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Departments of Clinical Biochemistry (C.C., M.L.S.L., E.D.B., J.P.G., L.B.N.) and Pathology (C.B.A.), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 2100; and Department of Clinical Physiology (E.B.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
Address all correspondence and requests for reprints to: Lars B. Nielsen, M.D., Ph.D., D.M.Sc., Department of Clinical Biochemistry KB3011, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 2100. E-mail: larsbo{at}rh.dk.
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Introduction |
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gene leads to lipid accumulation and deteriorated heart function (8). Streptozotocin-induced diabetes caused cardiac triglyceride accumulation and cardiac dysfunction in lean wild-type mice, whereas streptozotocin-treated diabetic apolipoprotein B (apo-B) transgenic mice had normal cardiac triglyceride levels and normal cardiac function (9). Although these studies suggest that cardiac triglyceride accumulation may be accompanied by ventricular dysfunction, the impact of obesity on cardiac lipid accumulation and the function of the mouse heart have not been investigated. Obesity-induced type II diabetes is associated with increased plasma concentrations of free fatty acids. This presumably results in an increased delivery of fat to the heart muscle (10). However, uptake and metabolism of free fatty acids and triglycerides by cardiac myocytes can be regulated at many levels, e.g. hydrolysis of triglycerides in myocardial capillaries [e.g. by lipoprotein lipase (11)], fatty acid transport across the myocyte cell membrane [e.g. by CD36 (12), fatty acid transport protein (FATP) 1, and FATP 4 (13)], intracellular transport of fatty acids [e.g. by heart-specific fatty acid binding protein (hFABP) (14) and carnitine palmitoyl-transferase (CPT)-1 (15)], and fatty acid ß-oxidation [involving a number of enzymes including long-chain acyl-coenzyme A (CoA) dehydrogenase (LCAD)]. Although the expression of several of these genes is affected in diabetic animals (14, 16, 17, 18), the relative contribution of activity changes in these pathways to lipid accumulation is not clear in the obese heart. In addition, the formation and secretion of triglycerides in apo-B-containing lipoproteins may also affect cardiac triglyceride stores (9, 19, 20). The transfer of triglycerides onto apo-B is conferred by microsomal triglyceride transfer protein (MTP) within the lumen of the endoplasmic reticulum (21). Pharmacological inhibition (22) or genetic ablation (20) of MTP activity in the heart reduces lipoprotein secretion and promotes triglyceride storage. Heart MTP gene expression levels appear to be increased in at least two settings in which the supplies of fatty acids to the myocardium exceed the utilization in ß-oxidation, i.e. in human ischemic myocardium (19) and in streptozotocin-treated diabetic mouse hearts (9). This may reflect that an increase of the lipoprotein secretion rate acts to maintain normal (low) intracellular triglyceride levels in the cardiac myocytes.
The aim of the present study was to improve the understanding of the effects of obesity on cardiac lipid accumulation and heart function. Therefore, we characterized the lipid content in the heart, the expression of genes involved in cardiac lipid metabolism (including apo-B and MTP expression), and cardiac function in obese diabetic ob/ob mice and in lean nondiabetic ob/+ control mice.
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Materials and Methods |
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Histology
For electron microscopy, the neutral lipids in biopsies from the ventricular portion of the heart were stained with an imidazole-based technique (23). After Epon embedding, sections (50–70 nm) were cut with a Reichard Jung Ultra WTE 701704 microtome and inspected in a Philips 201 electron microscope. To assess cardiac fibrosis, heart biopsies from 10 ob/ob and 10 ob/+ mice were fixed in 4% paraformaldehyde in 0.1 mol/liter Na2PO4 (pH 7.4) and embedded in paraffin. Cross-sections (5 µm) from the distal end of the ventricle of each heart were stained with Masson Trichrome. Four random digital images from each mouse were acquired with a Leica DC 300F digital camera (Leica Microsystems A/S, Herlev, Denmark). The area of blue-staining connective tissue was determined by digital image analysis using the ImageJ 1.29x freeware (http://rsb.info.nih.gov/ij). The sectioning, staining, and digital analysis of fibrosis were performed blinded with respect to mouse genotype.
