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Institut National de la Santé et de la Recherche Médicale, Unité 418-Institut National de la Recherche Agronomique Unité Mixte de Recherche 1245 and Institut Fédératif de Recherche 62, Hôpital Debrousse and Claude Bernard University (R.C.M., A.B., J.T., P.D., D.N., M.B.), 69005 Lyon, France; Molecular Diagnostic Laboratory, Aarhus University Hospital/Skejby (K.B.-D., T.F.O.), 8200 Aarhus, Denmark; and Institute of Biochemistry Food Science and Nutrition, Faculty of Agriculture, Hebrew University (A.G.), 76100 Rehovot, Israel
Address all correspondence and requests for reprints to: Dr. Martine Bégeot, Institut National de la Santé et de la Recherche Médicale, Unité 418-Institut National de la Recherche Agronomique Unité Mixte de Recherche 1245, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322, Lyon Cedex 05, France. E-mail: begeot{at}lyon.inserm.fr.
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Introduction |
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The diet-induced obesity (DIO) model has been largely used for studies involving obesity, leptin resistance, body fat accumulation, insulin resistance, and correlation with body weight change (2, 3, 4, 5, 6). However, the time necessary for the animals to become obese differs greatly between diets. Moreover, some diets do not mimic the western hemisphere diet, where fat is the most important environmental factor in obesity (1).
Leptin, a 16-kDa protein predominantly secreted by adipocytes, is the product of the ob gene (7) and acts on the brain to control food intake, energy expenditure, and endocrine functions (8, 9, 10). It has been demonstrated that body fat content correlates with circulating plasma leptin levels in human (11). In ob/ob mice, the truncated RNA encoding leptin is overexpressed, which indicates the existence of a feedback loop by leptin itself (7).
There is evidence that leptin is secreted by some other peripheral tissues (12). Some data seem to indicate that a dissociation exists between its effects at the central nervous system level over the appetite and food intake and its peripheral effects over the endocrine glands (13). Leptin action is exerted through specific receptors (14) that are highly expressed in many tissues. They are related to the class 1 cytokine receptor superfamily (14). Various alternatively spliced isoforms in addition to the long form (Ob-Rb) have been identified (15). Ob-Rb has a full-length cytosolic domain of 302 amino acids and is a Janus kinase-signal transducer and activator of transcription signaling receptor. The short forms, a, c, and d, have only 34-, 32-, and 40-amino acid cytosolic carboxyl termini, respectively. The soluble extracellular isoform (Ob-Re) lacks the transmembrane domain. The physiological significance of the short forms is uncertain, although some signaling motif for Ob-Ra, with diminished signaling capabilities, has been described (16, 17). The Ob-Rb is mainly expressed in the hypothalamus, but is also present in certain peripheral tissues, where the predominant form is Ob-Ra (18).
The C57BL/6J mouse has been used as a model of DIO and diabetes and is also the background for ob/ob and db/db obese mice. These models have been extensively used to study obesity, diabetes, and other complications caused by obesity (9, 19, 20). The ob/ob mice produce an inactive form of leptin, and in the db/db mice the long form of the leptin receptor is mutated and is not activated by leptin (7, 21), resulting in severe obesity. Besides the obese phenotype, they have a wide range of hormonal and metabolic alterations, including hyperinsulinemia, hyperglycemia, and hypercorticosteronemia (21).
The DIO model better reproduces human obesity than genetic models of obesity, as there are only a few patients reported in the literature in whom mutations of leptin or leptin receptor genes account for the obesity. Obese humans present high levels of leptin correlated to fat mass, indicating that the vast majority of human obesity cannot be attributed to defects in leptin or its receptors (22).
The aim of the present study was first to establish and characterize a model that mimics the physiological changes occurring in obesity by using a similar source of fat as that found in the western diet and a small time frame for the experiment. Secondly, we aimed to determine whether some alterations in gene expression occurred in adipose tissue from DIO mice. For this purpose we used oligonucleotide microarray analysis completed by a semiquantitative RT-PCR study for several of the genes that were differentially expressed in control and DIO mice.
