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Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, Department of Anatomy and Physiology, Université Laval, Québec, Canada
(Requests for offprints should be addressed to Jonny St-Amand, Director, SAGE Laboratory, Molecular Endocrinology and Oncology Research Center, Québec Genome Center, Laval University Medical Center (CHUL), 2705 Boul. Laurier, Ste-Foy (Québec) G1V 4G2, Canada; Email: Jonny.St-Amand{at}crchul.ulaval.ca)
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Abstract |
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, cyclin I, procollagen types I, III, IV, V and VI, SPARC and matrix metalloproteinase 2, were upregulated by DHT. Cell defense, division and signaling, protein expression and many novel transcripts were regulated by castration and DHT. The present results provide global genomic evidence for a stimulation of glycolysis, fatty acids and triacylglycerol production, lipolysis and cell shape reorganization, as well as cell proliferation and differentiation, by DHT. The novel transcripts regulated by DHT may contribute to identify new mechanisms involved in the action of sex hormones and their potential role in obesity.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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With the advent of DNA microarrays (Schena et al. 1995) and serial analysis of gene expression (SAGE) (Velculescu et al. 1995), new possibilities arose for large-scale transcriptome analysis and comparison. Both techniques enable characterization of the transcriptome under multiple experimental conditions. DNA microarrays are restricted to known sequences and have some limitations in quantification (Novak et al. 2002). However, the SAGE method is highly quantitative and does not require previous knowledge of the sequences under study. This powerful strategy allows us to characterize the entire transcriptome and perhaps discover novel genes (Velculescu et al. 1997, St-Amand et al. 2001).
We have already presented the transcriptome of normal adipose tissue in mice (Bolduc et al. 2004). In the present study, using the SAGE strategy, we show the effects of castration and dihydrotestosterone (DHT), the most potent androgen, on adipose tissue of male mice. The transcripts involved in fat metabolism are discussed, as well as many transcripts involved in various functions modulated by androgens in this tissue. These findings constitute the first step towards a precise understanding of the molecular mechanisms involved in the physiological effects of androgens on adipose tissue.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Retroperitoneal adipose tissue was obtained from 10 male C57BL6 12–14-week-old mice per group, purchased from Charles River Canada Inc (St Constant, Canada). The animals had access to Lab Rodent Diet No. 5002 and water ad libitum. A sham gonadectomy was performed 7 days prior to organ collection for the intact group, while gonadectomy was performed at the same time for the three gonadectomized (GDX) groups. DHT (0.1 mg) was injected 3 h (DHT3h) and 24 h (DHT24h) prior to killing in groups 3 and 4. The dose of DHT selected was the smallest dose that could restore the prostate weight of GDX mice to the level of intact mice. The control groups (intact and GDX) received vehicle solution (0.4% (w/v) Methocel A15LV Premium/ 5% ethanol) instead of DHT. All animal experimentation was conducted in accord with accepted standards of humane animal care. The retroperitoneal adipose tissue was dissected between 0900 and 1215 h. The samples from all mice of the same group were pooled to eliminate interindividual variations and to extract sufficient amount of mRNA. The tissues were stored at – 80 °C until RNA extraction.
Transcriptome analysis
The SAGE method was performed as previously described (Velculescu et al. 1995, 1997, Kenzelmann & Muhlemann 1999, St-Amand et al. 2001). Polyadenylated RNA was extracted with the mRNA direct kit (Dynal, Oslo, Norway), annealed with the biotin-5'-T18-3' primer and converted to cDNA with the cDNA synthesis kit (Invitrogen). The resulting cDNA library was digested with NlaIII (anchoring enzyme), and the 3' restriction fragments were isolated with streptavidin-coated magnetic beads (Dynal) and separated into two populations. Each population was ligated to one of the two annealed linker pairs and extensively washed to remove unligated linkers. The tag beside the most 3' NlaIII restriction site (CATG) of each transcript was released by digestion with BsmFI (tagging enzyme). The blunting kit from Takara Co. (Otsu, Japan) was used for the blunting and ligation of the two tag populations. The resulting ligation products containing the ditags were amplified by PCR with an initial denaturation step of 1 min at 95 °C, followed by 28 cycles of 20 s at 94 °C, 20 s at 60 °C and 2 s at 72 °C with 27 bp primers (St-Amand et al. 2001). Due to the low mRNA content of adipose tissue, a second PCR amplification was performed on the ditags for 14 cycles in order to enhance the size of the SAGE library without affecting the quantitative information required for group comparisons (Virlon et al. 1999). Each amplification was followed by acrylamide gel purification of the ditags. Finally, large-scale PCR was performed for eight cycles. The PCR product was digested with NlaIII, and the band containing the ditags was extracted from the acrylamide gel. The purified ditags were self-ligated to form concatemers. The concatemers of 500–1800 bp were isolated by agarose gel. The resulting DNA fragments were ligated into the SphI site of pUC19 and cloned into UltraMAX DH5FT (Invitrogen). White colonies were screened by PCR to select long inserts for automated sequencing.