Heart lipids
Lipids were extracted from approximately 30 mg of ventricular heart tissue with chloroform/methanol (24) and redissolved in toluol (1 µl/mg wet weight) for thin layer chromatography (TLC) (25). TLC plates (DC-fertigplatten SIL G-25, Macherey-Nagel, Duren, Germany; 20 x 20 cm) were impregnated with Na2 EDTA (1 mM; pH 5.5), dried, and washed in chloroform-methanol-water (60:40:10). The plates were activated at 110 C for 30 min, and 1-µl tissue extracts and lipid standards (all lipid standards were from Sigma, Vallensbaek Strand, Denmark) with defined amounts of lipids were applied. The plates were developed in a six-step procedure (25) before being placed in 10% cupric sulfate (wt/vol) in 8% phosphoric acid (vol/vol), dried, and baked for 2 min at 200 C. Lipids in heart extract were quantified by digital image analysis. All samples were analyzed in duplicate on separate TLC plates. The precision and accuracy of this assay have been reported elsewhere (9, 24).
Gene expression
Total RNA was isolated from approximately 40 mg of heart tissue and used for cDNA synthesis and quantitative real-time PCR analysis of mRNA expression with a Lightcycler (Roche A/S, Hvidovre, Denmark) (9). The following sense and antisense primers were used: PPAR-, 5'-aggaagccgttctgtgacat-3' and 5'-aatcccctcctgcaacttct-3'; PPAR-
, 5'-ggcacatctgttcttccaca-3' and 5'-gccatcccttagttcactgg-3'; lipoprotein lipase, 5'-agggctctgcctgagttgta-3' and 5'-agaaatttcgaaggcctggt-3'; CD36, 5'-tggagctgttattggtgcag-3' and 5'-tgggttttgcacatcaaaga-3'; FATP 1, 5'-gcttcaacagccgtatcctc-3' and 5'-tcttcttgttggtggcactg-3'; FATP 4, 5'-gtgttgaggtgccaggaact-3' and 5'-tccttccgcaactctgtctt-3'; hFABP, 5'-aggtcggtagcatgaccaag-3' and 5'-ctgcacatggatgagtttgc-3'; CPT-1, 5'-cccatgtgctcctaccagat-3' and 5'-cgaggattctctggaactgc-3'; LCAD, 5'-ttccgggagagtgtaaggaa-3' and 5'-tacgcttgctcttcccaagt-3'; glucose transporter 4 (GLUT-4), 5'- gctttgtggccttctttgag-3' and 5'-caggaggacggcaaatagaa-3'; phosphofructokinase, muscle (Pfkm), 5'-gggtcactgttctgggacat-3' and 5'-ggtcacgtctttggtcacct-3'; and acyl CoA:diacylglycerol acyltransferase (DGAT), 5'-tcctgaattggtgtgtggtg-3' and 5'-ggcgcttctcaatctgaaat-3'. Primer pairs for MTP, apo-B, sterol regulatory element binding proteins (SREBPs), ß-actin, and brain natriuretic peptide (BNP) mRNA amplification have been reported elsewhere (9, 24). For each PCR, the specificity was assured by agarose gel electrophoresis and by DNA-sequencing of the PCR product. The relation between the time point of the log-linear increase of the fluorescence signal during the PCR and the relative concentration of an mRNA transcript was determined by parallel analyses of dilutions of a pool of liver cDNA (for MTP and apo-B) or a pool of heart cDNA (all other genes) from normal mice.