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Materials and Methods |
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All mice were killed after 7 d of leptin infusion. Fat mass was measured by dual energy x-ray absorptiometry (PIXImus, Madison, WI) (24) just before death. Blood was collected in a heparinized tube for measurement of murine leptin (R&D Systems, Minneapolis, MN) with no cross-reactivity with OvLept, insulin (rat/mice insulin ELISA kit, Crystal Chem, Inc., Chicago, IL), glucose (OneTouch Ultra, Lifescan France, Issy-les-Moulineaux), and corticosterone (Octeia ELISA, Immunodiagnostic System, Boldon, UK). All procedures were performed in accordance with the principles and guidelines established by the NIH for the care and use of laboratory animals.
Statistical analysis was performed using one-way ANOVA, followed by post hoc testing with Fisher’s protected least squares difference test. Differences were considered significant at P < 0.05.
RNA preparation
Total abdominal white fat tissue was isolated, immediately frozen in liquid nitrogen, and kept at -80 C until use. The tissue was homogenized, and RNA was isolated using TRIzol (Invitrogen Life Technologies, Cergy Pontoise, France) following the manufacturer’s protocol.
Oligonucleotide microarrays
cRNA preparation.
cDNA synthesis and cRNA labeling were performed using 12 µg total RNA (prepared from four different mice) as reported previously (25).
Array hybridization and scanning.
Fifteen micrograms of cRNA were fragmented at 94 C for 35 min in a fragmentation buffer containing 40 mM Tris-acetate (pH 8.1), 100 mM potassium acetate, and 30 mM magnesium acetate. Before hybridization, the fragmented cRNA was heated at 95 C for 5 min in a 6x SSPE-T hybridization buffer [1 M NaCl, 10 mM Tris (pH 7.6), and 0.005% Triton] and subsequently at 40 C for 5 min before loading onto the Affymetrix probe array cartridge (Affymetrix, Inc., Santa Clara, CA). To check the quality of each sample with regard to housekeeping genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ß-actin, 15 µg labeled cRNA were run on Test2-Array (Affymetrix, Inc.). Murine Genome U74Av2 Arrays with 12.488 datasets (Affymetrix, Inc.) were incubated for 16 h at 45 C at constant rotation (60 rpm). The washing and staining procedure was performed in the Affymetrix Fluidics Station. The probe array was exposed to 10 washes in 6x SSPE-T at 25 C, followed by four washes in 0.5x SSPE-T at 50 C. The biotinylated cRNA was stained with a streptavidin-phycoerythrin conjugate (final concentration, 2 µg/µl; Molecular Probes, Eugene, OR) in 6x SSPE-T for 30 min at 25 C, followed by 10 washes in 6x SSPE-T at 25 C. An antibody amplification step was added using normal goat immunoglobulin G (final concentration, 0.1 mg/ml; Sigma-Aldrich Corp., Saint Quentin-Fallavier, France) and biotinylated antistreptavidin antibody (goat; final concentration, 3 µg/ml; Vector Laboratories, Inc., Peterborough, UK). This was followed by a staining step with a streptavidin-phycoerythrin conjugate (final concentration, 2 µg/µl; Molecular Probes) in 6x SSPE-T for 30 min at 25 C and 10 washes in 6x SSPE-T at 25 C. The probe arrays were scanned at 560 nm using a confocal laser-scanning microscope with an argon ion laser as the excitation source (GeneArray Scanner G2500A, Hewlett Packard, Birkerod, Denmark). The readings from the quantitative scanning were analyzed by the Affymetrix Gene Expression Analysis software and scaled to a global intensity of 150, as described previously (25). Absolute analyses and comparison analyses were performed using Microarray Suite 4.0 software (Affymetrix).
Data analysis and selection of candidate genes.
