma-Aldrich, Taufkirchen, Germany) for 30 min at room temperature.

Statistics
We used paired Student’s t test for significance analysis. Values are expressed as means ± SE.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effect of adipocyte-conditioned medium and control medium on cardiomyocytes
There was a small, insignificant increase in steady-state shortening amplitude from 6.4 ± 0.7 µm before to 7.1 ± 0.9 µm after incubation with control medium (CM; 1/6 dilution with HBSS), that is, +14.4 ± 13.2% (14 cells). The Fura-2 peak fluorescence signal decreased significantly (P<0.01) by –13.34 ± 0.9% (14 cells) upon incubation with CM. However, the adipocyte-conditioned medium (AM; 1/6 dilution with HBSS) significantly (P<0.001) decreased both shortening amplitude from 7.7 ± 0.8 µm to 4.5 ± 0.7 µm, that is, –45.7 ± 6.31%, and Fura-2 signal by –31.9 ± 2.0% (20 cells) (Fig. 1 , Fig. 2 ). Thus, incubation with AM generated a net decline of ~ 18% in Fura-2 peak fluorescence signal. The cause of the small but significant attenuation of Fura-2 peak fluorescence after incubation with CM is not clear, but may be due to bleaching and leakage effects from Fura-2 fluorescence dye.


Figure 1
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  		Figure 1. Effect of CM (control medium; A, C) and AM (adipocyte-conditioned medium; B, D) on shortening amplitudes of Fura-2-loaded adult rat cardiomyocytes. A, B) Representative chart recordings of shortening amplitudes. C, D) Single transients of cell shortening (top) and Fura-2 fluorescence ratio (bottom) from the time points indicated as I or II.


Figure 2
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  		Figure 2. Effect of control medium (open bars) and adipocyte-conditioned medium (filled bars) on shortening amplitude (top) and Fura-2 peak fluorescence (bottom) adult rat cardiomyocytes. Values are expressed as % change of shortening amplitude and Fura-2 signals during the preincubation period; mean ± SE; n = 14 (control medium) or 20 (adipocyte medium); **P < 0.01; ***P < 0.001.

The diastolic length of cardiomyocytes remained almost constant in both CM (115±4.8 µm before and 114±4.7 µm after incubation; 14 cells) and AM-treated cells (115±3.0 before and 114.9±3.0 after incubation; 20 cells). Likewise, no morphological changes were observed in CM- or AM-treated cells.

The cardiodepressant activity of AM was dose dependent. A stepwise dilution of AM with HBSS from 1:6 to 1:51 attenuated the negative inotropic activity of AM on the shortening amplitude of the cardiomyocytes (Fig. 3 ).


Figure 3
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  		Figure 3. Dose dependence of negative inotropic activity in adipocyte-conditioned medium (AM). Cardiomyocytes were incubated with AM diluted with HBSS in various ratios.

The cardiodepressant effect of AM was heat sensitive. After incubation with heated AM (99°C, 15 min), shortening amplitude of rat cardiomyocytes remained at preincubation level (Fig. 4 A). The cardiodepressant effect of AM could be removed on a 10 kDa cut-off filtration of AM (Fig. 4B ), but remained present on AM filtration with a 30 kDa cutoff (Fig. 4C ). The negative inotropic activity of AM was completely blunted by trypsin treatment (Fig. 4D ).


Figure 4
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  		Figure 4. Original chart recording of cardiomyocyte shortening amplitudes before and after incubation with A) adipocyte-conditioned medium heated at 95°C for 5 min (AMheat); B) AM filtrated through a 10 kDa cutoff (AM10 kDa); C) AM filtrated through a 30 kDa cutoff (AM30 kDa); D) AM treated with trypsin (AM trypsin), followed by untreated AM.

Characterization of the adipocyte-conditioned medium
Concentrations of leptin, IL-6, IL-1ß, IL-2, and TNF{alpha} were measured in the adipocyte-conditioned medium, and maximal concentrations from the experiment (dilution 1:6) were calculated (Table 1 ). A comparison with published data reveals that the cytokine concentrations found in the experiment were far below the effective threshold doses influencing cardiomyocyte contraction (Table 1) .


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  		Table 1. Concentration of adipokines in the adipocyte-conditioned mediuma

Analysis of peak calcium and shortening amplitude
In this study we used the peak height of the Fura-2 fluorescence signal as an indicator for intracellular free Ca2+ levels and shortening amplitudes of cardiomyocytes as a monitoring system. To demonstrate the correlation between peak Fura-2 fluorescence with shortening amplitude in our system and experimental design, we plotted normalized peak Fura-2 signals against the corresponding shortening amplitude during the negative staircase period. After a period of quiescence lasting at least 15 min, cardiomyocytes were electrically stimulated and the initial Fura-2 and shortening signals monitored, normalized, and correlated (Fig. 5 ).