Heart microsomal triglyceride transfer activity
Extracts of microsomal proteins were prepared by homogenization of approximately 40 mg ventricular heart tissue in 1 ml buffer (50 mmol/liter Tris-HCl, 50 mmol/liter KCl, 5 mmol/liter EDTA, and protease inhibitor, Roche A/S) with a PT 1200 Polytron (Buch & Holm A/S, Herlev, Denmark). The total protein concentration in each homogenate was determined with the bicinchoninic acid protein assay (Pierce, Copenhagen, Denmark) using BSA as standard. The protein concentration was adjusted to 1.75 mg/ml, and heart homogenates were subjected to centrifugation for 60 min at 100,000 x g in a Beckman Optima LE-80K ultracentrifuge (Beckman Coulter Inc., Fullerton, CA). The supernatant containing the microsomal fraction was added to 1/10 volume of 0.54% sodium deoxycholate (pH 7.5) and incubated on ice for 30 min, followed by overnight dialysis at 4 C against a buffer [15 mmol/liter Tris (pH 7.4), 40 mmol/liter NaCl, 10 mmol/liter EDTA, and 0.02% NaN3]. Triglyceride transfer activity in the microsomal protein fraction was measured at 37 C as the transfer of 14C-triglycerides from labeled donor vesicles to acceptor vesicles that contained unlabeled triglycerides (26). The donor vesicles contained 40 nmol phosphatidylcholine, 0.08 nmol 14C-triglyceride, 3.0 nmol cardiolipin, and 100 cpm/nmol 3H- phosphatidylcholine. The acceptor vesicles contained 240 nmol phosphatidylcholine, 0.48 nmol triolein, and 100 cpm/nmol 3H-phosphatidylcholine. In initial evaluations of the assay, the transfer of 14C-triglycerides during 1 h increased linearly with the amount of microsomal protein extract in a range corresponding to between 0 and 125 µg of total heart protein. When donor and acceptor vesicles were incubated with microsomal proteins corresponding to 100 µg total heart protein extract, the 14C-triglyceride transfer increased linearly with time for 5 h. Consequently, we measured the triglyceride transfer activity in mouse hearts by incubating the microsomal protein fraction corresponding to 100 µg of total heart protein with donor and acceptor vesicles for 4 h. The triglyceride transfer activity in each heart extract was always corrected for the transfer activity in a heat-inactivated (incubation at 65 C for 10 min) aliquot of the same extract (26) and for the spontaneous transfer between donor and acceptor vesicles in a test tube without heart extract. In each assay, we also performed parallel analysis of mouse liver microsomal extracts corresponding to 5, 10, and 20 µg total protein to assure the linearity of the assay. Samples from ob/ob and ob/+ mice were always alternated, and the presented results are the mean of three determinations in separate assays.
Cardiovascular function
Systolic blood pressure and heart rate were measured in conscious mice with a computerized tail-cuff system (BP 2000, Visitech Systems, Apex, NC). For each blood pressure determination in each mouse, the result was the mean of at least one set of 10 measurements with at least nine successful readings.
Transthoracic echocardiography with Doppler flow analysis was performed in anesthetized mice with the Vived Five instrument (GE Ultrasound, Copenhagen, Denmark) and a 10-MHz transducer head. All recordings and measurements were performed by the same experienced examiner (E.B.). Left ventricular mass was calculated as 1.055 x [(LVD + PW + AW)3 - (LVD)3]; LVD is the left ventricular diameter in the diastolic phase, and PW and AW are the thickness of the posterior and anterior walls of the left ventricle, respectively. Anesthesia was induced with a sc injection of 0.05–0.08 ml/10 g body weight of fentanyl 0.079 mg/ml, fluanisone 2.5 mg/ml, and midazolam 1.25 mg/ml (Hypnorm/Dormicum, 1:1). In each mouse, the investigations were repeated after an ip injection of dobutamine (1 µg/g body weight).
Statistics
Differences between groups were analyzed with Student’s t test. Welch’s correction for unequal variances was used whenever appropriate. Results are expressed as mean ± SEM.
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). Of note, we did not observe infiltration of adipocytes in the ventricular myocardium using oil-red-O staining of frozen heart sections (data not shown). To examine the lipid composition of mouse hearts, we adapted a TLC-based technique (Fig. 2A). The heart triglyceride content was 3.0-fold higher in ob/ob mice compared with ob/+ mice (Fig. 2B). The heart phosphatidylcholine and phosphatidylinositol contents were also significantly higher in ob/ob than in ob/+ mice, whereas the heart sphingomyelin, phosphatidylserine, phosphatidylethanoamine, cardiolipin, and unesterified cholesterol contents were similar in ob/ob and ob/+ mice (Fig. 2B).