Analysis was performed on two samples (C and DIO), and candidates were selected by a combination of absolute analysis and comparison analysis. A total of 12,488 datasets were sorted according to stringent criteria. Filter 1: Datasets were excluded if the absolute call (Abs Call) was A (absent) on both arrays or the difference call (Diff Call) was not changed (NC) in all comparisons or if it was marked as AFFX internal control. This resulted in 4798 datasets. Filter 2: Comparison analysis showed 786 genes increasing or decreasing from C to DIO. Filter 3: To avoid false positives we excluded all genes that were absent in both, decreased from or increased to less than 100 average difference, increased from absent to present or marginal present absolute call, but the signal was less than 50 Avg Diff or increased or decreased from absent to absent. This resulted in 472 genes from comparison DIO vs. C.
RT-PCR
Semiquantitative RT-PCR was used to study the expression of six genes differentially expressed from data obtained with DNA arrays (Table 2). Moreover, the expression of genes that were not modified [adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein-1a (SREBP1a)] or not present on DNA arrays (Ob-Ra and Ob-Rb), but were considered as reference genes in the context of obesity was also studied. RT was performed using total RNA prepared from adipose tissue from six to nine different mice. First strand cDNA was prepared with 1 µg RNA using Moloney murine leukemia virus reverse transcriptase (Invitrogen Life Technologies) according to the manufacturer’s protocol. One microliter of reverse transcribed cDNA was used for PCR reactions. The number of cycles used was first determined to be sure that the end of the reaction for the control samples was in the middle of the exponential curve of amplification.
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. Primer3 Internet software (Whitehead Institute for Biomedical Research) was used to design the primers. All PCR amplifications were performed using Taq Platinum (Invitrogen) at 95 C for 30 sec for denaturation, at 57 C for 40 sec for annealing, and at 72 C for 45 sec for extension in a thermal cycler, with a fixed number of cycles for each pair of primers. GAPDH was used for normalization. Statistical analysis was performed using one-way ANOVA analysis, followed by post hoc testing with Fisher’s protected least squares difference. Differences were considered significant at P < 0.05.
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Results |
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). Differences in body weight became noticeable from 2 wk of the diet and became significant after 4 wk. The DIO animals were clearly obese about wk 5 under the diet, where the weight of these animals were 20% above the controls (Fig. 1). Although hyperphagia was observed in the first week of the high fat diet, that was not observed in the subsequent weeks. The average energy intake of animals under high fat diet was higher than that in control diet-fed animals (data not shown).
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) at the end of the experiment and the body fat (Table 3) in DIO animals were two times higher than those in control animals. This is a clear sign that the high fat diet induced a profound accumulation of energy in the form of body fat, as observed during analysis by dual energy x-ray absorptiometry, including fat pad, epididymal, mesenteric, retroperitoneal, and peritoneal fat masses.
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). The ingestion of food was greatly reduced in the first 24 h after the surgery and then slowly increased. However, this group was unable to reach the amount of ingestion observed before the surgery. The body weight loss in DIO mice was weak and identical in animals treated, or not, with OvLept.
Plasma leptin, insulin, glucose, and corticosterone measurements.
Plasma leptin, insulin, glucose, and corticosterone levels in the various groups of mice used in this study are summarized in Table 4. Control animals presented the normal range for plasma murine leptin (7). Sham-operated DIO animals showed a 6-fold increase in plasma murine leptin compared with control animals. After treatment with OvLept, endogenous murine leptin levels were slightly, but significantly, reduced compared with those in sham-operated DIO. However, the circulating murine leptin was reduced to particularly low levels in C+OvLept animals due to a dramatic reduction of adipose tissue (it should be noted that the exogenous OvLept was not measured by this ELISA, which is specific for murine leptin).
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Plasma corticosterone levels were higher in DIO animals, and treatment with OvLept had no effect on this. On the contrary, C+OvLept showed a 2-fold reduction in corticosterone levels.
Gene expression studies in white adipose tissue
Microarrays studies.
