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CARDIOVASCULAR
and Interleukin-6 in Zucker Rats and Reduce Adipogenesis in Human Mesenchymal Stem CellsDepartments of Pharmacology (D.H.K., A.P.B., M.L., N.P., N.G.A.) and Medicine (P.L.T., F.A., J.A.M., N.G.A.), New York Medical College, Valhalla, New York
Received December 21, 2007; accepted March 10, 2008.
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and interleukin (IL)-6 compared with Zucker lean (ZL) rats. Treatment of ZF animals with 2 mg/kg cobalt protoporphyrin IX (CoPP) increased protein levels of HO-1 and HO activity, but HO-2 was unaffected. The increase in HO-1 was associated with a decrease in superoxide levels (p < 0.05) and an increase in plasma adiponectin (p < 0.005), compared with untreated ZF rats. CoPP treatment decreased visceral and s.c. fat content, and it reduced weight gain (p < 0.01). In addition, the inflammatory cytokines TNF- and IL-6 were decreased (p < 0.04 and p < 0.008, respectively). Treatment of human bone marrow-derived adipocytes cultured with CoPP resulted in an increase in HO-1 and a decrease in superoxide levels. Up-regulation of HO-1 caused adipose remodeling, smaller adipocytes, and increased adiponectin secretion in the culture medium of human bone marrow-derived adipocytes. In summary, this study demonstrates that the antiobesity effect of HO-1 induction results in an increase in adiponectin secretion, in vivo and in vitro, a decrease in TNF- and IL-6, and a reduction in weight gain. These findings highlight the pivotal role and symbiotic relationship of HO-1 and adiponectin in the modulation of the metabolic syndrome phenotype.
; Namikoshi et al., 2007). Excessive generation of reactive oxygen species (ROS) is the underlying mechanism of endothelial injury, resulting in an accelerated rate of apoptosis and endothelial cell sloughing (Kruger et al., 2005; Bahia et al., 2006; Kim et al., 2007a). In addition, reduced plasma adiponectin levels have been documented in patients with coronary artery disease and diabetes, presumably as a result of an increases in ROS (Bakkaloglu et al., 2006; Ohashi et al., 2006; Haider et al., 2007). Lin et al. (2005) highlighted the importance of ROS production in adipocytes and the associated insulin resistance and changes in serum levels of adiponectin, suggesting that the increases in ROS are associated with an induced inflammatory response in the adipocyte.
Adipose tissue plays an important role in insulin resistance through the production and secretion of a variety of proteins such as tumor necrosis factor (TNF)-, IL-6, leptin, and adiponectin (Berg and Scherer, 2005). Of these proteins, adiponectin has recently attracted much attention because it has insulin-sensitizing properties that reduce serum triglyceride levels and enhance fatty acid oxidation, insulin activity in the liver, and hepatic glucose uptake (Berg et al., 2001; Kim et al., 2007b). Adiponectin is exclusively secreted from adipose tissue and its expression is higher in s.c. compared with visceral adipose tissue (Fain et al., 2004). It circulates in the blood, and it is found as both low-molecular-weight oligomers and high-molecular-weight (HMW) multimers (Basu et al., 2007). HMW adiponectin is reported to be more active and to correlate more significantly with glucose and insulin levels compared with both low-molecular-weight and total adiponectin (Lara-Castro et al., 2006). Low plasma levels of HMW adiponectin have been consistently associated with obesity, insulin resistance, type 2 diabetes, and coronary artery disease (Arita et al., 1999). L'Abbate et al. (2007) recently reported that increased adiponectin levels associated with increased expression of HO-1 resulted in enhanced cardiac protection from ROS. PPAR
-response element has been found to increase expression of adiponectin (Iwaki et al., 2003) and also to regulate the expression of HO-1 in human vascular cells (Krönke et al., 2007).