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). Genes encoding Pfkm and GLUT-4 (key regulators of glucose metabolism) were also increased in ob/ob compared with ob/+ mouse hearts, whereas the expression of the PPAR- and PPAR- genes was similar in the two groups (Fig. 3A).
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). Apo-B mRNA expression was similar in ob/ob and ob/+ mouse hearts (104 ± 25% vs. 100 ± 21% of the mean in ob/+ mice; n = 2 x 10). Although a correlation between mRNA and protein expression has been indicated previously for many of the genes examined in Fig. 3A, it is unknown whether increased MTP mRNA expression in the heart also confers increased MTP protein expression. Therefore, we examine the physiological result of MTP gene expression, i.e. triglyceride transfer activity in heart microsomal extracts. The triglyceride transfer activity was significantly higher in the ob/ob than in the ob/+ mouse hearts (Fig. 3B).
Cardiac function in ob/ob mice
Cardiac function was assessed in 10- to 11-wk-old female mice. The systolic blood pressure was approximately 10 mm Hg lower in ob/ob when compared with ob/+ mice (Fig. 4A). The heart rate was lower in ob/ob than in ob/+ mice in the morning, but not in the afternoon (Fig. 4B). Two previous studies have reported divergent results on the blood pressure in ob/ob mice. One study (27) found increased blood pressure in 6-wk-old female ob/ob mice during the daytime and normal blood pressure during the night using a blood pressure telemeter implanted in the left common carotid artery. The other study (28) found a lower blood pressure in 10- to 14-wk-old male ob/ob mice when the measurements were performed in darkness and blood pressure was measured with arterial catheterization. Thus, the discrepant findings might reflect differences in methodology for measuring blood pressure or the age of the mice studied.
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). Nevertheless, there was no significant difference between ob/ob and ob/+ mice in the diameters of the left ventricle during systole or diastole (Table 1). To evaluate interstitial fibrosis, we stained sections of ob/ob and ob/+ ventricles with Masson Trichrome and assessed the content of intercellular collagen in the ventricular portion with morphometry. The area of the blue-staining collagen was 1.0 ± 0.1% (of total area) (n = 10 in ob/ob mice and 0.9 ± 0.1%; n = 10 in ob/+ mice; P = 0.6).
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, A and B). The E-wave was similar in ob/ob and ob/+ mice (Table 1). Correspondingly, the ratio of E to A was significantly lower in ob/ob compared with ob/+ mice (Table 1). LV diastolic parameters could not be evaluated after the dobutamine injection because of the high heart rates.
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and Table 1). Fractional shortening was similar at baseline but slightly lower after dobutamine administration (1 µg/g body weight) in ob/ob compared with ob/+ mice (Fig. 5C). Thus, the dobutamine-induced increase in fractional shortening was significantly smaller in ob/ob compared with ob/+ mice (8.5 ± 1.5 vs. 17.9 ± 1.6%; P = 0.0003). Accordingly, dobutamine also increased the circumferential shortening to a lesser extent in ob/ob mice than in ob/+ mice (4.2 ± 0.4 vs. 5.7 ± 0.3 circumferences/sec; P = 0.004) (Table 1). Of note, the effect of dobutamine on the heart rate was similar in ob/ob and ob/+ mice (Table 1), indicating that the adrenergic stimulus was similar in the two groups.
The expression of BNP mRNA was similar in ob/ob and ob/+ mice (Fig. 5D). Our recent studies suggest that BNP mRNA expression is a highly sensitive indicator of mild cardiac dysfunction in streptozotocin-treated diabetic mice (9) as in humans (29). Thus, the unchanged BNP mRNA expression supports the idea of a very mild (or no) affection of the cardiac systolic function in ob/ob mice.