The pattern of gene expression in white adipose tissue from control and DIO mice was analyzed by oligonucleotide microarrays. The screening process led to the identification of a total of 472 genes that were differentially expressed (1.2-fold or more, but at a sufficient level for detection in the adipose tissue mRNA from control and/or DIO mice). A total of 98 genes or expressed sequence tags (21%) were differentially expressed 3-fold or more in the DIO samples (see Table 5 for the known genes only). The majority of these genes had a decreased expression in DIO mice (69%), and the remaining genes had an increased expression level (31%).
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(-1.6-fold), pyruvate kinase (-1.6-fold), and 6-phosphofructokinase (-2.6-fold). An interesting result was found for the glucocorticoid-regulated inflammatory prostaglandin synthase gene, with a 41.1-fold decrease in its expression in DIO mice. This enzyme is specifically involved in the biosynthesis of prostaglandin during inflammatory processes and tissue injury and is an important target for antiinflammatory agents such as glucocorticoids. This gene could also be considered a marker of adipocyte differentiation. Another interesting result was the great number of genes encoding enzymes involved in detoxification processes whose expression was greatly altered in DIO adipose tissue. This is exemplified by mouse vas deferens protein (-59-fold), a member of the aldoketo reductase gene superfamily whose expression has been reported in several steroidogenic tissues, but has never been reported in adipose tissue. The expression of some genes encoding enzymes with antioxidant properties was decreased, such as glutathione-S-transferase 4 (-10.3-fold) and µ-class glutathione-S-transferase (-2.5-fold), which exerted antioxidant effects on lipid peroxidation metabolites; D-amino-oxidase, which is involved in the detoxification of exogenous amino acids in several tissues (-12.7-fold); cytochrome P450 naphthalene hydroxylase (-6.2-fold); thio-rhodanese (-3.8-fold); and carbonyl reductase (-2.9-fold). Among those, several mitochondrial enzymes also had decreased expression in DIO adipose tissue, such as aldehyde dehydrogenase (-1.7-fold), flavin-containing monooxygenase (-1.8-fold), and 
-aminolevulinate dehydratase (-1.7-fold). Interestingly, nitric oxide synthase also exhibited decreased expression in DIO mice (-3.7-fold).
Furthermore, approximately 20 genes encoding cytoskeleton or structural proteins, some belonging to the vascular smooth muscle cells, were greatly decreased. This is the case for calponin, with a 68.2-fold decrease resulting in the absence of expression in DIO adipose tissue; smoothelin (-18.4-fold); myosin heavy chain 11 (-11.6-fold); and smooth muscle -actin (-2.5-fold). Some genes encoding cell-cell or cell-matrix adhesion molecules or extracellular matrix secreted proteins also had decreased expression in DIO, such as R-spondin (-3.2-fold), cadherin 16 (-5.8-fold), and matrilysin (4.2-fold), and lymphocyte markers, such as pcp4 (-44.4-fold), an inhibitor of signaling in quiescent B cells whose expression is almost absent in DIO mice and ß-chemokine thymus-derived chemotaxic agent 4 (-7.1-fold).
A few genes encoding transcription factors or signaling molecules were also decreased, such as B6CBALisch7 (-7.5-fold), melanocyte-specific gene 1(-4.4-fold), ets transcription factor ELF3 (-2.9-fold), as well as preproenkephalin (-1.8-fold), as were two genes encoding receptors, PRL receptor (-2.9-fold) and fibroblast growth factor receptor 2 (-1.5-fold).
The expression of the steroidogenic enzyme 11ß-hydroxysteroid dehydrogenase type 1, which converts inactive 11-dehydrocorticosterone into active corticosterone, was also slightly decreased in DIO mice (-1.8-fold). This enzyme controlled the production of local glucocorticoids and could be important in adipogenesis.
Up-regulated genes in DIO white adipose tissue (Table 5B).