The HO system provides both antioxidant and antiapoptotic properties due to its products bilirubin/biliverdin and CO (Ollinger et al., 2007). HO-1 is induced by oxidant stress, and it plays a crucial role in protection against oxidative insult in diabetes and cardiovascular disease (Abraham and Kappas, 2008). Up-regulation of HO-1 gene expression prevents vascular dysfunction and endothelial cell death through decreases in ROS levels (Abraham et al., 2004).
In the present study, we report that HO activity and HO-1 protein expression were decreased in obese rats, and we hypothesized that induction of HO-1 might serve to counteract the negative effects of type 2 diabetes mellitus and the metabolic syndrome. Using cobalt protoporphyrin IX (CoPP), an inducer and tin mesoporphyrin (SnMP, an inhibitor) to manipulate HO activity, we report here, for the first time, that induction of HO-1 was associated with reduced fat content and prevention of weight gain as a result of reduced adipogenesis in both in vitro and in vivo models of type 2 diabetes mellitus.
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). Glucose monitoring was performed using an automated analyzer (Lifescan Inc., Milpitas, CA). Beginning at 11 weeks when all rats had established diabetes, CoPP, SnMP (Frontier Science, Logan, UT), or both were given weekly at a dose of 2 and 5 mg/kg once and three times a week, respectively, by i.p. injection for 6 weeks. Control animals were administered an equal volume of vehicle (0.1 M sodium citrate buffer, pH 7.8) i.p. Six groups of Zucker rats were used: 1) ZL, 2) ZL-CoPP, 3) ZL-CoPP + SnMP, 4) ZF, 5) ZF-CoPP, and 6) ZF-CoPP + SnMP. There was no difference in the food intake among the treatment groups. The Animal Care and Use Committee of New York Medical College approved all experiments.
Tissue Preparation for Western Blot of Adipocyte Stem Cells, Heart, Kidney, and Aorta. At the time of sacrifice, s.c. and visceral fat in the abdomen (visible mesenteric fat, fat around the liver, fat around the kidney, and fat around the spleen) was dissected free, pooled for each mouse, weighed, and used to isolate adipocyte mesenchymal stem cells. Cells were frozen until needed for protein measurements. Aorta, heart, and kidney were also harvested, drained of blood, and flash-frozen in liquid nitrogen. Specimens were maintained at -80°C until needed. Frozen aorta and kidney segments were pulverized, and then they were placed in homogenization buffer [10 mM phosphate buffer, 250 mM sucrose, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride, and 0.1% Tergitol (Mallinckrodt Baker, Phillipsburg, NJ), pH 7.5] and homogenized using a standard glass homogenizer and pestle. Homogenates were centrifuged at 27,000g for 10 min at 4°C. The supernatant was isolated, and protein levels were assayed by Bradford method (Bradford, 1976). The supernatant was used for measurement of HO-1 and HO-2 (Nventa Biopharmaceuticals, San Diego, CA). Protein levels were visualized by immunoblotting with antibodies against each specific mouse protein. Actin was used to ensure adequate sample loading for all Western blots. Antibodies were prepared in the following dilution: HO-1 and HO-2, 1:1000. In brief, 20 µg of lysate supernatant was separated by 12% SDS-polyacrylamide gel electrophoresis, and then it was transferred to a nitrocellulose membrane (GE Healthcare, Chalfont St. Giles, UK) with a semidry transfer apparatus (Bio-Rad, Hercules, CA). The membranes were incubated with 10% milk in 10 mM Tris-HCl, pH 7.4, 150 mM NaCl, and 0.05% Tween 20 buffer at 4°C overnight. After they were washed with 10 mM Tris-HCl, pH 7.4, 150 mM NaCl, and 0.05% Tween 20, the membranes were incubated with anti-HO-1 or anti-HO-2 for 1 h at room temperature, with constant shaking. The filters were washed and subsequently probed with horseradish peroxidase-conjugated donkey anti-rabbit or anti-mouse IgG (GE Healthcare). Chemiluminescence detection was performed with the Amersham enhanced chemiluminescence detection kit, according to the manufacturer's instructions.