Figure 5
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  		Figure 5. Relationship between normalized Fura-2 peak fluorescence and normalized peak shortening amplitude during the negative staircase (228 signals of 7 different cardiomyocytes). All values are expressed as a percentage of the maximal (initial) shortening or Fura-2 signals. The values were fitted by a single exponential function (y=2.45 e0.037x; n=228 signals of 7 cardiomyocytes; r2=0.86).

We obtained an exponential correlation (y=2.45 e0.037x; n=228 signals of 7 cardiomyocytes; r2=0.86) between both normalized signals; that is, the higher the Fura-2 peak fluorescence signal, the higher the shortening amplitude. According to this calibration curve, a reduction of shortening amplitude by 42% should be associated with a concomitant decrease of the Fura-2 signal by ~ 18%.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present data reveal that mature human adipocytes release a substance that strongly and acutely suppresses contraction of electrically paced adult cardiomyocytes. Adipocyte-derived negative inotropic activity (ADNIA) could be completely blunted by heating and by trypsin treatment, indicating the involvement of a protein. By fractionating AM using filtration devices, ADNIA could be removed by 10 kDa cut-off filtration, but remained after 30 kDa cut-off filtration, defining the molecular mass of the protein as between 10 and 30 kDa.

The strong cardiodepressant action of human ADNIA was accompanied by a slight but significant decline of ~ 18% in the net Fura-2 peak signal. This slight decline may indeed be responsible for the much larger relative decline of shortening amplitude indicated by the normalized shortening amplitude/Fura-2 calibration curve. We observed an exponential relationship between the Fura-2 peak fluorescence and shortening amplitude; thus, a decline of only 18% in the Fura-2 signal may indeed correspond to a decrease of 45% in contraction.

Adipose tissue is an endocrine organ that secretes a wide variety of bioactive peptides and proteins (adipokines), which seem to mediate communication between adipose tissue and other organs such as muscle, liver, pancreas, brain, and vascular endothelium (10) . Several cytokines have been subject to speculation as possibly playing a role in the onset of cardiac dysfunction with inflammation; one of these cytokines also released from adipocytes may be responsible for the cardiodepressant activity observed in this study. However, the concentrations of leptin, TNF{alpha}, IL-1ß, and IL-6 present in our experiments were several orders of magnitude lower than the effective threshold dosages for these cytokines. Therefore, even the total concentration of these adipokines taken together cannot account for the large ADNIA described. Furthermore, prolonged (14 h) rather than acute incubation of cardiomyocytes with TNF{alpha} and IL-1ß have been found to be a prerequisite for the induction of a negative inotropic effect by these cytokines (19) .

Adipose tissue expresses several components of the renin-angiotensin system and produces considerable levels of angiotensinogen and angiotensin (ANG) II (20) . However, ANG II has no effect on single cardiomyocytes (21) or a positive inotropic effect on papillary muscle (22) . Furthermore, the molecular mass of ANG II is considerably lower than the molecular mass of ADNIA (between 10 and 30 kDa). It is therefore hardly possible to link adipose ANG II to the cardiodepressant activity exerted by human adipocytes as verified in this report.

As a consequence of the release of (hitherto unidentified) paracrine substances, cardiodepression has also been observed in cultured hypoxic-induced endothelial cells (23) as well as coronary effluent from hypoxic isolated perfused heart (24) . However, these factors were heat resistant, had a lower molecular mass (<500 Da) than the adipocyte-derived cardiodepressant factor described in this report, and showed clear myofibrillar-desensitizing activity. Furthermore, another set of negative inotropic substances released after cardiac ischemia during reperfusion of isolated hearts was stable to heat and showed decreased intracellular Ca2+, which was probably due to reduction in Ca2+ influx through the L-type Ca2+ channel (25) .

Recently, we reported on heat-labile mineralocorticoid-releasing activity exerted by human adipocytes (15) . This activity, however, revealed a molecular mass of >50 kDa, which was considerably higher than the negative inotropic activity in the AM. The results of our experiments are similar to the effects of periadventitial fat, which also exerts heat-labile activity by mechanisms as yet unidentified, with anticontractile effects on smooth muscle cells in blood vessels (26) .