Bioinformatic analysis
All SAGE tag sequences were deposited in the GEO database at the National Centre for Biotechnology Information (NCBI). Sequence files were analyzed by the SAGEana program, a modification of SAGEparser (ftp://ftp.pbrc.edu/public/eesnyder/SAGE/). Tags corresponding to linker sequences were discarded, and duplicate concatemers were counted only once. Identification of the transcripts was obtained by matching the 15 bp (CATG+11 bp tags) with the UniGene and GenBank databases. The matching procedure used was very restrictive since, in order to avoid the possibility of sequencing errors in the expressed sequence tags (EST) database, we did not consider the matches that were identified only once among the numerous sequences of an UniGene cluster. Indeed, the chance of matches with EST containing sequencing errors drops dramatically when at least two EST are identified in a UniGene cluster for a given tag sequence. A minimum of one EST with a known polyA tail had to be in the UniGene cluster to identifiy the last NlaIII site on the corresponding cDNA. Classification of the genes was based upon the updated information of the genome directory (Adams et al. 1995) found at the TIGR website (www.tigr.org/). To analyze the promoter sequences for the presence of hormone-responsive elements (HRE), the 2 kb upstream regions of the annotated transcription start of the differentially expressed transcripts were extracted from the mouse genome at NCBI (build 32, version 1). With a Perl script, the promoter sequences were parsed to find the occurrence and positions of the sequences TGTTCT and AGAACA, which are present in more than one natural androgen-responsive elements (Nelson et al. 1999). When the genes were on the minus strand of the mouse genome, the downloaded sequences were transformed into their reverse-complement before the parsing procedure.
Statistical analysis
We used the comparative count display (CCD) test to identify the transcripts that were differentially expressed significantly (P
0.05) between the groups with more than a twofold change. The CCD test makes a key-by-key comparison of two key-count distributions by generating a probability that the frequency of any key in the distribution differs by more than a given fold factor from the other distribution. This statistical test has been described elsewhere (Lash et al. 2000). The data are normalized to 50 000 tags in order to facilitate visual comparison in the tables.
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Results |
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). The 196 well-characterized transcripts differentially expressed at a significant level (P0.05) are presented in Tables 2–8, according to their functions. There were 117 transcripts upregulated by DHT, 69 transcripts downregulated by DHT and 10 transcripts regulated by castration.
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), as well as transcripts implicated in de novo fatty acid synthesis, such as ATP citrate lyase and fatty acid synthase, were upregulated by DHT (Table 2). Furthermore, two transcripts of the tri-acylglycerol synthesis pathway, namely, glycerol-3-phosphate dehydrogenase 1 (soluble) (GPD1) and diacylglycerol O-acyltransferase (DGAT) 1, were upregulated (Table 2). Genes involved in lipolysis, such as hormone-sensitive lipase, were also upregulated by DHT. Apolipoprotein E and low-density lipoprotein receptor-related protein 1 gene expression was increased by DHT, whereas a switch of transcript species of lipoprotein lipase (LPL) and monoglyceride lipase was observed (Table 2).
Transcripts implicated in energy metabolism (Table 3) as well as in amino-acid metabolism, nucleotide metabolism, transport metabolism, protein modification and general metabolism (Table 4), displayed numerous patterns of gene expression after androgen modulation. Cell division was also affected, since almost all the differentially expressed genes related to cell cycle, including cyclin I, and the genes associated with apoptosis, such as fat-specific gene 27, were upregulated by DHT (Table 5).