Aortic HO activity was assayed as described previously (Abraham et al., 2003) using a technique in which bilirubin, the end product of heme degradation, was extracted with chloroform, and its concentration was determined spectrophotometrically (dual UV-visible beam spectrophotometer Lambda 25; PerkinElmer Life and Analytical Sciences, Waltham, MA) using the difference in absorbance at a wavelength from 460 to 530 nm, with an extinction coefficient of 40 mM-1 cm-1.
Human Bone Marrow-Derived Adipocyte Mesenchymal Stem Cells. Frozen bone marrow mononuclear cells were purchased from Allcells (Emeryville, CA). After thawing the cells, mononuclear cells were resuspended in an -minimal essential medium (Invitrogen, Carlsbad, CA) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen) and 1% antibiotic/antimycotic solution (Invitrogen). The cells were plated at a density of 1 to 5 x 106 cells per 100-cm2 dish. The cultures were maintained at 37°C in a 5% CO2 incubator, and the medium was changed after 48 h and every 3 to 4 days thereafter. When the MSCs were confluent, the cells were recovered by the addition of 0.25% trypsin/EDTA (Invitrogen). MSCs (passages 2–3) were plated in a 60-cm2 dish at a density of 1 to 2 x 104 and cultured in -minimal essential medium with 10% FBS for 7 days. The medium was replaced with adipogenic medium, and the cells were cultured for an additional 21 days. The adipogenic media consisted of complete culture medium supplemented with DMEM-high glucose, 10% (v/v) FBS, 10 µg/ml insulin, 0.5 mM dexamethasone (Sigma-Aldrich, St. Louis, MO), 0.5 mM isobutyl methylxanthine (Sigma-Aldrich), and 0.1 mM indomethacin (Sigma-Aldrich).
Oil Red O Staining. For Oil Red O staining, 0.5% Oil Red O solution (Sigma-Aldrich) was used. In brief, adipocytes were fixed in 1% formaldehyde, washed in Oil Red O for 20 min, rinsed with 85% propylene glycol (Sigma-Aldrich) for 3 min, washed in distilled water, and then mounted with aqueous mounting medium (Bavendiek et al., 2005).
Measurement of Mesenchymal 
Levels and Inflammatory Cytokines and Adiponectin. Using previously described methods, control and fat mesenchymal stem cells, 0.3 mg of protein, approximately 3 x 105 cells, were placed in plastic scintillation minivials containing 5 µM lucigenin for the detection of and other additions in a final volume of 1 ml of air-equilibrated Krebs' solution buffered with 10 mM HEPES-NaOH, pH 7.4. Lucigenin chemiluminescence was measured in a liquid scintillation counter (LS6000IC; Beckman Coulter, Fullerton, CA) at 
37°C, and data are reported as counts per minute per milligram of protein after background subtraction.
Adiponectin (HMW), TNF-, and IL-6 were determined in rat serum using an enzyme-linked immunosorbent assay. Multiple assay kits were used for quantification of the proteins in rat serum, and assays were conducted according to the manufacturer's protocol (Pierce, Woburn, MA). Plates were analyzed using a Luminex 100IS analyzer (Luminex Inc., Austin, TX). The data were evaluated as the median fluorescence intensity using appropriate curve-fitting software. A five-parameter logistic method with weighing was used. All measurements were performed in triplicate. Cytokine assays were done according to instructions provided by BD Gentest (Woburn, MA).
Detection of MSC Cell Markers by FACS Analysis. Human MSCs are defined by an array of positive and negative markers. MSCs are normally plastic-adherent under standard culture conditions, expressing CD105, CD73, and CD90. MSCs must lack expression of CD45, CD34, CD14, or CD11b, CD79 or CD19, and human leukocyte antigen DR-1. In addition, MSCs must be able to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro (Keating, 2006).