Although a causal relationship between increased body mass index and heart failure is broadly acknowledged (3 , 4) , the pathophysiological mechanisms involved remain unclear. The development of heart failure in obesity has mainly been explained by altered left ventricular remodeling due to increased hemodynamic load and/or neurohormonal activation (7) . A direct causal effect of obesity on myocardium dysfunction has also been suggested by Zhou et al. (8) , demonstrating a statistical correlation between impaired contractile function and intramyocardial lipid accumulation in an animal model of obesity. The authors suggested that cardiac dysfunction in obesity might be caused by lipotoxicity and lipoapoptosis, a mechanism similar to the increased lipoapoptosis previously observed in pancreatic islet cells from obese rats (27) . This apparently applies to severe obesity and cannot explain the increased heart failure risk in mild-to-moderate overweight patients (28) . Our results, however, suggest that adipose tissue exerts a highly effective impact by directly and acutely depressing cardiomyocyte contractility, without affecting cell viability. This observation may well explain the increased cardiovascular risk in overweight patients.

In conclusion, our data demonstrate that adipocytes exert a hitherto unknown negative inotropic effect on cardiomyocytes by reducing intracellular Ca2+. These findings suggest a direct involvement of adipose tissue in the pathogenesis of myocardium dysfunction, thus explaining the tight association between obesity and heart failure. This is especially important given the increasing worldwide tendency toward overweight and obesity, and reinforces the importance of efforts to promote optimal body weight in the population.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge the expert technical assistance of Uta Buro, Petra Pierschalek, and Wolfgang-Peter Schlegel. We thank Dr. Lobodasch and his team, DRK Clinic, Chemnitz-Rabenstein for their help in obtaining human adipose tissue. This study was supported in part by the Das Zuckerkranke Kind foundation (to V.L.Z. and S.R.B.) and Deutsche Forschungsgemeinschaft (grant EH 161/4–1 to M.E.B. and S.R.B.).