We also examined hearts of 25-wk-old male ob/ob and ob/+ mice. The heart BNP mRNA levels were similar in these ob/ob and ob/+ mice [125 ± 43% (n = 12) vs. 100 ± 14% (n = 12) of the mean in ob/+ mice; P = 0.5] despite markedly higher cardiac triglyceride concentrations in the ob/ob compared with ob/+ mice (8.4 ± 2.9 vs. 1.7 ± 0.2 nmol/mg wet weight; P < 0.001).
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Discussion |
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The plasma concentrations of free fatty acids are increased in obese type II diabetic individuals. This is believed to cause fat accumulation in muscles (10). The present study suggests that, in addition to the effect of increased plasma fatty acid concentrations, there are also changes in cardiac gene expression that promote the accumulation of free fatty acids in the cardiac myocytes. Of note, the observed changes can result from altered gene transcription rates, changes in mRNA stability, or a combination. Nevertheless, the analysis of mRNA from genes that control essential steps in myocardial fatty acid metabolism suggests that the handling of fatty acids is affected at many levels in obese diabetic mice. Thus, the results suggest that increased lipolysis in the heart (by lipoprotein lipase) increased fatty acid transport across the myocyte cell membrane (by increased expression of CD36, FATP 1, and FATP 4), and increased expression of DGAT may all participate in increasing triglyceride stores in ob/ob hearts. These conclusions can be further tested in the future by studying the metabolism of radiolabeled fatty acids in ex vivo perfused hearts.
MTP gene expression and MTP activity were increased in the ob/ob mouse hearts. Inasmuch as an increased MTP activity results in increased secretion of lipoprotein triglycerides from the heart [which is the case in the liver of ob/ob mice (24)], this result is compatible with the idea that cardiac formation of apo-B-containing lipoproteins plays a role in removing excess triglycerides from the cardiomyocytes. We previously observed that the MTP gene expression is also increased in ischemic human hearts (19) and in streptozotocin-diabetic mouse hearts (9). The present study adds further evidence to the idea that an up-regulation of MTP expression in the heart serves as a protective mechanism to unload excess lipids when the supply of fatty acids exceeds the utilization. The molecular mechanisms that lead to increased MTP gene transcription in the heart are unknown. SREBP-1 suppresses the activity of the MTP gene promoter in cultured liver (HepG2) cells (31), and we have observed a close negative correlation between SREBP-1 and MTP mRNA expression in ischemic human hearts (19). However, we did not observe differences in cardiac SREBP-1c, -1a, or -2 mRNA levels between ob/ob and ob/+ control mice (data not shown). Hence, other mechanisms than altered expression of the SREBP genes cause increased MTP expression in the ob/ob mouse heart.
Echocardiography with Doppler flow analysis revealed pronounced changes in the cardiac diastolic function in 11-wk-old ob/ob mice. An affect on diastolic function was seen as specific increases in the peak height of the A-wave and a corresponding decrease in E/A in ob/ob mice. This finding probably reflects impaired relaxation of the left ventricle during diastole. The type II diabetic Otsuka Long Evans Tokushima Fatty (OLETF) rat model develops diastolic cardiac dysfunction in parallel with interstitial collagen accumulation (32). In the present study, however, we could not detect a difference in interstitial collagen deposition in hearts of 10- to 11-wk-old ob/ob mice with diastolic dysfunction. Nevertheless, the observations of increased left ventricular mass and unchanged relative wall thickness suggested that diastolic dysfunction was paralleled by mild eccentric cardiac hypertrophy in ob/ob mice.