Human MSC phenotype was confirmed by flow cytometry (Elite ESP 2358; Beckman Coulter) using several markers known to be found on MSCs. The negative markers used were anti-CD34 and anti-CD45 (BD Biosciences Pharmingen, San Diego, CA), also known to be expressed as hematopoietic stem cell marker and common lymphocyte antigen. CD90, CD105, and CD166 were used as positive markers for MSCs. The data were analyzed using WinMDI 2.8 software (http://facs.scripps.edu/software.html).
Culture Conditions of Adipocytes and Effect of HO-1 Inducers and Inhibitors. Adipogenic differentiation of hMSCs was induced by incubation in an adipogenesis induction medium (25 mM DMEM-high glucose supplemented with 10 µg/ml insulin, 1 µM dexamethasone, 0.2 mM indomethacin, 10% FBS, and 1% antibiotic-antimycotic solution). Medium was changed every 3 to 4 days (Novikoff et al., 1980; Tondreau et al., 2005). In addition, treatment with 5 µM SnMP and glucose was administered every 2 days. CoPP (2 µM) treatment and media changes were applied every 4 days. The conditioned media was harvested after 6 days of culture, and the levels of adiponectin were determined.
Statistical Analyses. Statistical significance between experimental groups was determined by the Fisher method of analysis of multiple comparisons (p < 0.05). For comparison between treatment groups, the null hypothesis was tested by a single-factor analysis of variance for multiple groups or unpaired t test for two groups. Data are presented as mean ± S.E.
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Moreover, in a separate set of experiments, CoPP administration, once a week for 6 weeks resulted in a significant increase in HO-1 protein levels in both sets of animals. HO-1 protein was increased 4.3-fold in ZF CoPP-treated animals (p < 0.005) compared with ZF animals and 1.3-fold in CoPP-treated ZL animals (p < 0.05) compared with ZL animals (Fig. 1B). The levels of HO-2 were unchanged after CoPP administration. Similar results were seen in heart and kidney (data not shown).
HO activity was measured in the aorta of ZF and ZL rats after CoPP and CoPP + SnMP treatment. CoPP administration, in ZF rats, increased HO activity 4- to 5-fold compared with untreated ZF rats (Fig. 2). As seen in Fig. 2, HO activity was increased in ZF rats after CoPP treatment (2.3 ± 0.1 nmol bilirubin formed/mg protein/h; p < 0.001) compared with control (0.34 ± 0.04 nmol bilirubin formed/mg protein/h). A similar effect on HO activity was seen in ZL animals. Treatment with the HO inhibitor SnMP in combination with CoPP inhibited HO activity in both ZF and ZL animals compared with ZF and ZL animals treated with CoPP alone (Fig. 2). It should be noted that HO activity was lower on ZF animals compared with ZL animals (p < 0.05). This parallels the decrease in HO-1 and HO-2 protein levels described above (Fig. 1, A and B). Similar results were seen in heart and kidney (data not shown).
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. To investigate the connection between HO induction and classic risk factors of type 2 diabetes, we assessed IL-6 and TNF- levels in ZF and ZL animals in response to treatment with CoPP for 6 weeks. Cytokines TNF- and IL-6 were significantly (p < 0.002 and p < 0.03, respectively) increased in ZF animals compared with ZL animals (Figs. 3B). After treatment with CoPP, the levels of both proinflammatory cytokines (IL-6 and TNF-) were significantly decreased in CoPP-treated ZF rats compared with control ZF rats (p < 0.008 and p < 0.04, respectively). These effects were blocked by coadministration of SnMP with CoPP (Fig. 3B).