Received for publication November 25, 2005. Accepted for publication March 31, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. He, J., Ogden, L. G., Bazzano, L. A., Vupputuri, S., Loria, C., Whelton, P. K. (2001) Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch. Intern. Med. 161,996-1002[Abstract/Free Full Text]
  2. Hubert, H. B., Feinleib, M., McNamara, P. M., Castelli, W. P. (1983) Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67,968-977[Abstract/Free Full Text]
  3. Kenchaiah, S., Evans, J. C., Levy, D., Wilson, P. W., Benjamin, E. J., Larson, M. G., Kannel, W. B., Vasan, R. S. (2002) Obesity and the risk of heart failure. N. Engl. J. Med. 347,305-313[Abstract/Free Full Text]
  4. Wong, C. Y., O’Moore-Sullivan, T., Leano, R., Byrne, N., Beller, E., Marwick, T. H. (2004) Alterations of left ventricular myocardial characteristics associated with obesity. Circulation 110,3081-3087[Abstract/Free Full Text]
  5. Wilhelmsen, L., Rosengren, A., Eriksson, H., Lappas, G. (2001) Heart failure in the general population of men—morbidity, risk factors and prognosis. J. Intern. Med. 249,253-261[CrossRef][Medline]
  6. Lauer, M. S., Anderson, K. M., Kannel, W. B., Levy, D. (1991) The impact of obesity on left ventricular mass and geometry. The Framingham Heart Study. J. Am. Med. Assoc. 266,231-236[Abstract]
  7. Alpert, M. A. (2001) Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. Am. J. Med. Sci. 321,225-236[CrossRef][Medline]
  8. Zhou, Y. T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., Orci, L., Unger, R. H. (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc. Natl. Acad. Sci. U. S. A. 97,1784-1789[Abstract/Free Full Text]
  9. Krug, A.W., Ehrhart-Bornstein, M. (2005) Newly discovered endocrine functions of white adipose tissue: possible relevance in obesity-related diseases. Cell Mol. Life Sci. 62,1359-1362[CrossRef][Medline]
  10. Kershaw, E. E., Flier, J. S. (2004) Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89,2548-2556[Abstract/Free Full Text]
  11. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J. M. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372,425-432[CrossRef][Medline]
  12. Staiger, H., Haring, H. U. (2005) Adipocytokines: fat-derived humoral mediators of metabolic homeostasis. Exp. Clin. Endocrinol. Diabetes 113,67-79[CrossRef][Medline]
  13. Hauner, H. (2004) The new concept of adipose tissue function. Physiol. Behav. 83,653-658[CrossRef][Medline]
  14. Wajchenberg, B. L. (2000) Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21,697-738[Abstract/Free Full Text]
  15. Ehrhart-Bornstein, M., Lamounier-Zepter, V., Schraven, A., Langenbach, J., Willenberg, H. S., Barthel, A., Hauner, H., McCann, S. M., Scherbaum, W. A., Bornstein, S. R. (2003) Human adipocytes secrete mineralocorticoid releasing factors. Proc. Natl. Acad. Sci. U. S. A. 100,14211-14216[Abstract/Free Full Text]
  16. Sharma, V., McNeill, J. H. (2005) The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology. Curr. Vasc. Pharmacol. 3,169-180[CrossRef][Medline]
  17. Nickola, M. W., Wold, L. E., Colligan, P. B., Wang, G. J., Samson, W. K., Ren, J. (2000) Leptin attenuates cardiac contraction in rat ventricular myocytes. Role of NO. Hypertension 36,501-505
  18. Holycross, B. J., Radin, M. J. (2002) Cytokines in heart failure: potential interactions with angiotensin II and leptin. Mol. Interv. 2,424-427[Abstract/Free Full Text]
  19. Stein, B., Frank, P., Schmitz, W., Scholz, H., Thoenes, M. (1996) Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J. Mol. Cell Cardiol. 28,1631-1639[CrossRef][Medline]
  20. Engeli, S., Negrel, R., Sharma, A. M. (2000) Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 35,1270-1277[Abstract/Free Full Text]
  21. Lefroy, D. C., Crake, T., Del, M. F., Vescovo, G., Dalla, L. L., Harding, S., Poole-Wilson, P. A. (1996) Angiotensin II and contraction of isolated myocytes from human, guinea pig, and infarcted rat hearts. Am. J. Physiol. 270,H2060-H2069
  22. Watanabe, A., Endoh, M. (1998) Relationship between the increase in Ca2+ transient and contractile force induced by angiotensin II in aequorin-loaded rabbit ventricular myocardium. Cardiovasc. Res. 37,524-531[Abstract/Free Full Text]
  23. Shah, A. M., Mebazaa, A., Yang, Z. K., Cuda, G., Lankford, E. B., Pepper, C. B., Sollott, S. J., Sellers, J. R., Robotham, J. L., Lakatta, E. G. (1997) Inhibition of myocardial crossbridge cycling by hypoxic endothelial cells: a potential mechanism for matching oxygen supply and demand?. Circ. Res. 80,688-698[Abstract/Free Full Text]
  24. Yang, Z. K., Draper, N. J., Shah, A. M. (1999) Ca2+-independent inhibition of myocardial contraction by coronary effluent of hypoxic rat hearts. Am. J. Physiol. 276,H623-H632
  25. Stangl, V., Baumann, G., Stangl, K., Felix, S. B. (2002) Negative inotropic mediators released from the heart after myocardial ischaemia-reperfusion. Cardiovasc. Res. 53,12-30[Abstract/Free Full Text]
  26. Lohn, M., Dubrovska, G., Lauterbach, B., Luft, F.C., Gollasch, M., Sharma, A. M. (2002) Periadventitial fat releases a vascular relaxing factor. FASEB J. 16,1057-1063[Abstract/Free Full Text]
  27. Haber, E. P., Ximenes, H. M., Procopio, J., Carvalho, C. R., Curi, R., Carpinelli, A. R. (2003) Pleiotropic effects of fatty acids on pancreatic beta-cells. J. Cell. Physiol. 194,1-12[CrossRef][Medline]
  28. Massie, B. M. (2002) Obesity and heart failure—risk factor or mechanism?. N. Engl. J. Med. 347,358-359[Free Full Text]
  29. Kumar, A., Thota, V., Dee, L., Olson, J., Uretz, E., Parrillo, J. E. (1996) Tumor necrosis factor alpha and interleukin 1ß are responsible for in vitro myocardial cell depression induced by human septic shock serum. J. Exp. Med. 183,949-958[Abstract/Free Full Text]
  30. Amadou, A., Nawrocki, A., Best-Belpomme, M., Pavoine, C., Pecker, F. (2002) Arachidonic acid mediates dual effect of TNF-alpha on Ca2+ transients and contraction of adult rat cardiomyocytes. Am. J. Physiol. 282,C1339-C1347
  31. Cao, C. M., Xia, Q., Bruce, I. C., Zhang, X., Fu, C., Chen, J. Z. (2003) Interleukin-2 increases activity of sarcoplasmic reticulum Ca2+-ATPase, but decreases its sensitivity to calcium in rat cardiomyocytes. J. Pharmacol. Exp. Ther. 306,572-580[Abstract/Free Full Text]



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Coculture with Primary Visceral Rat Adipocytes from Control But Not Streptozotocin-Induced Diabetic Animals Increases Glucose Uptake in Rat Skeletal Muscle Cells: Role of Adiponectin
Endocrinology, September 1, 2007; 148(9): 4411 - 4419.
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 Endocr. Rev.Home page
R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon
Cardiovascular Actions of Insulin
Endocr. Rev., August 1, 2007; 28(5): 463 - 491.
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E. Nisoli, E. Clementi, M. O. Carruba, and S. Moncada
Defective Mitochondrial Biogenesis: A Hallmark of the High Cardiovascular Risk in the Metabolic Syndrome?
Circ. Res., March 30, 2007; 100(6): 795 - 806.
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