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). Genes associated with cell signaling, such as resistin and growth hormone receptor, were upregulated by DHT, whereas others, such as calmodulin 4, were downregulated (Table 5). Keratins (K), which are implicated in the cytoskeleton, were all downregulated by DHT (Table 6). On the other hand, other cytoskeletal components, such as actin beta cytoplasmic and gelsolin, as well as transcripts related to extra-cellular matrix, such as various procollagen isoforms, secreted acidic cysteine-rich glycoprotein (SPARC) and matrix metalloproteinase 2 (MMP-2), were upregulated by DHT (Table 6). Genes involved in cell and organism defense, such as superoxide dismutase 3 extracellular, glutathione peroxidases 3 and 4, and transcripts of the histocompatibility 2 complex, were upregulated by DHT (Table 7). In contrast, other transcripts, such as carbonic anhydrases, heat-shock proteins 1 and 4, adipsin (EST) and lysozyme, were down-regulated. Finally, transcripts associated with protein synthesis were affected in different ways by the androgen (Table 8). In addition, many novel transcripts were significantly differentially expressed (Table 9). Remarkably, 24 h after DHT injection, the tag CATG TTTGACAATGA was increased 353 times, whereas the tag CATG TCCCTATAAGC was decreased by almost 300-fold.
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–8, excluding the transcripts from mitochondrial genome, 118 possessed one or more potential HRE in there promoter sequence. Moreover, 29 of these transcripts had one or more potential HRE 500 bp upstream of the transcription initiation start. |
Discussion |
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, which shows some of the changes mediated by the androgen on energy substrate pathways and adipocyte differentiation in male mice retro-peritoneal adipose tissue.
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The upregulation of transcripts involved in de novo fatty acid and triacylglycerol synthesis could reflect the differentiation of preadipocytes into adipocytes, since many of these genes are stimulated in the adipocyte-differentiation process (Mackall et al. 1976, Coleman et al. 1978). In addition, C/EBP alpha, which is a major factor involved in adipocyte differentiation and in the expression of adipocyte-specific genes (Gregoire et al. 1998), is upregulated. Moreover, the present data also show an upregulation of DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 5 by DHT. The expression of this gene has been associated with adipogenesis (Kitamura et al. 2001), and it has been identified among the transcripts associated with adipose tissue fattening in the cow (Oishi et al. 2000). Cell structure reorganization is necessary for the differentiation process (Croissandeau et al. 2002). Keratin (K) proteins gather in pairs of acidic and basic keratins to form intermediate filaments. For example, in the skin, K5 and K14 form heterodimers, and alteration of one of these two molecules leads to skin fragility (Schuilenga-Hut et al. 2003). The downregulation of these and other keratins in this study may affect adipocyte cell shape. Extracellular matrix (ECM) components, such as collagen types I, III, IV, V and VI, increase three- to sixfold under adipogenic conditions (Nakajima et al. 2002). Moreover, MMP-2 is also involved in adipocyte development, since it regulates the balance between ECM deposition and degradation. In fact, inhibition of MMP can block the adipocyte differentiation process (Croissandeau et al. 2002). Transcripts related to all these ECM components are upregulated by DHT in the present study. All these mechanisms can promote the adipocyte differentiation process. It should be mentioned that the stimulation by DHT of collagen type 1 in osteoblastic cells (Kasperk et al. 1996) and of MMP-2 in human prostate cancer cells (Liao et al. 2003) has already been observed.
Besides lipogenesis, transcripts involved in the lipolysis process are also upregulated. In fact, hormone-sensitive lipase and carboxylesterase 3, a lipase participating in the mobilization of fatty acids from the triacylglycerol content of adipose tissue (Dolinsky et al. 2001), are upregulated by DHT, while monoglyceride lipase is also upregulated (except one EST). On the other hand, the adipocyte complement-related protein, also known as adiponectin, is upregulated. Knockout of this gene revealed an increased ß-oxidation in muscle and liver of mice (Ma et al. 2002). Furthermore, knockout of the aP2 gene, encoding for adipocyte FABP4, has indicated a defect in basal and stimulated lipolysis (Coe et al. 1999). The present study shows that the expression of this gene is downregulated by DHT. Finally, fatty acid coenzyme A ligase long chain 2, which activates long-chain fatty acids for both lipid synthesis and degradation via ß-oxidation (Weiner et al. 1991), is upregulated by DHT, the most potent androgen.