Effect of CoPP on Body Weight and Fat Content. In examining the effects of HO-1 on body weight, we used age and weight-matched ZL and age and weight matched ZF animals. Both the vehicle-treated and the CoPP-treated rats gained weight. In the ZF controls, weight was increased to a final value of 637 ± 22.6 g. The rate of body weight gain in ZF rats treated with CoPP was less, and a difference (p < 0.05) was seen after as little as 2 weeks. Subsequently, the weight curves continued to diverge, and they were different at every subsequent time point (Fig. 4A). The coadministration of SnMP with CoPP blocked the effect of CoPP on weight gain. Similar results were also found in the ZL group. After treatment, ZL rats gained weight, whereas CoPP-treated Zucker lean rats maintained the same approximate body weight. Weight gain was significantly (p < 0.05) less in the CoPP-treated rats even after 2 weeks, and the weight curves continued to diverge throughout the next 6 weeks (Fig. 4B). There was no difference in food intake during the 6-week treatment period between ZF and ZL rats treated with either vehicle or CoPP (data not shown).
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Determination of Human Mesenchymal Stem Phenotype and HO-1 Expression in Human MSCs. hMSCs were examined for various positive and negative markers by flow cytometry to establish the identity of mesenchymal stem cells. Confirmation of hMSC phenotype was made by the presence of positive markers CD 90, CD105, and CD166. The absence of CD34, a hematopoietic stem cell marker, and CD 45, a lymphocytic marker, confirmed that MSCs were not contaminated (Fig. 5). Our population of hMSCs was found to be 99.7% positive for CD90, 87.5% positive for CD105, and 96.9% positive for CD166. There was less than 0.2% positivity for both negative markers, CD45 and CD34 (Fig. 5).
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Levels. Measurements of superoxide levels in mesenchymal stem cells demonstrated increased levels of in these cells isolated from ZF animals compared with cells isolated from ZL animals (p = 0.04, n = 4) (Fig. 7). CoPP-treated ZF rats showed a significant decrease in levels compared with untreated ZF rats, from 5.67 ± 3.1 to 3.47 ± 0.7 (p = 0.03). These results show the effect of CoPP treatment resulting in decreased levels of .
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and IL-6. Fourth, up-regulation of HO-1 by CoPP treatment caused a decrease in droplet formation and adipogenesis in human bone marrow-derived adipocyte stem cells but increased secretion of adiponectin in the culture media. This important observation is bolstered by the demonstration that the increased HO activity resulted in a reciprocal decrease in secretion of TNF- and IL-6. These decreases in cytokine levels when considered with increases in adiponectin signify that a favorable outcome can be achieved by increased levels of HO-1 in obesity.
The effect of CoPP on body weight, achieved with normal food intake, is not unexpected. Multiple low-dose regimens result in a prolonged decrease in the rate of body weight gain in genetically obese rats and mice (Galbraith and Kappas, 1990, 1991). Low-dose regimes are associated with no reduction in food intake. The action of CoPP is thought to be a central nervous system action (Galbraith et al., 1992; Li et al., 2006). The effect of CoPP on body weight (Fig. 4A) in obese rats confirms these studies, and it extends them by demonstrating the potential role of HO-1-mediated increase in adiponectin in a reduction in weight gain. The HO-1 mediated increase in serum adiponectin is manifest by an improvement in the metabolic syndrome, which, in turn, may lead to improvements in arterial and heart disease (Bahia et al., 2006; Kim et al., 2007b). Increases in obesity are considered a risk factor for cardiovascular complications (Lazar, 2005). Metabolic syndrome and obesity are characterized by an increase in serum levels of inflammatory cytokines such as TNF- and IL-6, with a resultant decrease in insulin sensitivity (Muse et al., 2007). Increases in adiponectin levels and the associated reduction in body weight and both s.c. and visceral fat content (Fig. 4D) are important antagonists of the metabolic syndrome, resulting in a decrease in arterial and heart disease (Bahia et al., 2006; Fontana et al., 2007). The beneficial effects of adiponectin in a variety of cardiovascular diseases have been reviewed by Hopkins et al. (2007).