Several genes encoding cell adhesion proteins were modified in DIO adipose tissue, showing increased expression (Table 5B). Some of these genes had very low expression levels in control mouse adipose tissue, such as thrombospondin 1 (+3.6-fold) and ADAM7 (+3.0-fold). Most of the genes displaying increased expression in DIO adipose tissue were involved in the acute phase reaction or inflammatory processes, such as plasminogen activator-1 (+11.7-fold), and in extracellular matrix remodeling and turnover, such as macrophage metalloelastase (+21.8-fold), 1-protease inhibitor 3, inducible cytokine A2 and A6, glycoprotein 49A, or cathepsin S (+2.7-fold; Table 5B). Some of these genes were not highly up-regulated in DIO, but had a relatively high expression in C and were further increased in DIO. This is the case for proteins involved in inflammatory processes such as lipopolysaccharide-binding protein (+1.7-fold) and complement component 1 (+1.9-fold), as well as for other proteins involved in various processes: carnitine palmitoyl transferase 1 (+1.8-fold), which plays a role in the ß-oxidation of long-chain fatty acids; leukotriene C4 synthase (+1.9-fold); the phospholipid transfer protein (+2.2-fold); and the calcium-binding protein calcyclin (+1.9-fold).
Some genes whose expression is up-regulated in DIO adipose tissue are involved in cell growth, such as zinc finger protein (Peg 3; +8.3-fold), Peg1 (+8.1-fold), and IIGP protein interferon-
-induced guanosine triphosphatase (+3.8-fold).
Semiquantitative RT-PCR.
By semiquantitative RT-PCR, the expressions of six genes differentially expressed in DNA arrays analysis were selected to evaluate quantitative changes in gene expression. The data were obtained from a greater number of mice in both control and DIO groups than that used in DNA array analysis. Among them four genes had their expression decreased in adipose tissue of DIO mice (Fig. 2, A–D), and two had increased expression (Fig. 2, E and F). As illustrated, the general profile for all of these genes was similar to that observed with the DNA arrays. Moreover, the intensity of fold changes was on the same order of magnitude for most of the genes, confirming the data from the DNA array analysis. Adipocyte determination and differentiation factor 1/SREBP1a showed no change in its expression level, as observed using DNA arrays (Fig. 2G).
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). In contrast, no change in the Ob-Rb mRNA expression level was detected (Fig. 3B).
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Discussion |
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DIO mice presented with hypercorticosteronemia, as shown in ob/ob mice (35), but treatment with OvLept did not affect the level of corticosterone in these DIO mice, which is in favor of adrenal gland resistance to the action of leptin.
The comparison of gene expression levels by oligonucleotide microarray analyses in DIO and control mice adipose tissue established that the development of obesity has a significant effect on the phenotype of this tissue at the molecular level, as previously reported in other models (36). This effect concerned a great number of genes, as more than 472 genes showed consistent changes with obesity. The profile and intensity of fold changes in the expression of these genes was confirmed by RT-PCR data on a selected number of genes that were differentially expressed or not modified, indicating that the data obtained from DNA array analysis are robust. The identification of genes that are differentially expressed in DIO revealed some aspects previously described in leptin-deficient obese ob/ob mice. This is true for several genes involved in lipid metabolism as well as markers of adipocyte differentiation, whose expression is decreased in DIO and ob/ob mice even though this decrease is greater in ob/ob (20, 37). However, in our model we did not find any impairment in the expression of the gene encoding SREBP-1 using both DNA array and RT-PCR analyses contrarily to ob/ob mice, where a 2-fold decrease was reported (20, 37). SREBP-1 controls the transcription of several genes encoding enzymes involved in fatty acid and cholesterol metabolism, including Fas (38, 39), and leptin decreases the expression of the fas gene in primary cultured rat adipocytes (40). However, as fas gene expression is reduced in DIO mice as well as in ob/ob adipose tissue, this decrease should involve a mechanism independent of leptin and not related to a concomitant decrease in SREBP1 gene expression. Such a decrease in fas gene expression has also been found in the adipose tissue of obese humans (41), whereas fas expression increases in liver.