As presented in Tables 2–8, the changes in androgen state affected all cell functions at various levels. In our previous study on the adipose tissue transcritpome under intact animal condition, many genes involved in the cell and organism defense were among the most highly expressed (Bolduc 2004et al.). The present study shows that carbonic anhydrase 3, the most highly expressed gene in adipose tissue, is downregulated by DHT. It is still unclear why this gene is so highly expressed and what role it has in adipose tissue. In addition, the isoform carbonic anhydrase 5a is also downregulated. Generally, we have observed an upregulation by DHT of antioxidant proteins such as glutathione peroxidase 3 and 4, as well as superoxide dismutase 3 extracellular. Tags matching for the same gene or UniGene cluster were frequently found in the present study, particulary for the most abundant transcripts. For example, this was found for carbonic anhydrase 3. This may be partly explained by alternative polyadenylation cleavage site selection (Pauws et al. 2001) and alternative splicing (Mironov et al. 1999).
Analysis of all the data shows that various pathways are regulated by DHT in adipose tissue, and the gene expression profile changes induced by DHT suggest a promotion of fatty acid and triacylglycerol production as well as lypolysis in retroperitoneal adipose tissue. The equilibrium between these processes may bend on one side or the other, resulting in fat accumulation or fat loss. An in vitro study revealed that DHT could stimulate lipolysis through adenylate cyclase activation (Xu et al. 1990). However, it has been observed, in intact men, that DHT treatment increased visceral fat mass (Marin 1995). These findings on the acute effects of DHT seem to contradict the observations revealing a negative correlation between abdominal obesity and serum testosterone levels in men (Seidell et al. 1990, Zumoff et al. 1990, Tsai et al. 2000). In fact, testosterone treatment can reduce visceral fat mass and waist–hip ratio (WHR) in men (Marin et al. 1992, Marin 1995). Moreover, testosterone inhibited triacylglycerol uptake in abdominal adipose tissue of obese men (Marin et al. 1995). On the other hand, DHT had no significant effect on either WHR (Marin et al. 1995) or triacylglycerol uptake (Marin et al. 1995). Differential display PCR has already shown that testosterone and DHT have different effects on prostate gene expression (Avila et al. 1998). The different and sometimes opposite actions of testosterone and DHT may indicate that testosterone effects are mediated by a compound created via the aromatization process (Jensen 2000).
While DHT administration affected the expression of hundreds of genes, 7 days of gonadectomy affected only a few. In fact, only 13 classified transcripts were significantly differentially expressed between the intact and the GDX groups. Several of them, such as NADH dehydrogenase subunit 4, pheromone receptor V3R4 and three novel transcripts, showed an inverse pattern of expression in comparing the effect of castration and DHT injection. The tag CATG ATTTTCAGTTT, classified as a novel transcript, displayed a very sharp regulation by androgen modulation. The expression level of this tag changed from 7 in intact to 136 in GDX, falling back to 7 in DHT3h and rising to 115 in DHT24h. On the other hand, the expression of protamine 2, a transcript associated with chromatin condensation in sperm (Aoki & Carrell 2003), could never be restored after castration. This gene may be a target of testosterone, which may have different effects from DHT on gene expression.
Several HRE possibilities were found in the promoter of the significantly differentially expressed transcripts, many of them being included in the 500 bp upstream region of the transcription initiation start. Since the occurrence of a 6 bp sequence by chance alone is equal to once each 4096 pb, this finding reinforces the idea that these genes are potentially regulated by DHT.
In conclusion, the present data suggest that the administration of DHT to GDX male mice promotes processes involved in glycolysis, fatty acid and triacylglycerol production, lipolysis and cell shape reorganization, as well as cell proliferation and differentiation in retroperitoneal adipose tissue. Moreover, the steroid hormone affected almost all aspects of cell function by modulating hundreds of transcripts. In addition, many of those correspond to novel transcripts.
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Acknowledgements |
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Received 14 May 2004
Accepted 25 June 2004
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