The mechanism by which HO-1 is involved in increased adiponectin levels may be related to the function of HO-1 as a stress response/chaperone protein as well as its ability to increase antioxidants levels via an increase in glutathione and extracellular superoxide dismutase levels (Abraham et al., 2008). Galinier et al. (2006) reported that an increase in antioxidants resulted in the promoted accumulation of triglycerides in the adipocyte (Galinier et al., 2006). The latter suggest that obesity is associated with an increase in intracellular antioxidants even under the stressful conditions of obesity (Galinier et al., 2006). This result is not contradictory to the present findings, because the levels of the antioxidant may not be sufficient; furthermore, the levels of antioxidants measured may be dependent on the stage of obesity. The mechanism by which HO-1 acts as an antiobesity agent is not only due to its antioxidant properties of heme removal but also the effect of HO-1-derived product activity. Up-regulation of HO-1 increases the levels of numerous signaling molecules, including phospho-AKT and endothelial NO synthase, increases mitochondrial transport, restores mitochondrial cytochrome oxidase, inhibits caspase activity, and decreases the number of CD11c dendritic cells (Di Noia et al., 2006; Kruger et al., 2006; Li et al., 2007). Up-regulation of HO-1 caused adipose tissue remodeling, resulting in smaller adipocytes and inhibition of adipogenesis. In addition, increased levels of HO-1 protein were mirrored by increased levels of adiponectin.
PPAR agonists are known to induce both HO-1 (Krönke et al., 2007) and the rate-limiting chaperone protein EroL (Wang et al., 2007). PPAR agonist, which increases adiponectin, may do so by increasing the levels of EroL chaperone protein. Because PPAR also increases HO-1 protein levels (Krönke et al., 2007) and HO-1 is known as a chaperone protein, it is possible that one of the mechanisms by which HO-1 can increase adiponectin levels is through more efficient adiponectin stabilization and protection. This would add substance to the report that the chaperone protein EroL increased adiponectin levels (Wang et al., 2007).
The seminal finding described in this report is the crucial role of HO-1-adiponectin axis in ameliorating obesity-mediated increases in plasma levels of inflammatory cytokines. This is associated with increased secretion of adiponectin in vivo and in vitro. However, the critical effect of antioxidants and HO-1 expression may be related to adipocyte compensation mechanism to increase adiponectin levels (Figs. 3 and 9B). In cultured mesenchymal stem cells, CoPP increases adiponectin during the early stages of adipocyte stem cell growth. However, CoPP inhibits adipogenesis and decreases adiponectin and the number of adipocytes due to the inhibition of adipogenesis. The mechanism remains to be clarified. However, these results support recent reports that describe the beneficial effect of increases in adiponectin in metabolic syndrome and obesity (Kim et al., 2007b; Li et al., 2008). The present data are of considerable interest from a clinical and basic science perspective, clearly defining the existence of an HO-1-adiponectin regulatory axis that can be manipulated to ameliorate obesity and metabolic syndrome and prevent critical areas of cell damage associated with cardiovascular disease.
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Acknowledgements |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: ROS, reactive oxygen species; TNF, tumor necrosis factor; IL, interleukin; HMW, high molecular weight; PPAR, peroxisome proliferator-activated receptor; HO, heme oxygenase; CoPP, cobalt protoporphyrin IX; SnMP, tin mesoporphyrin; ZL, Zucker lean; ZF, Zucker fat; FBS, fetal bovine serum; MSC, mesenchymal stem cell; , superoxide; FACS, fluorescence-activated cell sorting; DMEM, Dulbecco's modified Eagle's medium; h, human.
Address correspondence to: Dr. Nader G. Abraham, Dept. of Pharmacology, Rm. 527 New York Medical College, Valhalla, NY 10595. E-mail: nader_abraham{at}nymc.edu
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, p < 0.001, CoPP-treated fat versus SnMP-treated fat. The results are expressed as picograms per milliliter of serum for IL-6 and TNF-