The global decrease in the expression of genes mostly involved in adipocyte differentiated functions reveals that adipocytes are engaged in a dedifferentiation process that could be the result of their enlargement induced by obesity. This probably indicates that progressive development of a leptin resistance phenomenon is taking place in some peripheral tissues, such as adipose tissue, when obesity is beginning in DIO mice. This is confirmed by the fact that several signaling molecules, such as hormone receptors, also exhibited a decreased expression level. Moreover, some genes encoding factors involved in cell growth exhibited a strong increase, which could be partly responsible for the hyperplasia of adipocytes and consequently the decreased differentiation of these cells.
11ß-Hydroxysteroid dehydrogenase type 1, which plays a pivotal role in the production of local glucocorticoid from the inactive 11-keto form, also has decreased expression in adipose tissue in DIO. This enzyme could not be primarily involved in the development of abdominal fat in this model of obesity, in contrast to the transgenic model, where visceral obesity was induced by overexpression of this enzyme selectively in adipose tissue (42). However, it was previously reported that omental adipose tissue from obese patients expressed higher 11ß-hydroxysteroid dehydrogenase type 1 activity despite an identical or even decreased mRNA expression level compared with control tissue (43).
Two sets of genes exhibited a strong inhibition of expression levels in DIO. The first is represented by genes encoding structural components of the cytoskeleton of vascular smooth cells, such as calmodulin and the actin-binding protein calponin, which plays a role in cytoskeletal organization in association with microfilament network (44), promotes actin polymerization (45), and plays a regulatory role in actin-myosin interactions (44). Similarly, myosin and actin, which are coexpressed with calponin (46), have a decreased expression level. The consequences of the global decrease in this cluster of genes will be a reduction and a disorganization of the vascular compartment in adipose tissue of DIO mice. The second set of genes is represented by those encoding enzymes involved in detoxification processes. This is the major cluster of genes whose expression is highly reduced in DIO. Such modifications in a number of key regulatory proteins probably result in specific physiological effects on cell differentiation and cell apoptosis (47). The result will be an accumulation of lipid peroxidation metabolites, such as 4-hydroxy-2,3-nonenal, which is a biologically active and toxic product of the oxidative decomposition of fatty acids (47) and is the major substrate for glutathione-S-transferase and mouse vas deferens protein. Moreover, the decreased expression of many of these genes could be responsible for the difficulties in metabolizing drugs in the adipose tissue of obese animals.
On the other hand, several sets of genes had an increased expression level in adipose tissue of DIO. This is true for some genes encoding inflammatory markers, such as acute phase reactants, and products of macrophage, such as proteinases, which are highly expressed in DIO compared with controls. This observation was previously reported in ob/ob mice (20) and could indicate that an inflammatory process is taking place in this tissue, although the expression of the glucocorticoid-regulated inflammatory prostaglandin G/H synthase has a decreased expression. Macrophage-mediated proteolysis is important in physiological conditions such as wound repair, but abnormal expression leads to tissue damage that could contribute to the pathogenesis of vascular diseases (48). Moreover, overexpression of acute phase reactants such as plasminogen activator inhibitor-1 could lead to chronic elevation of systemic levels, which may be responsible for an increased incidence of cardiovascular problems in the metabolic syndrome, and a link between inflammation and insulin insensitivity is evident (49, 50, 51).
To conclude, our model of DIO will be very useful to evaluate the progressive impairment of the expression of some of these modified groups of genes. As this could be due to mechanisms dependent, or not, on leptin, this model is more suitable than other models of obesity due to a default in leptin or leptin receptor genes.
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Acknowledgments |
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Footnotes |
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Abbreviations: C, Control; C+OvLept, mice treated with ovine leptin; DIO, diet-induced obesity; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; OvLept, ovine leptin; SREBP1a, sterol regulatory element-binding protein-1a.
Received April 11, 2003.
Accepted for publication August 4, 2003.
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