Both fractional and circumferential shortening were similar in ob/ob and ob/+ mice at baseline. Moreover, the BNP mRNA expression was unaffected in 10- to 11-wk-old as well as in 25-wk-old ob/ob mice. These data suggest that even marked lipid accumulation in ob/ob mouse hearts does not lead to major cardiac systolic dysfunction, at least up to 25 wk of age. This notion is in agreement with a clinical observation that impairment of diastolic heart function precedes the impairment of systolic function by decades in human diabetic individuals (3). Conscious ob/ob mice had decreased blood pressure throughout the day and decreased heart rates in the morning. These findings are opposite to findings in obese human individuals, in which blood pressure is often increased (33). The lower blood pressure in ob/ob mice (despite pronounced obesity) might reflect decreased sympathetic drive due to the leptin deficiency (34). An increased afterload in hypertensive obese humans has been suggested as an important impetus for development of concentric cardiac hypertrophy and cardiac systolic dysfunction (35). That notion is in agreement with the present findings of unchanged indexes of systolic function in obese ob/ob mice without hypertension. Another possible explanation for the preserved systolic function in ob/ob hearts is that the toxicity of cardiac lipid accumulation only precipitates when the heart is stressed by additional stimuli, e.g. hypertension, cardiac ischemia, or perhaps fasting (36). That idea is equivalent to the two-hit (or more) hypothesis of lipid accumulation-associated liver damage, i.e. lipid accumulation in hepatocytes renders the liver more susceptible to injury by different hepato-toxins (37) and the development of steatohepatitis and cirrhosis only occurs in a subset of patients with steatosis (38). A third explanation might be that lipid-induced systolic dysfunction precipitates later than diastolic dysfunction.
The lack of overt systolic dysfunction in ob/ob mice, however, should be interpreted with caution because the echocardiographic measurements were performed in anesthetized mice. Although we chose two drugs with little negative inotropic effect, the anesthesia reduced the heart rate from approximately 600 bpm to approximately 400 bpm, and Semeniuk et al. (39) recently reported that echocardiography only detected systolic dysfunction in conscious db/db mice, but not in anesthetized db/db mice (39). Also, the contractile response to a dobutamine injection was smaller in ob/ob mice than in ob/+ mice. This finding may reflect that the induced contractile response of the heart is at least partly impaired during stress in 11-wk-old ob/ob mice. This agrees with findings of a progressive impairment of systolic/contractile function in db/db mice (39) and OLETF rats (32).
Interestingly, we previously observed a normalization of heart diastolic function in mice with streptozotocin-induced diabetes when the cardiac triglyceride content was normalized by genetically increased lipoprotein secretion from the heart (9). This observation supports the principal finding of the present study, which is that neutral lipid accumulation in the ob/ob mouse heart primarily is associated with diastolic dysfunction. Of note, in our former study (9) the normalization of cardiac triglycerides was also accompanied by a slight improvement of systolic function.
In conclusion, obese diabetic mouse hearts display a marked increase in triglyceride content as well as an altered phospholipid composition. The increased content of neutral lipids in the heart may, at least in part, reflect increased expression of cardiac gene products that stimulate myocyte fatty acid uptake and triglyceride storage at several levels. The lipid accumulation in ob/ob hearts occurs despite increased MTP expression, suggesting that the capacity of local lipoprotein synthesis to prevent lipid accumulation in cardiac myocytes is exceeded in ob/ob mouse hearts. Echocardiography with Doppler flow analysis and measurements of cardiac BNP expression suggested that the accumulation of neutral lipids in the heart primarily is associated with diastolic dysfunction, but only discrete signs of systolic dysfunction. Thus, the precipitation of lipotoxic heart disease with systolic dysfunction is a slower process or is dependent on other factors than triglyceride accumulation per se.
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Acknowledgments |
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Footnotes |
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Abbreviations: apo-B, Apolipoprotein B; BNP, brain natriuretic peptide; CoA, coenzyme A; CPT, carnitine palmitoyl-transferase; DGAT, acyl CoA:diacylglycerol acyltransferase; FATP, fatty acid transport protein; GLUT-4, glucose transporter 4; hFABP, heart-specific fatty acid binding protein; LCAD, long-chain acyl-CoA dehydrogenase; LV, left ventricular; MTP, microsomal triglyceride transfer protein; Pfkm, muscle phosphofructokinase; PPAR, peroxisomal proliferator-activated receptor; SREBP, sterol regulatory element binding protein; TLC, thin layer chromatography.
Received February 24, 2003.
Accepted for publication May 5, 2003.
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overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130[CrossRef][Medline]
and -Iß genes. Am J Med Sci 318:43–48[CrossRef][Medline]
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